Gary M. Shaw
NICU Nurses Professor and Professor (Research), by courtesy, of Epidemiology and Population Health and of Obstetrics and Gynecology (Maternal Fetal Medicine)
Pediatrics - Neonatal and Developmental Medicine
Bio
Research interests include; epidemiology of birth defects; gene-environment approaches to perinatal outcomes; and nutrition and reproductive outcomes. I currently serve as Co-PI of the March of Dimes Prematurity Research Center at Stanford, PI of the California Center Finding Causes and Preventives of Birth Defects, and formerly a PI for UC Berkeley/Stanford Children’s Environmental Health Center.
Academic Appointments
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Professor (Research), Pediatrics - Neonatal and Developmental Medicine
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Professor (Research) (By courtesy), Epidemiology and Population Health
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Professor (Research) (By courtesy), Obstetrics & Gynecology - Maternal Fetal Medicine
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Member, Bio-X
Administrative Appointments
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Chair, Committee on Graduate Studies, Stanford University (2018 - 2020)
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Associate Chair Clinical Research, Dept of Pediatrics (2012 - Present)
Boards, Advisory Committees, Professional Organizations
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Associate Editor, Am J Med Genetics (2008 - Present)
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Associate Editor, Birth Defects Res A (2005 - Present)
Professional Education
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DrPH, UC Berkeley, Epidemiology (1986)
Current Research and Scholarly Interests
Primary research interests include 1) epidemiology of birth defects, 2) gene-environment approaches to perinatal outcomes, and 3) nutrition and reproductive outcomes.
2024-25 Courses
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Independent Studies (11)
- Directed Reading in Environment and Resources
ENVRES 398 (Aut, Win, Spr) - Directed Reading in Epidemiology
EPI 299 (Aut, Win, Spr, Sum) - Directed Reading in Pediatrics
PEDS 299 (Aut, Win, Spr, Sum) - Directed Research in Environment and Resources
ENVRES 399 (Aut, Win, Spr) - Early Clinical Experience
PEDS 280 (Aut, Win, Spr, Sum) - Graduate Research
EPI 399 (Aut, Win, Spr, Sum) - Graduate Research
PEDS 399 (Aut, Win, Spr, Sum) - Medical Scholars Research
MED 370 (Aut, Win, Spr, Sum) - Medical Scholars Research
PEDS 370 (Aut, Win, Spr, Sum) - Undergraduate Directed Reading/Research
PEDS 199 (Aut, Win, Spr, Sum) - Undergraduate Research
EPI 199 (Aut, Win, Spr, Sum)
- Directed Reading in Environment and Resources
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Prior Year Courses
2023-24 Courses
- The A to Z of Translational Medicine: Emerging Trends in Drug Development and Next-gen Innovations
MED 251C (Spr) - The A to Z of Translational Medicine: Fundamentals and Technical Considerations of Drug Development
MED 251A (Aut) - The A to Z of Translational Medicine: Strategic Challenges in Drug Development
MED 251B (Win)
- The A to Z of Translational Medicine: Emerging Trends in Drug Development and Next-gen Innovations
Stanford Advisees
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Med Scholar Project Advisor
Richard Liang -
Master's Program Advisor
Vaishnavi Bhamidi -
Doctoral Dissertation Co-Advisor (AC)
Saskia Comess
All Publications
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Sociodemographic Trends and Perinatal Outcomes in Fathers 50 Years and Older.
JAMA network open
2024; 7 (8): e2425269
Abstract
The age of fathers at childbirth is rising, with an increasing number of births attributed to older fathers. While the impact of advanced paternal age has been documented, sociodemographic data about fathers aged 50 years and older remain scarce.To explore sociodemographic and temporal trends among the oldest US fathers (age ≥50 years) and their associations with perinatal outcomes.This retrospective cross-sectional study included data from all US births from 2011 to 2022 using the National Vital Statistics System. Data were analyzed from August 2023 and May 2024.Reported paternal age at childbirth.Outcomes of interest were sociodemographic factors, temporal trends in older fatherhood, and perinatal outcomes, including preterm birth, low birth weight, gestational diabetes, gestational hypertension, assisted reproductive technology (ART), rates of maternal primiparity, and the infant sex ratio.From 2011 to 2022, the US recorded 46 195 453 births, with an overall mean (SD) paternal age of 31.5 (6.8) years and 484 507 (1.1%) involving fathers aged 50 years or older, 47 785 (0.1%) aged 60 years or older, and 3777 (0.008%) aged 70 years or older. Births to fathers aged 50 years or older increased from 1.1% in 2011 to 1.3% in 2022 (P for trend < .001). Fathers aged 50 years or older were more diverse, with variations in educational achievement and race and ethnicity. Marital status and maternal racial and ethnic and educational backgrounds also varied by paternal age and race. Despite controlling for maternal age and other sociodemographic and perinatal factors, every 10-year increase in paternal age was consistently associated with greater use of ART (eg, age 50-59 years: adjusted odds ratio [aOR], 2.23; 95% CI, 2.19-2.27), higher likelihood of first maternal birth (eg, age 50-59 years: aOR, 1.16; 95% CI, 1.15-1.17), and increased risks of preterm birth (eg, age 50-59 years: aOR, 1.16; 95% CI, 1.15-1.18) and low birth weight (eg, age 50-59 years: aOR, 1.14; 95% CI, 1.13-1.15) compared with fathers aged 30 to 39 years. No significant changes in the infant sex ratio were observed, except among fathers aged 70 years or older (aOR, 0.92; 95% CI, 0.86-0.99) and 75 years or older (aOR, 0.84; 95% CI, 0.73-0.97), who showed a decreased likelihood of having male offspring.In this cross-sectional study of all US births from 2011 to 2022, the percentage attributed to older fathers, while small, increased. Notable variations in paternal and maternal race and education were identified. Older fatherhood was associated with increased ART use, first-time maternal births, adverse perinatal outcomes, and altered sex ratio. Further research of this population is crucial for improving patient counseling and family planning.
View details for DOI 10.1001/jamanetworkopen.2024.25269
View details for PubMedID 39088214
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Association of pregnancy complications and postpartum maternal leukocyte telomeres in two diverse cohorts: a nested case-control study.
BMC pregnancy and childbirth
2024; 24 (1): 490
Abstract
Biologic strain such as oxidative stress has been associated with short leukocyte telomere length (LTL), as well as with preeclampsia and spontaneous preterm birth, yet little is known about their relationships with each other. We investigated associations of postpartum maternal LTL with preeclampsia and spontaneous preterm birth.This pilot nested case control study included independent cohorts of pregnant people with singleton gestations from two academic institutions: Cohort 1 (hereafter referred to as Suburban) were enrolled prior to 20 weeks' gestation between 2012 and 2018; and Cohort 2 (hereafter referred to as Urban) were enrolled at delivery between 2000 and 2012. Spontaneous preterm birth or preeclampsia were the selected pregnancy complications and served as cases. Cases were compared with controls from each study cohort of uncomplicated term births. Blood was collected between postpartum day 1 and up to 6 months postpartum and samples were frozen, then simultaneously thawed for analysis. Postpartum LTL was the primary outcome, measured using quantitative polymerase chain reaction (PCR) and compared using linear multivariable regression models adjusting for maternal age. Secondary analyses were done stratified by mode of delivery and self-reported level of stress during pregnancy.156 people were included; 66 from the Suburban Cohort and 90 from the Urban Cohort. The Suburban Cohort was predominantly White, Hispanic, higher income and the Urban Cohort was predominantly Black, Haitian, and lower income. We found a trend towards shorter LTLs among people with preeclampsia in the Urban Cohort (6517 versus 6913 bp, p = 0.07), but not in the Suburban Cohort. There were no significant differences in LTLs among people with spontaneous preterm birth compared to term controls in the Suburban Cohort (6044 versus 6144 bp, p = 0.64) or in the Urban Cohort (6717 versus 6913, p = 0.37). No differences were noted by mode of delivery. When stratifying by stress levels in the Urban Cohort, preeclampsia was associated with shorter postpartum LTLs in people with moderate stress levels (p = 0.02).Our exploratory results compare postpartum maternal LTLs between cases with preeclampsia or spontaneous preterm birth and controls in two distinct cohorts. These pilot data contribute to emerging literature on LTLs in pregnancy.
View details for DOI 10.1186/s12884-024-06688-5
View details for PubMedID 39033276
View details for PubMedCentralID 5967638
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Mode of delivery predicts postpartum maternal leukocyte telomere length.
European journal of obstetrics, gynecology, and reproductive biology
2024; 300: 224-229
Abstract
Recent studies have suggested that pregnancy accelerates biologic aging, yet little is known about how biomarkers of aging are affected by events during the peripartum period. Given that immune shifts are known to occur following surgery, we explored the relation between mode of delivery and postpartum maternal leukocyte telomere length (LTL), a marker of biologic aging.Postpartum maternal blood samples were obtained from a prospective cohort of term, singleton livebirths without hypertensive disorders or peripartum infections between 2012 and 2018. The primary outcome was postpartum LTLs from one blood sample drawn between postpartum week 1 and up to 6 months postpartum, measured from thawed frozen peripheral blood mononuclear cells using quantitative PCR in basepairs (bp). Multivariable linear regression models compared LTLs between vaginal versus cesarean births, adjusting for age, body mass index, and nulliparity as potential confounders. Analyses were conducted in two mutually exclusive groups: those with LTL measured postpartum week 1 and those measured up to 6 months postpartum. Secondarily, we compared multiomics by mode of delivery using machine-learning methods to evaluate whether other biologic changes occurred following cesarean. These included transcriptomics, metabolomics, microbiomics, immunomics, and proteomics (serum and plasma).Of 67 included people, 50 (74.6 %) had vaginal and 17 (25.4 %) had cesarean births. LTLs were significantly shorter after cesarean in postpartum week 1 (5755.2 bp cesarean versus 6267.8 bp vaginal, p = 0.01) as well as in the later draws (5586.6 versus 5945.6 bp, p = 0.04). After adjusting for confounders, these differences persisted in both week 1 (adjusted beta -496.1, 95 % confidence interval [CI] -891.1, -101.1, p = 0.01) and beyond (adjusted beta -396.8; 95 % CI -727.2, -66.4. p = 0.02). Among the 15 participants who also had complete postpartum multiomics data available, there were predictive signatures of vaginal versus cesarean births in transcriptomics (cell-free [cf]RNA), metabolomics, microbiomics, and proteomics that did not persist after false discovery correction.Maternal LTLs in postpartum week 1 were nearly 500 bp shorter following cesarean. This difference persisted several weeks postpartum, even though other markers of inflammation had normalized. Mode of delivery should be considered in any analyses of postpartum LTLs and further investigation into this phenomenon is warranted.
View details for DOI 10.1016/j.ejogrb.2024.07.026
View details for PubMedID 39032311
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Increased Risk of Preterm Delivery Subtypes and Hypertensive Disorders of Pregnancy in First Deliveries of Patients With Systemic Vasculitis.
ACR open rheumatology
2024
Abstract
The goal of this study was to investigate the risk of preterm birth subtypes and hypertensive disorders of pregnancy in patients with systemic vasculitis using large, statewide databases.Births to nulliparous patients with prevalent systemic vasculitides (Takayasu arteritis [TAK], Behçet disease [BD], antineutrophil cytoplasmic antibody-associated vasculitis [AAV], and Kawasaki disease [KD]) were identified using International Classification of Diseases, Ninth Revision codes in linked administrative data and birth records from the California Department of Health Care Access and Information and California Vital Statistics from 1991 to 2012. Hypertensive disorders of pregnancy and preterm delivery (PTD) subtypes were identified. Multivariable-adjusted Poisson models estimated risk ratios (RRs) of these outcomes compared with the general birthing population without history of rheumatic disease.A total of 96 births to nulliparous patients with systemic vasculitis were identified (TAK, 14; AAV, 31; BD, 26; KD, 15) and compared with 4,191,900 births of the nulliparous general population. Adjusted RRs for all PTD types were elevated in patients with vasculitis (RR 3.21, 95% confidence interval [CI] 2.15-4.79), as were the RRs of all PTD subtypes including preterm premature rupture of membranes (RR 4.30, 95% CI 2.05-9.01) and spontaneous PTD (RR 4.99, 95% CI 3.01-8.28). Of the spontaneous PTDs among patients with vasculitis, 16.7% were early PTDs (20-31 weeks), with the remaining 83.3% occurring between 32 to 36 weeks. Patients with vasculitis also had an elevated risk of hypertensive disorders of pregnancy (RR 2.96, 95% CI 1.72-5.10).Among first-time births, we found that patients with systemic vasculitis have an elevated risk of PTD subtypes as well as hypertensive disorders of pregnancy.
View details for DOI 10.1002/acr2.11702
View details for PubMedID 38970474
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Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study.
Birth defects research
2024; 116 (7): e2384
Abstract
Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants.We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI.Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2).Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.
View details for DOI 10.1002/bdr2.2384
View details for PubMedID 38990107
View details for PubMedCentralID PMC11245170
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Hydroxychloroquine and Preeclampsia in a Diverse Cohort of Women with SLE.
Arthritis care & research
2024
Abstract
Patients with systemic lupus erythematosus (SLE) are at risk for pregnancy complications such as preeclampsia and eclampsia. These clinically important complications are associated with maternal morbidity, mortality and postpartum cardiovascular disease. Some studies suggest that hydroxychloroquine (HCQ) may reduce preeclampsia risk in lupus pregnancy. Using a cohort of pregnancies in prevalent SLE patients at Kaiser Permanente Northern California (KPNC), we investigated whether HCQ use in early pregnancy reduced the risk of preeclampsia/eclampsia.Among SLE pregnancies from 2011-2020, we assessed HCQ use from three months before pregnancy through the first trimester. HCQ exposure was defined multiple ways to account for adherence and duration of use. Propensity scores accounted for multiple confounders and modified Poisson models estimated risk ratios (RR) and 95% confidence intervals of the association between HCQ and preeclampsia/eclampsia. Effect modification by pregestational hypertension, history of nephritis, and antiphospholipid antibody status was investigated through stratified analysis.There were 399 pregnancies among 324 patients with SLE at KPNC between 2011 and 2020. Considering multiple exposure definitions, we consistently found a null association between HCQ and preeclampsia/eclampsia. The RRs were consistently lower among the nullipara pregnancies, and RRs were consistently protective but not statistically significant among the high-risk subgroup of those with history of nephritis, aPL positivity, or pregestational hypertension (both nullipara and multipara).Although this study found no reduced risk of HCQ on preeclampsia/eclampsia, residual confounding may be attenuating the effect despite an integrated health care delivery system setting with detailed clinical data.
View details for DOI 10.1002/acr.25386
View details for PubMedID 38926748
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Preterm Birth.
Clinics in perinatology
2024; 51 (2): xxv-xxvi
View details for DOI 10.1016/j.clp.2024.03.002
View details for PubMedID 38705657
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Ambient Environment and the Epidemiology of Preterm Birth.
Clinics in perinatology
2024; 51 (2): 361-377
Abstract
Preterm birth (PTB) is associated with substantial mortality and morbidity. We describe environmental factors that may influence PTB risks. We focus on exposures associated with an individual's ambient environment, such as air pollutants, water contaminants, extreme heat, and proximities to point sources (oil/gas development or waste sites) and greenspace. These exposures may further vary by other PTB risk factors such as social constructs and stress. Future examinations of risks associated with ambient environment exposures would benefit from consideration toward multiple exposures - the exposome - and factors that modify risk including variations associated with the structural genome, epigenome, social stressors, and diet.
View details for DOI 10.1016/j.clp.2024.02.004
View details for PubMedID 38705646
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Solving the Puzzle of Preterm Birth.
Clinics in perinatology
2024; 51 (2): 291-300
Abstract
Solving the puzzle of preterm birth has been challenging and will require novel integrative solutions as preterm birth likely arises from many etiologies. It has been demonstrated that many sociodemographic and psychological determinants of preterm birth relate to its complex biology. It is this understanding that has enabled the development of a novel preventative strategy, which integrates the omics profile (genome, epigenome, transcriptome, proteome, metabolome, microbiome) with sociodemographic, environmental, and psychological determinants of individual pregnant people to solve the puzzle of preterm birth.
View details for DOI 10.1016/j.clp.2024.02.001
View details for PubMedID 38705641
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Outcome of pregnancy oral glucose tolerance test and preterm birth.
Epidemiology (Cambridge, Mass.)
2024
Abstract
Gestational diabetes is associated with adverse outcomes such as preterm birth (<37 weeks). However, there is no international consensus on screening criteria or diagnostic levels for gestational diabetes, and it is unknown whether body mass index (BMI) or obesity modifies the relation between glucose level and preterm birth.We studied a pregnancy cohort restricted to two Danish regions from the linked Danish Medical Birth Register to study associations between glucose measurements from the 2-hour post-load 75-gram oral glucose tolerance test (one-step approach) and preterm birth from 2004-2018. In Denmark, gestational diabetes screening is a targeted strategy for mothers with identified risk factors. We used Poisson regression to estimate rate ratios (RR) of preterm birth with z-standardized glucose measurements. We assessed effect measure modification by stratifying analyses and testing for heterogeneity.Among 11,337 pregnancies (6.2% delivered preterm), we observed an adjusted preterm birth RR of 1.2 (95% CI: 1.1-1.3) for a 1 standard deviation glucose increase of 1.4 mmol/L from the mean 6.7 mmol/L. There was evidence for effect measure modification by obesity, e.g., adjusted RR for non-obese (BMI <30): 1.2 (95%CI: 1.1-1.3) vs. obese (BMI ≥30): 1.3 (95%CI: 1.2-1.5), P=0.05 for heterogeneity.Among mothers screened for gestational diabetes, increased glucose levels, even those below the diagnostic level for gestational diabetes in Denmark, were associated with increased preterm birth risk. Obesity (BMI ≥30) may be an effect measure modifier, not just a confounder, of the relation between blood glucose and preterm birth risk.
View details for DOI 10.1097/EDE.0000000000001752
View details for PubMedID 38771706
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Regulatory elements in SEM1-DLX5-DLX6 (7q21.3) locus contribute to genetic control of coronal nonsyndromic craniosynostosis and bone density-related traits.
Genetics in medicine open
2024; 2
Abstract
The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown.We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model.Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E-12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence.Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.
View details for DOI 10.1016/j.gimo.2024.101851
View details for PubMedID 39345948
View details for PubMedCentralID PMC11434253
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Neighborhood sociodemographic characteristics and prevalence of congenital anomalies in Texas
PERGAMON-ELSEVIER SCIENCE LTD. 2024
View details for Web of Science ID 001295309300015
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Vascular health years after a hypertensive disorder of pregnancy: The EPOCH Study.
American heart journal
2024
Abstract
Preeclampsia is associated with a two-fold increase in a woman's lifetime risk of developing atherosclerotic cardiovascular disease (ASCVD), but the reasons for this association are uncertain. The objective of this study was to examine the associations between vascular health and a hypertensive disorder of pregnancy among women ≥ 2 years postpartum.Pre-menopausal women with a history of either a hypertensive disorder of pregnancy (cases: preeclampsia or gestational hypertension) or a normotensive pregnancy (controls) were enrolled. Participants were assessed for standard ASCVD risk factors and underwent vascular testing, including measurements of blood pressure, endothelial function, and carotid artery ultrasound. The primary outcomes were blood pressure, ASCVD risk, reactive hyperemia index measured by EndoPAT and carotid intima-medial thickness. The secondary outcomes were augmentation index normalized to 75 beats per minute and pulse wave amplitude measured by EndoPAT, and carotid elastic modulus and carotid beta-stiffness measured by carotid ultrasound.Participants had a mean age of 40.7 years and were 5.7 years since their last pregnancy. In bivariate analyses cases (N=68) were more likely than controls (N=71) to have hypertension (18% vs. 4%, p=0.034), higher calculated ASCVD risk (0.6 vs 0.4, p=0.02), higher blood pressures (systolic: 118.5 vs. 111.6 mm Hg, p=0.0004; diastolic: 75.2 vs 69.8 mm Hg, p=0.0004), and higher augmentation index values (7.7 vs. 2.3 p=0.03). They did not, however, differ significantly in carotid intima-media thickness (0.5 vs. 0.5, p=0.29) or reactive hyperemia index (2.1 vs 2.1, p=0.93), nor in pulse wave amplitude (416 vs 326, p=0.11), carotid elastic modulus (445 vs 426, p=0.36), or carotid beta stiffness (2.8 vs 2.8, p=0.86).Women with a prior hypertensive disorder of pregnancy had higher ASCVD risk and blood pressures several years postpartum, but did not have more endothelial dysfunction or subclinical atherosclerosis.
View details for DOI 10.1016/j.ahj.2024.03.004
View details for PubMedID 38484963
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A search for factors associated with reduced carbohydrate intake and NTD risk in two population-based studies.
Birth defects research
2024; 116 (3): e2328
Abstract
BACKGROUND: Two population-based case-control studies have reported an increased risk of neural tube defect (NTD)-affected pregnancies among women with low carbohydrate diet in the periconceptional period. Given that only two studies have investigated this association, it is unclear to what degree the findings could be impacted by residual confounding. Here, we further interrogated both studies that observed this association with the objective to identify factors from a much larger number of factors that might explain the association.METHODS: By employing a machine learning algorithm (random forest), we investigated a baseline set of over 200 variables. These analyses produced the top 10 variables in each data set for cases and controls that predicted periconceptional low carbohydrate intake.RESULTS: Examining those prediction variables with logistic regression modeling, we did not observe any particular variable that substantially contributed to the NTD-low carbohydrate association in either data set.CONCLUSIONS: If there are underlying factors that explain the association, our findings suggest that none of the 200+ variables we examined were sufficiently correlated with what that true explanatory exposure may be. Alternatively, our findings may suggest that there are other unidentified factor(s) at play, or the association observed in two independent data sets is directly related to low carbohydrate intake.
View details for DOI 10.1002/bdr2.2328
View details for PubMedID 38450884
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Author Correction: Abrupt perturbation and delayed recovery of the vaginal ecosystem following childbirth.
Nature communications
2024; 15 (1): 1744
View details for DOI 10.1038/s41467-024-46160-8
View details for PubMedID 38409135
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Corrigendum: Advances and potential of omics studies for understanding the development of food allergy.
Frontiers in allergy
2024; 5: 1373485
Abstract
[This corrects the article DOI: 10.3389/falgy.2023.1149008.].
View details for DOI 10.3389/falgy.2024.1373485
View details for PubMedID 38464397
View details for PubMedCentralID PMC10921899
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Air Pollution and Pregnancy: Insights into Immune Response, Histone Modifications, and Cytokine Signatures
MOSBY-ELSEVIER. 2024: AB370
View details for Web of Science ID 001267526000850
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Large-scale proteomics in the first trimester of pregnancy predict psychopathology and temperament in preschool children: an exploratory study.
Journal of child psychology and psychiatry, and allied disciplines
2024
Abstract
Understanding the prenatal origins of children's psychopathology is a fundamental goal in developmental and clinical science. Recent research suggests that inflammation during pregnancy can trigger a cascade of fetal programming changes that contribute to vulnerability for the emergence of psychopathology. Most studies, however, have focused on a handful of proinflammatory cytokines and have not explored a range of prenatal biological pathways that may be involved in increasing postnatal risk for emotional and behavioral difficulties.Using extreme gradient boosted machine learning models, we explored large-scale proteomics, considering over 1,000 proteins from first trimester blood samples, to predict behavior in early childhood. Mothers reported on their 3- to 5-year-old children's (N = 89, 51% female) temperament (Child Behavior Questionnaire) and psychopathology (Child Behavior Checklist).We found that machine learning models of prenatal proteomics predict 5%-10% of the variance in children's sadness, perceptual sensitivity, attention problems, and emotional reactivity. Enrichment analyses identified immune function, nervous system development, and cell signaling pathways as being particularly important in predicting children's outcomes.Our findings, though exploratory, suggest processes in early pregnancy that are related to functioning in early childhood. Predictive features included far more proteins than have been considered in prior work. Specifically, proteins implicated in inflammation, in the development of the central nervous system, and in key cell-signaling pathways were enriched in relation to child temperament and psychopathology measures.
View details for DOI 10.1111/jcpp.13948
View details for PubMedID 38287782
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Hydroxychloroquine in lupus pregnancy and risk of preeclampsia.
Arthritis & rheumatology (Hoboken, N.J.)
2024
Abstract
OBJECTIVE: Systemic lupus (SLE) disproportionately affects females during childbearing years, and hydroxychloroquine (HCQ) is the standard first-line treatment. Preeclampsia complicates up to one-third of lupus pregnancies, although reports vary by parity and multi-fetal gestation. We investigated whether HCQ use early in pregnancy may reduce the risk of preeclampsia.METHODS: We studied 1068 livebirth singleton pregnancies among 1020 privately insured patients with SLE (2007-2016). HCQ use was defined as 3 months preconception through the first trimester and prescription fills were a proxy for use. Modified Poisson regression estimated risk ratios (RRs) and 95% confidence intervals (95% CI) stratified by parity. Propensity scores accounted for confounders and stratified analyses examined effect modification.RESULTS: Approximately 15% of pregnancies were diagnosed with preeclampsia. 52% of pregnancies had ≥1 HCQ fill. HCQ-exposed pregnancies had more comorbidities, SLE activity, and azathioprine use. We found no evidence of a statistical association between HCQ and preeclampsia among nulliparous (RR=1.26, 95% CI 0.82, 1.93) and multiparous pregnancies (RR=1.20, 95% CI 0.80, 1.70). Additional control for confounding decreased the RRs towards the null (nulliparous: PS-adj RR=1.09, 95% CI 0.68, 1.76 and multiparous: PS-adj RR=1.01, 95% CI 0.66, 1.53).CONCLUSION: Using a large insurance-based database, we did not observe a decreased risk of preeclampsia associated with HCQ use in pregnancy, although we cannot rule out residual and unmeasured confounding and misclassification. Further studies leveraging large population-based data and prospective collection could characterize how HCQ influences preeclampsia risk in SLE pregnancy and among persons at greater risk of hypertensive disorders of pregnancy.
View details for DOI 10.1002/art.42793
View details for PubMedID 38272838
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Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.
Science advances
2024; 10 (3): eadk1057
Abstract
Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts. We uncovered previously unidentified sPTB genes that are involved in myometrial muscle relaxation and inflammatory responses and that are regulated by the progesterone receptor near labor onset. We studied genomic variants in these genes in our recruited pregnant women administered progestin prophylaxis. We observed that mutation burden in these genes was predictive of responses to progestin treatment for preterm birth. To advance therapeutic development, we screened ~4000 compounds, identified candidate molecules that affect our identified genes, and experimentally validated their therapeutic effects on regulating labor. Together, our integrative approach revealed the druggable genome in preterm birth and provided a generalizable framework for studying complex diseases.
View details for DOI 10.1126/sciadv.adk1057
View details for PubMedID 38241369
View details for PubMedCentralID PMC10798565
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Pregnancy outcomes in a diverse US Lupus Cohort.
Arthritis care & research
2024
Abstract
OBJECTIVE: Although the systemic lupus (SLE) patient population is racially and ethnically diverse, many study populations are homogeneous. Further, data are often lacking on critical factors such as antiphospholipid (aPL) antibodies. We investigated livebirth rates in patients with SLE at Kaiser Permanente Northern California including race/ethnicity and aPL data.METHODS: Electronic health records of pregnancies with outcomes observed from 2011-2020 were identified among patients with SLE. Prevalent SLE was defined as ≥2 ICD coded visits ≥7days apart before the last menstrual period (LMP). We summarized patient characteristics, medication orders, and healthcare utilization, and medication use. Pregnancy outcomes (livebirth, stillbirth, spontaneous abortion, ectopic, molar) were presented overall, and stratified by race/ethnicity, aPL status, and nephritis history.RESULTS: We identified 657 pregnancies among 453 patients with SLE. The cohort was diverse reflecting the Northern California population (27% Asian, 26% Hispanic, 26% Non-Hispanic (NH) White, 13% NH Black, 5% Multiracial, about 2% Islander, Native American). Approximately 74% of observed pregnancies ended in livebirth, 23% resulted in spontaneous abortion, 2% were ectopic or molar pregnancies, and <1% were stillbirths. There was limited variability in livebirths by race/ethnic group (72%-79%), aPL (69.5%-77%), and nephritis (71%-75%) CONCLUSION: Our findings are consistent with previous studies, however, some methodologic differences may yield a range of livebirth rates. We found that approximately 74% of pregnancies in SLE ended in livebirth, with modest variability in spontaneous abortion by race/ethnicity, nephritis, and aPL.
View details for DOI 10.1002/acr.25279
View details for PubMedID 38221659
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Factors associated with infant sex and preterm birth status for selected birth defects from the National Birth Defects Prevention Study, 1997-2011.
Birth defects research
2023
Abstract
Birth defects and preterm birth co-occur, with some overlapping risk factors. Many birth defects and preterm births tend to have a male preponderance. We explored potential risk factors impacting sex and preterm (<37 weeks of gestation) birth differences among infants with selected birth defects delivered from 1997 to 2011 using data from the National Birth Defects Prevention Study (NBDPS).The NBDPS was a large multisite, population-based case-control study. Using random forests, we identified important predictors of male preterm, female preterm, and male term, each compared with female term births for each birth defect. Using logistic regression, we estimated odds ratios for associations between important predictors and sex-preterm birth status by birth defect.We examined 11,379 infants with nine specific birth defects. The top 10 most important predictors of sex-preterm birth status from the random forests varied greatly across the birth defects and sex-preterm comparisons within a given defect group, with several being novel factors. However, one consistency was that short interpregnancy interval was associated with sex-preterm birth status for many of the studied birth defects. Although obesity has been identified as a risk factor for preterm birth and birth defects in other research, it was not associated with sex-preterm birth status for any of the examined defects.We confirmed expected associations for sex-preterm birth status differences and found new potential risk factors for further exploration among the studied birth defects.
View details for DOI 10.1002/bdr2.2294
View details for PubMedID 38155422
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Bias analyses to investigate the impact of differential participation: Application to a birth defects case-control study.
Paediatric and perinatal epidemiology
2023
Abstract
Certain associations observed in the National Birth Defects Prevention Study (NBDPS) contrasted with other research or were from areas with mixed findings, including no decrease in odds of spina bifida with periconceptional folic acid supplementation, moderately increased cleft palate odds with ondansetron use and reduced hypospadias odds with maternal smoking.To investigate the plausibility and extent of differential participation to produce effect estimates observed in NBDPS.We searched the literature for factors related to these exposures and participation and conducted deterministic quantitative bias analyses. We estimated case-control participation and expected exposure prevalence based on internal and external reports, respectively. For the folic acid-spina bifida and ondansetron-cleft palate analyses, we hypothesized the true odds ratio (OR) based on prior studies and quantified the degree of exposure over- (or under-) representation to produce the crude OR (cOR) in NBDPS. For the smoking-hypospadias analysis, we estimated the extent of selection bias needed to nullify the association as well as the maximum potential harmful OR.Under our assumptions (participation, exposure prevalence, true OR), there was overrepresentation of folic acid use and underrepresentation of ondansetron use and smoking among participants. Folic acid-exposed spina bifida cases would need to have been ≥1.2× more likely to participate than exposed controls to yield the observed null cOR. Ondansetron-exposed cleft palate cases would need to have been 1.6× more likely to participate than exposed controls if the true OR is null. Smoking-exposed hypospadias cases would need to have been ≥1.2 times less likely to participate than exposed controls for the association to falsely appear protective (upper bound of selection bias adjusted smoking-hypospadias OR = 2.02).Differential participation could partly explain certain associations observed in NBDPS, but questions remain about why. Potential impacts of other systematic errors (e.g. exposure misclassification) could be informed by additional research.
View details for DOI 10.1111/ppe.13026
View details for PubMedID 38102868
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Preconception dietary glycemic index and risk for large-for-gestational age births.
Nutrition (Burbank, Los Angeles County, Calif.)
2023; 119: 112322
Abstract
OBJECTIVES: Diets with a high glycemic index (GI) leading to elevated postprandial glucose levels and hyperinsulinemia during pregnancy have been inconsistently linked to an increased risk for large-for-gestational-age (LGA) births. The effects of prepregnancy dietary GI on LGA risk are, to our knowledge, unknown. We examined the association of prepregnancy dietary GI with LGA births and joint associations of GI and maternal overweight/obesity and infant sex with LGA births among 10 188 infants born without congenital anomalies from 1997 to 2011, using data from the National Birth Defects Prevention Study (NBDPS). The aim of this study was to investigate this association among infants without major congenital anomalies (controls) who participated in the NBDPS and to evaluate how prepregnancy BMI and infant sex may modify this association on the additive scale.METHODS: Dietary intake was ascertained using a 58-item food frequency questionnaire. We dichotomized dietary GI into high and low categories using spline regression models. Infants with a birth weight at or above the 90th percentile for gestational age and sex, according to a U.S. population reference, were considered LGA. We used logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs).RESULTS: Of the infants, 859 (9%) had a high dietary GI (cut-point: 59), and 1244 infants (12%) were born LGA. Unadjusted analysis suggested an inverse association between high dietary GI and LGA (OR, 0.79; 95% CI, 0.62-0.99). No association was observed in multivariable models when comparing high dietary GI intake between LGA births and all other births (OR, 0.94; 95% CI, 0.74-1.20) or when excluding small-for-gestational-age (SGA) births (OR, 0.94; 95% CI, 0.73-1.19). No joint associations with maternal overweight/obesity or infant sex were observed.CONCLUSION: High prepregnancy maternal GI was not associated with LGA births independently of or jointly with other factors.
View details for DOI 10.1016/j.nut.2023.112322
View details for PubMedID 38199030
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Neighborhood Deprivation and Neural Tube Defects.
Epidemiology (Cambridge, Mass.)
2023; 34 (6): 774-785
Abstract
Individual measures of socioeconomic status (SES) have been associated with an increased risk of neural tube defects (NTDs); however, the association between neighborhood SES and NTD risk is unknown. Using data from the National Birth Defects Prevention Study (NBDPS) from 1997 to 2011, we investigated the association between measures of census tract SES and NTD risk.The study population included 10,028 controls and 1829 NTD cases. We linked maternal addresses to census tract SES measures and used these measures to calculate the neighborhood deprivation index. We used generalized estimating equations to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) estimating the impact of quartiles of census tract deprivation on NTDs adjusting for maternal race-ethnicity, maternal education, and maternal age at delivery.Quartiles of higher neighborhood deprivation were associated with NTDs when compared with the least deprived quartile (Q2: aOR = 1.2; 95% CI = 1.0, 1.4; Q3: aOR = 1.3, 95% CI = 1.1, 1.5; Q4 (highest): aOR = 1.2; 95% CI = 1.0, 1.4). Results for spina bifida were similar; however, estimates for anencephaly and encephalocele were attenuated. Associations differed by maternal race-ethnicity.Our findings suggest that residing in a census tract with more socioeconomic deprivation is associated with an increased risk for NTDs, specifically spina bifida.
View details for DOI 10.1097/EDE.0000000000001655
View details for PubMedID 37757869
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Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome.
HGG advances
2023; 4 (4): 100232
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10-5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.
View details for DOI 10.1016/j.xhgg.2023.100232
View details for PubMedID 37663545
View details for PubMedCentralID PMC10474499
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MALE FIRSTBORN AND SUBSEQUENT PREGNANCY LOSS - A REAPPRAISAL USING REAL-WORLD DATA.
ELSEVIER SCIENCE INC. 2023: E81-E82
View details for Web of Science ID 001084670200191
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Pregnancy Outcomes Among Patients with Vasculitis Using Administrative Claims Data
WILEY. 2023: 4801-4803
View details for Web of Science ID 001190014305027
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Hydroxychloroquine and Preeclampsia Risk in Lupus Pregnancy: Results from a Large Regional Integrated Health Network
WILEY. 2023: 912-913
View details for Web of Science ID 001190014300470
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Is gastroschisis associated with county-level socio-environmental quality during pregnancy?
Birth defects research
2023
Abstract
Gastroschisis prevalence more than doubled between 1995 and 2012. While there are individual-level risk factors (e.g., young maternal age, low body mass index), the impact of environmental exposures is not well understood.We used the U.S. Environmental Protection Agency's Environmental Quality Index (EQI) as a county-level estimate of cumulative environmental exposures for five domains (air, water, land, sociodemographic, and built) and overall from 2006 to 2010. Adjusted odds ratios (aOR) and 95% confidence interval (CI) were estimated from logistic regression models between EQI tertiles (better environmental quality (reference); mid; poorer) and gastroschisis in the National Birth Defects Prevention Study from births delivered between 2006 and 2011. Our analysis included 594 cases with gastroschisis and 4105 infants without a birth defect (controls).Overall EQI was modestly associated with gastroschisis (aOR [95% CI]: 1.29 [0.98, 1.71]) for maternal residence in counties with poorer environmental quality, compared to the reference (better environmental quality). Within domain-specific indices, only the sociodemographic domain (aOR: 1.51 [0.99, 2.29]) was modestly associated with gastroschisis, when comparing poorer to better environmental quality.Future work could elucidate pathway(s) by which components of the sociodemographic domain or possibly related psychosocial factors like chronic stress potentially contribute to risk of gastroschisis.
View details for DOI 10.1002/bdr2.2250
View details for PubMedID 37772934
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Deep representation learning identifies associations between physical activity and sleep patterns during pregnancy and prematurity.
NPJ digital medicine
2023; 6 (1): 171
Abstract
Preterm birth (PTB) is the leading cause of infant mortality globally. Research has focused on developing predictive models for PTB without prioritizing cost-effective interventions. Physical activity and sleep present unique opportunities for interventions in low- and middle-income populations (LMICs). However, objective measurement of physical activity and sleep remains challenging and self-reported metrics suffer from low-resolution and accuracy. In this study, we use physical activity data collected using a wearable device comprising over 181,944 h of data across N = 1083 patients. Using a new state-of-the art deep learning time-series classification architecture, we develop a 'clock' of healthy dynamics during pregnancy by using gestational age (GA) as a surrogate for progression of pregnancy. We also develop novel interpretability algorithms that integrate unsupervised clustering, model error analysis, feature attribution, and automated actigraphy analysis, allowing for model interpretation with respect to sleep, activity, and clinical variables. Our model performs significantly better than 7 other machine learning and AI methods for modeling the progression of pregnancy. We found that deviations from a normal 'clock' of physical activity and sleep changes during pregnancy are strongly associated with pregnancy outcomes. When our model underestimates GA, there are 0.52 fewer preterm births than expected (P = 1.01e - 67, permutation test) and when our model overestimates GA, there are 1.44 times (P = 2.82e - 39, permutation test) more preterm births than expected. Model error is negatively correlated with interdaily stability (P = 0.043, Spearman's), indicating that our model assigns a more advanced GA when an individual's daily rhythms are less precise. Supporting this, our model attributes higher importance to sleep periods in predicting higher-than-actual GA, relative to lower-than-actual GA (P = 1.01e - 21, Mann-Whitney U). Combining prediction and interpretability allows us to signal when activity behaviors alter the likelihood of preterm birth and advocates for the development of clinical decision support through passive monitoring and exercise habit and sleep recommendations, which can be easily implemented in LMICs.
View details for DOI 10.1038/s41746-023-00911-x
View details for PubMedID 37770643
View details for PubMedCentralID 3796350
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Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population-based case-control study of women meeting the folic acid recommendations.
The American journal of clinical nutrition
2023; 118 (3): 720-728
Abstract
Neural tube defects (NTDs) still occur among some women who consume 400 μg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs.To investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations.Data were from the National Birth Defects Prevention Study (United States population-based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 μg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center.NTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake.Our findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.
View details for DOI 10.1016/j.ajcnut.2023.05.034
View details for PubMedID 37661108
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Exome sequencing findings in children with annular pancreas.
Molecular genetics & genomic medicine
2023: e2233
Abstract
Annular pancreas (AP) is a congenital defect of unknown cause in which the pancreas encircles the duodenum. Theories include abnormal migration and rotation of the ventral bud, persistence of ectopic pancreatic tissue, and inappropriate fusion of the ventral and dorsal buds before rotation. The few reported familial cases suggest a genetic contribution.We conducted exome sequencing in 115 affected infants from the California birth defects registry.Seven cases had a single heterozygous missense variant in IQGAP1, five of them with CADD scores >20; seven other infants had a single heterozygous missense variant in NRCAM, five of them with CADD scores >20. We also looked at genes previously associated with AP and found two rare heterozygous missense variants, one each in PDX1 and FOXF1.IQGAP1 and NRCAM are crucial in cell polarization and migration. Mutations result in decreased motility which could possibly cause the ventral bud to not migrate normally. To our knowledge, this is the first study reporting a possible association for IQGAP1 and NRCAM with AP. Our findings of rare genetic variants involved in cell migration in 15% of our population raise the possibility that AP may be related to abnormal cell migration.
View details for DOI 10.1002/mgg3.2233
View details for PubMedID 37635636
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Maternal physical activity, sitting, and risk of non-cardiac birth defects.
Pediatric research
2023
Abstract
BACKGROUND: The relationship between maternal physical activity (PA)/sitting and birth defects is largely unexplored. We examined whether pre-pregnancy PA/sitting were associated with having a pregnancy affected by a birth defect.METHODS: We used data from two United States population-based case-control studies: 2008-2011 deliveries from the National Birth Defects Prevention Study (NBDPS; 9 states) and 2014-2018 deliveries from the Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS; 7 states). Cases with one of 12 non-cardiac birth defects (n=3798) were identified through population-based registries. Controls (n=2682) were live-born infants without major birth defects randomly sampled using vital/hospital records. Mothers self-reported pre-pregnancy PA/sitting. Unconditional logistic regression models estimated associations between PA/sitting categories and the 12 birth defects.RESULTS: Mothers engaging in pre-pregnancy PA was associated with a reduced odds of five (spina bifida, cleft palate, anorectal atresia, hypospadias, transverse limb deficiency) and a higher odds of two (anencephaly, gastroschisis) birth defects. Mothers spending less time sitting in pre-pregnancy was associated with a reduced odds of two (anorectal atresia, hypospadias) and a higher odds of one (cleft lip with or without cleft palate) birth defect.CONCLUSIONS: Reasonable next steps include replication of these findings, improved exposure assessment, and elucidation of biologic mechanisms.IMPACT: Using data from two population-based case-control studies, we found that mothers engaging in different types of physical activity in the 3 months before pregnancy had an infant with a reduced odds of five and a higher odds of two birth defects. Mothers spending less time sitting in the 3 months before pregnancy had an infant with a reduced odds of two and a higher odds of one birth defect. Clarification and confirmation from additional studies are needed using more precise exposure measures, distinguishing occupational from leisure-time physical activity, and elucidation of mechanisms supporting these associations.
View details for DOI 10.1038/s41390-023-02768-y
View details for PubMedID 37543708
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Comparative predictive power of serum vs plasma proteomic signatures in feto-maternal medicine.
AJOG global reports
2023; 3 (3): 100244
Abstract
Blood proteins are frequently measured in serum or plasma, because they provide a wealth of information. Differences in the ex vivo processing of serum and plasma raise concerns that proteomic health and disease signatures derived from serum or plasma differ in content and quality. However, little is known about their respective power to predict feto-maternal health outcomes. Predictive power is a sentinel characteristic to determine the clinical use of biosignatures.This study aimed to compare the power of serum and plasma proteomic signatures to predict a physiological pregnancy outcome.Paired serum and plasma samples from 73 women were obtained from biorepositories of a multinational prospective cohort study on pregnancy outcomes. Gestational age at the time of sampling was the predicted outcome, because the proteomic signatures have been validated for such a prediction. Multivariate and cross-validated models were independently derived for serum and plasma proteins.A total of 1116 proteins were measured in 88 paired samples from 73 women with a highly multiplexed platform using proximity extension technology (Olink Proteomics Inc, Watertown, MA). The plasma proteomic signature showed a higher predictive power (R=0.64; confidence interval, 0.42-0.79; P=3.5×10-6) than the serum signature (R=0.45; confidence interval, 0.18-0.66; P=2.2×10-3). The serum signature was validated in plasma with a similar predictive power (R=0.58; confidence interval, 0.34-0.75; P=4.8×10-5), whereas the plasma signature was validated in serum with reduced predictive power (R=0.53; confidence interval, 0.27-0.72; P=2.6×10-4). Signature proteins largely overlapped in the serum and plasma, but the strength of association with gestational age was weaker for serum proteins.Findings suggest that serum proteomics are less informative than plasma proteomics. They are compatible with the view that the partial ex-vivo degradation and modification of serum proteins during sample processing are an underlying reason. The rationale for collecting and analyzing serum and plasma samples should be carefully considered when deriving proteomic biosignatures to ascertain that specimens of the highest scientific and clinical yield are processed. Findings suggest that plasma is the preferred matrix.
View details for DOI 10.1016/j.xagr.2023.100244
View details for PubMedID 37456144
View details for PubMedCentralID PMC10339042
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Corrigendum to Divergent Patterns of Mitochondrial and Nuclear Ancestry Are Associated with the Risk for Preterm Birth [The Journal of Pediatrics 194(2018):40-46.e4].
The Journal of pediatrics
2023: 113345
View details for DOI 10.1016/j.jpeds.2023.01.017
View details for PubMedID 37495478
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Are individual-level risk factors for gastroschisis modified by neighborhood-level socioeconomic factors?
Birth defects research
2023
Abstract
Two strong risk factors for gastroschisis are young maternal age (<20 years) and low/normal pre-pregnancy body mass index (BMI), yet the reasons remain unknown. We explored whether neighborhood-level socioeconomic position (nSEP) during pregnancy modified these associations.We analyzed data from 1269 gastroschisis cases and 10,217 controls in the National Birth Defects Prevention Study (1997-2011). To characterize nSEP, we applied the neighborhood deprivation index and used generalized estimating equations to calculate odds ratios and relative excess risk due to interaction.Elevated odds of gastroschisis were consistently associated with young maternal age and low/normal BMI, regardless of nSEP. High-deprivation neighborhoods modified the association with young maternal age. Infants of young mothers in high-deprivation areas had lower odds of gastroschisis (adjusted odds ratio [aOR]: 3.1, 95% confidence interval [CI]: 2.6, 3.8) than young mothers in low-deprivation areas (aOR: 6.6; 95% CI: 4.6, 9.4). Mothers of low/normal BMI had approximately twice the odds of having an infant with gastroschisis compared to mothers with overweight/obese BMI, regardless of nSEP (aOR range: 1.5-2.3).Our findings suggest nSEP modified the association between gastroschisis and maternal age, but not BMI. Further research could clarify whether the modification is due to unidentified biologic and/or non-biologic factors.
View details for DOI 10.1002/bdr2.2224
View details for PubMedID 37439400
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Abrupt perturbation and delayed recovery of the vaginal ecosystem following childbirth.
Nature communications
2023; 14 (1): 4141
Abstract
The vaginal ecosystem is closely tied to human health and reproductive outcomes, yet its dynamics in the wake of childbirth remain poorly characterized. Here, we profile the vaginal microbiota and cytokine milieu of participants sampled longitudinally throughout pregnancy and for at least one year postpartum. We show that delivery, regardless of mode, is associated with a vaginal pro-inflammatory cytokine response and the loss of Lactobacillus dominance. By contrast, neither the progression of gestation nor the approach of labor strongly altered the vaginal ecosystem. At 9.5-months postpartum-the latest timepoint at which cytokines were assessed-elevated inflammation coincided with vaginal bacterial communities that had remained perturbed (highly diverse) from the time of delivery. Time-to-event analysis indicated a one-year postpartum probability of transitioning to Lactobacillus dominance of 49.4%. As diversity and inflammation declined during the postpartum period, dominance by L. crispatus, the quintessential health-associated commensal, failed to return: its prevalence before, immediately after, and one year after delivery was 41%, 4%, and 9%, respectively. Revisiting our pre-delivery data, we found that a prior live birth was associated with a lower odds of L. crispatus dominance in pregnant participants-an outcome modestly tempered by a longer ( > 18-month) interpregnancy interval. Our results suggest that reproductive history and childbirth in particular remodel the vaginal ecosystem and that the timing and degree of recovery from delivery may help determine the subsequent health of the woman and of future pregnancies.
View details for DOI 10.1038/s41467-023-39849-9
View details for PubMedID 37438386
View details for PubMedCentralID 4355684
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Persistent Bacterial Vaginosis and Risk for Spontaneous Preterm Birth.
American journal of perinatology
2023
Abstract
The aim of this study was to determine the association between persistent bacterial vaginosis (BV) in pregnancy and risk for spontaneous preterm birth (sPTB). Retrospective data from IBM MarketScan Commercial Database were analyzed. Women aged between 12 and 55 years with singleton gestations were included and linked to an outpatient medications database and medications prescribed during the pregnancy were analyzed. BV in pregnancy was determined based on both a diagnosis of BV and treatment with metronidazole and/or clindamycin, and persistent treatment of BV was defined as BV in more than one trimester or BV requiring more than one antibiotic prescription. Odds ratios were calculated comparing sPTB frequencies in those with BV, or persistent BV, to women without BV in pregnancy. Survival analysis using Kaplan-Meier curves for the gestational age at delivery was also performed. Among a cohort of 2,538,606 women, 216,611 had an associated International Classification of Diseases, 9th Revision or 10th Revision code for diagnosis of BV alone, and 63,817 had both a diagnosis of BV and were treated with metronidazole and/or clindamycin. Overall, the frequency of sPTB among women treated with BV was 7.5% compared with 5.7% for women without BV who did not receive antibiotics. Relative to those without BV in pregnancy, odds ratios for sPTB were highest in those treated for BV in both the first and second trimester (1.66 [95% confidence interval [CI]: 1.52, 1.81]) or those with three or more prescriptions in pregnancy (1.48 [95% CI: 1.35, 1.63]. Persistent BV may have a higher risk for sPTB than a single episode of BV in pregnancy.· Persistent BV beyond one trimester may increase the risk for sPTB.. · Persistent BV requiring more than one prescription may increase the risk for sPTB.. · Almost half of antibiotic prescriptions treating BV in pregnancy are filled after 20 weeks gestation..
View details for DOI 10.1055/s-0043-1770703
View details for PubMedID 37379861
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Oxidative balance scores and neural crest cell-related congenital anomalies.
Birth defects research
2023
Abstract
Oxidative stress and redox imbalance adversely affect embryonic development. We developed two oxidative balance scores (OBS) that include dietary and nondietary exposures. We hypothesized that higher scores (i.e., lower oxidative stress) would be associated with lower risk of neural tube defects, orofacial clefts, conotruncal heart defects, and limb deficiencies. We used data from the National Birth Defects Prevention Study to create a dietary OBS based on intake of 13 nutrients and an overall OBS that included the 13 nutrients and eight additional nondietary factors related to oxidative balance (e.g., smoking). We used logistic regression to examine odds ratios associated with having low or high scores (i.e., <10th or >90th percentiles). Continuous models indicated reduced odds associated with high versus low scores (i.e., comparing odds at the 90th versus 10th percentile values of the distribution) on the overall OBS for cleft lip with or without cleft palate [adjusted odds ratio (aOR) 0.72, 95% confidence interval (CI) 0.63-0.82], longitudinal limb deficiency (aOR 0.73, CI 0.54-0.99), and transverse limb deficiency (aOR 0.74, CI 0.58-0.95); increased odds for anencephaly (aOR 1.40, CI 1.07-1.84); and primarily nonsignificant associations with conotruncal heart defects. Results for the dietary OBS were similar. This study provides some evidence that oxidative stress contributes to congenital anomalies related to neural crest cell development.
View details for DOI 10.1002/bdr2.2211
View details for PubMedID 37309307
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Development of a Urine Metabolomics Biomarker-Based Prediction Model for Preeclampsia during Early Pregnancy.
Metabolites
2023; 13 (6)
Abstract
Preeclampsia (PE) is a condition that poses a significant risk of maternal mortality and multiple organ failure during pregnancy. Early prediction of PE can enable timely surveillance and interventions, such as low-dose aspirin administration. In this study, conducted at Stanford Health Care, we examined a cohort of 60 pregnant women and collected 478 urine samples between gestational weeks 8 and 20 for comprehensive metabolomic profiling. By employing liquid chromatography mass spectrometry (LCMS/MS), we identified the structures of seven out of 26 metabolomics biomarkers detected. Utilizing the XGBoost algorithm, we developed a predictive model based on these seven metabolomics biomarkers to identify individuals at risk of developing PE. The performance of the model was evaluated using 10-fold cross-validation, yielding an area under the receiver operating characteristic curve of 0.856. Our findings suggest that measuring urinary metabolomics biomarkers offers a noninvasive approach to assess the risk of PE prior to its onset.
View details for DOI 10.3390/metabo13060715
View details for PubMedID 37367874
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Multiomic signals associated with maternal epidemiological factors contributing to preterm birth in low- and middle-income countries.
Science advances
2023; 9 (21): eade7692
Abstract
Preterm birth (PTB) is the leading cause of death in children under five, yet comprehensive studies are hindered by its multiple complex etiologies. Epidemiological associations between PTB and maternal characteristics have been previously described. This work used multiomic profiling and multivariate modeling to investigate the biological signatures of these characteristics. Maternal covariates were collected during pregnancy from 13,841 pregnant women across five sites. Plasma samples from 231 participants were analyzed to generate proteomic, metabolomic, and lipidomic datasets. Machine learning models showed robust performance for the prediction of PTB (AUROC = 0.70), time-to-delivery (r = 0.65), maternal age (r = 0.59), gravidity (r = 0.56), and BMI (r = 0.81). Time-to-delivery biological correlates included fetal-associated proteins (e.g., ALPP, AFP, and PGF) and immune proteins (e.g., PD-L1, CCL28, and LIFR). Maternal age negatively correlated with collagen COL9A1, gravidity with endothelial NOS and inflammatory chemokine CXCL13, and BMI with leptin and structural protein FABP4. These results provide an integrated view of epidemiological factors associated with PTB and identify biological signatures of clinical covariates affecting this disease.
View details for DOI 10.1126/sciadv.ade7692
View details for PubMedID 37224249
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Postpartum long-acting reversible contraception among privately insured: national analysis 2007-2016, by term and preterm birth.
Contraception
2023: 110065
Abstract
To investigate postpartum long-acting reversible contraception (LARC) use among privately insured women, with specific consideration of use after preterm delivery.We used the national IBM® MarketScan® Commercial Database to identify singleton deliveries from 2007-2016, spontaneous preterm birth, and follow up ≤12 weeks postpartum. We assessed ≤12 week postpartum LARC placement overall and after spontaneous preterm deliveries, across study years. We examined timing of placement, rates of postpartum follow-up, and state-level variation in postpartum LARC.Among 3,132,107 singleton deliveries, 6.6% were spontaneous preterm. Over the time period, total postpartum LARC use increased: 4.8% to 11.7% for intrauterine devices (IUDs), 0.2% to 2.4% for implants. In 2016, those who experienced a spontaneous preterm birth were less likely to initiate postpartum IUDs compared to their peers (10.2% vs 11.8%, p<0.001), minimally more likely to initiate implants (2.7% vs 2.4%, p=0.04) and more likely to present for postpartum care (61.7% vs 55.9%, p<0.001). LARC placement prior to hospital discharge was rare (preterm: 8 per 10,000 deliveries vs all others: 6.3 per 10,000 deliveries, p=0.002). State level analysis showed wide variation in postpartum LARC (range 6%-32%).While postpartum LARC use increased among the privately insured 2007 to 2016, few received LARC prior to hospital discharge. Those experiencing preterm birth were no more likely to receive inpatient LARC. Postpartum follow-up remained low and regional variation of LARC was high, highlighting the need for efforts to remove barriers to inpatient postpartum LARC for all who desire it-public and privately insured alike.Among the half of U.S. births that are privately insured, postpartum LARC is increasing after both term and preterm births, yet exceedingly few (<0.1%) received LARC prior to hospital discharge.
View details for DOI 10.1016/j.contraception.2023.110065
View details for PubMedID 37210023
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Noninvasive Prenatal Testing Using Circulating DNA and RNA: Advances, Challenges, and Possibilities.
Annual review of biomedical data science
2023
Abstract
Prenatal screening using sequencing of circulating cell-free DNA has transformed obstetric care over the past decade and significantly reduced the number of invasive diagnostic procedures like amniocentesis for genetic disorders. Nonetheless, emergency care remains the only option for complications like preeclampsia and preterm birth, two of the most prevalent obstetrical syndromes. Advances in noninvasive prenatal testing expand the scope of precision medicine in obstetric care. In this review, we discuss advances, challenges, and possibilities toward the goal of providing proactive, personalized prenatal care. The highlighted advances focus mainly on cell-free nucleic acids; however, we also review research that uses signals from metabolomics, proteomics, intact cells, and the microbiome. We discuss ethical challenges in providing care. Finally, we look to future possibilities, including redefining disease taxonomy and moving from biomarker correlation to biological causation. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
View details for DOI 10.1146/annurev-biodatasci-020722-094144
View details for PubMedID 37196360
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Vaginal Progesterone is Associated with Intrahepatic Cholestasis of Pregnancy.
American journal of perinatology
2023
Abstract
Background The frequency of intrahepatic cholestasis of pregnancy peaks during the third trimester of pregnancy when plasma progesterone levels are highest. Furthermore, twin pregnancies are characterized by higher progesterone levels than singletons, and have a higher frequency of cholestasis. Therefore, we hypothesized that exogenous progestogens administered for reducing the risk of spontaneous preterm birth may increase the risk of cholestasis. Objectives Utilizing the large IBM MarketScan Commercial Claims and Encounters Database, we investigated the frequency of cholestasis in patients treated with vaginal progesterone or intramuscular 17alpha-hydroxyprogesterone caproate for the prevention of preterm birth. Study design We identified 1,776,092 live-born singleton pregnancies between 2010-2014. We confirmed 2nd and 3rd trimester administration of progestogens by cross-referencing the dates of progesterone prescriptions with the dates of scheduled pregnancy events such as nuchal translucency scan, fetal anatomy scan, glucose challenge test, and Tdap vaccination. We excluded pregnancies with missing data regarding timing of scheduled pregnancy events, or progesterone treatment prescribed only during the 1st trimester. Cholestasis of pregnancy was identified based on prescriptions for ursodeoxycholic acid. We used multivariable logistic regression to estimate adjusted (for maternal age) odds ratios for cholestasis in patients treated with vaginal progesterone, and in patients treated with 17alpha-hydroxyprogesterone caproate compared to those not treated with any type of progestogen (the reference group). Results The final cohort consisted of 870,599 pregnancies. Among patients treated with vaginal progesterone during the 2nd and 3rd trimester, the frequency of cholestasis was significantly higher than the reference group (0.75% vs 0.23%, aOR 3.16, 95% CI 2.23-4.49). In contrast, there was no significant association between 17alpha-hydroxyprogesterone caproate and cholestasis (0.27%, aOR 1.12, 95% CI 0.58-2.16) Conclusions Using a robust dataset, we observed that vaginal progesterone but not intramuscular 17alpha-hydroxyprogesterone caproate was associated with an increased risk for intrahepatic cholestasis of pregnancy.
View details for DOI 10.1055/a-2081-2573
View details for PubMedID 37100422
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Large-scale correlation network construction for unraveling the coordination of complex biological systems
NATURE COMPUTATIONAL SCIENCE
2023
View details for DOI 10.1038/s43588-023-00429-y
View details for Web of Science ID 000968297800002
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Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate.
medRxiv : the preprint server for health sciences
2023
Abstract
Orofacial clefts (OFCs) are the most common craniofacial birth defects and are often categorized into two etiologically distinct groups: cleft lip with or without cleft palate (CL/P) and isolated cleft palate (CP). CP is highly heritable, but there are still relatively few established genetic risk factors associated with its occurrence compared to CL/P. Historically, CP has been studied as a single phenotype despite manifesting across a spectrum of defects involving the hard and/or soft palate. We performed GWAS using transmission disequilibrium tests using 435 case-parent trios to evaluate broad risks for any cleft palate (ACP, n=435), as well as subtype-specific risks for any cleft soft palate (CSP, n=259) and any cleft hard palate (CHP, n=125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p=4.24×10 -8 ) associated with CHP. One gene at this locus, angiopoietin-like 2 ( ANGPTL2 ), plays a role in osteoblast differentiation. It is expressed in craniofacial tissue of human embryos, as well as in the developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p<5×10 -6 ), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios (ORs) for each of the 20 loci were most similar across all three groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either the CSP or CHP groups. We also found nominal evidence of replication (p<0.05) for 22 SNPs previously associated with cleft palate (including CL/P). Interestingly, most SNPs associated with CL/P cases were found to convey the opposite effect in those replicated in our dataset for CP only. Ours is the first study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.
View details for DOI 10.1101/2023.03.01.23286642
View details for PubMedID 37066311
View details for PubMedCentralID PMC10104215
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Large-scale correlation network construction for unraveling the coordination of complex biological systems.
Nature computational science
2023; 3 (4): 346-359
Abstract
Advanced measurement and data storage technologies have enabled high-dimensional profiling of complex biological systems. For this, modern multiomics studies regularly produce datasets with hundreds of thousands of measurements per sample, enabling a new era of precision medicine. Correlation analysis is an important first step to gain deeper insights into the coordination and underlying processes of such complex systems. However, the construction of large correlation networks in modern high-dimensional datasets remains a major computational challenge owing to rapidly growing runtime and memory requirements. Here we address this challenge by introducing CorALS (Correlation Analysis of Large-scale (biological) Systems), an open-source framework for the construction and analysis of large-scale parametric as well as non-parametric correlation networks for high-dimensional biological data. It features off-the-shelf algorithms suitable for both personal and high-performance computers, enabling workflows and downstream analysis approaches. We illustrate the broad scope and potential of CorALS by exploring perspectives on complex biological processes in large-scale multiomics and single-cell studies.
View details for DOI 10.1038/s43588-023-00429-y
View details for PubMedID 38116462
View details for PubMedCentralID PMC10727505
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Leveraging electronic health records to identify risk factors for recurrent pregnancy loss across two medical centers: a case-control study.
Research square
2023
Abstract
Recurrent pregnancy loss (RPL), defined as 2 or more pregnancy losses, affects 5-6% of ever-pregnant individuals. Approximately half of these cases have no identifiable explanation. To generate hypotheses about RPL etiologies, we implemented a case-control study comparing the history of over 1,600 diagnoses between RPL and live-birth patients, leveraging the University of California San Francisco (UCSF) and Stanford University electronic health record databases. In total, our study included 8,496 RPL (UCSF: 3,840, Stanford: 4,656) and 53,278 Control (UCSF: 17,259, Stanford: 36,019) patients. Menstrual abnormalities and infertility-associated diagnoses were significantly positively associated with RPL in both medical centers. Age-stratified analysis revealed that the majority of RPL-associated diagnoses had higher odds ratios for patients <35 compared with 35+ patients. While Stanford results were sensitive to control for healthcare utilization, UCSF results were stable across analyses with and without utilization. Intersecting significant results between medical centers was an effective filter to identify associations that are robust across center-specific utilization patterns.
View details for DOI 10.21203/rs.3.rs-2631220/v1
View details for PubMedID 36993325
View details for PubMedCentralID PMC10055527
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Neighborhood-level socioeconomic position during early pregnancy and risk of gastroschisis.
Epidemiology (Cambridge, Mass.)
2023
Abstract
Neighborhood-level socioeconomic position has been shown to influence birth outcomes, including selected birth defects. This study examines the understudied association between neighborhood-level socioeconomic position during early pregnancy and risk of gastroschisis, an abdominal birth defect of increasing prevalence.We conducted a case-control study of 1,269 gastroschisis cases and 10,217 controls using data from the National Birth Defects Prevention Study (1997 - 2011). To characterize neighborhood-level socioeconomic position, we conducted principal component analysis to construct two indices - Neighborhood Deprivation Index (NDI) and Neighborhood Socioeconomic Position Index (nSEPI). We created neighborhood-level indices using census socioeconomic indicators corresponding to census tracts associated with addresses where mothers lived the longest during the periconceptional period. We used generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with multiple imputation for missing data and adjustment for maternal race-ethnicity, household income, education, birth year, and duration of residence.Mothers residing in moderate (NDI Tertile 2 aOR: 1.2; 95% CI: 1.0, 1.5 and nSEPI Tertile 2 aOR: 1.2; 95% CI: 1.0, 1.5) or low socioeconomic neighborhoods (NDI Tertile 3 aOR: 1.3; 95% CI: 1.01, 1.6 and nSEPI Tertile 3 aOR: 1.3, 95% CI: 1.1, 1.6) were more likely to deliver an infant with gastroschisis compared with mothers residing in high socioeconomic neighborhoods.Our findings suggest that lower neighborhood-level socioeconomic position during early pregnancy is associated with elevated odds of gastroschisis. Additional epidemiologic studies may aid in confirming this finding and evaluating potential mechanisms linking neighborhood-level socioeconomic factors and gastroschisis.
View details for DOI 10.1097/EDE.0000000000001621
View details for PubMedID 36976718
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Advances and potential of omics studies for understanding the development of food allergy.
Frontiers in allergy
2023; 4: 1149008
Abstract
The prevalence of food allergy continues to rise globally, carrying with it substantial safety, economic, and emotional burdens. Although preventative strategies do exist, the heterogeneity of allergy trajectories and clinical phenotypes has made it difficult to identify patients who would benefit from these strategies. Therefore, further studies investigating the molecular mechanisms that differentiate these trajectories are needed. Large-scale omics studies have identified key insights into the molecular mechanisms for many different diseases, however the application of these technologies to uncover the drivers of food allergy development is in its infancy. Here we review the use of omics approaches in food allergy and highlight key gaps in knowledge for applying these technologies for the characterization of food allergy development.
View details for DOI 10.3389/falgy.2023.1149008
View details for PubMedID 37034151
View details for PubMedCentralID PMC10080041
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Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants.
American journal of medical genetics. Part A
2023
Abstract
The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.
View details for DOI 10.1002/ajmg.a.63185
View details for PubMedID 36942736
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Associations between pregnancy glucose measurements and risk of preterm birth: a retrospective cohort study of commercially insured women in the United States from 2003-2021.
Annals of epidemiology
2023
Abstract
To investigate associations between glucose measurements during pregnancy and risk of preterm birth (PTB).Retrospective cohort study of commercially insured women with singleton live births in the United States from 2003-2021 using longitudinal medical claims, socioeconomic data, and eight glucose results from different types of fasting and post-load tests performed between 24-28 weeks of gestation for gestational diabetes screening. Risk ratios of PTB (<37 weeks) were estimated via Poisson regression for z-standardized glucose measures. Non-linear relationships for continuous glucose measures were examined via generalized additive models.Elevations in all eight glucose measures were associated with increased risk (adjusted risk ratio point estimates: 1.05-1.19) of PTB for 196,377 women with non-fasting 50-gram glucose challenge test (one glucose result), 31,522 women with complete 100-gram, 3-hour fasting oral glucose tolerance test (OGTT) results (four glucose results), and 10,978 women with complete 75-gram, 2-hour fasting OGTT results (three glucose results). Associations were consistent after adjusting for and stratifying by sociodemographic and clinical factors. Substantial non-linear relationships (U-, J-, and S-shaped) were observed between several glucose measurements and PTB.Elevations in various glucose measures were linearly and non-linearly associated with increased risk of PTB, even before diagnostic thresholds for gestational diabetes.
View details for DOI 10.1016/j.annepidem.2023.03.002
View details for PubMedID 36905977
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Data-driven longitudinal characterization of neonatal health and morbidity.
Science translational medicine
2023; 15 (683): eadc9854
Abstract
Although prematurity is the single largest cause of death in children under 5 years of age, the current definition of prematurity, based on gestational age, lacks the precision needed for guiding care decisions. Here, we propose a longitudinal risk assessment for adverse neonatal outcomes in newborns based on a deep learning model that uses electronic health records (EHRs) to predict a wide range of outcomes over a period starting shortly before conception and ending months after birth. By linking the EHRs of the Lucile Packard Children's Hospital and the Stanford Healthcare Adult Hospital, we developed a cohort of 22,104 mother-newborn dyads delivered between 2014 and 2018. Maternal and newborn EHRs were extracted and used to train a multi-input multitask deep learning model, featuring a long short-term memory neural network, to predict 24 different neonatal outcomes. An additional cohort of 10,250 mother-newborn dyads delivered at the same Stanford Hospitals from 2019 to September 2020 was used to validate the model. Areas under the receiver operating characteristic curve at delivery exceeded 0.9 for 10 of the 24 neonatal outcomes considered and were between 0.8 and 0.9 for 7 additional outcomes. Moreover, comprehensive association analysis identified multiple known associations between various maternal and neonatal features and specific neonatal outcomes. This study used linked EHRs from more than 30,000 mother-newborn dyads and would serve as a resource for the investigation and prediction of neonatal outcomes. An interactive website is available for independent investigators to leverage this unique dataset: https://maternal-child-health-associations.shinyapps.io/shiny_app/.
View details for DOI 10.1126/scitranslmed.adc9854
View details for PubMedID 36791208
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Congenital male genital malformations and paternal health: an analysis of US claims data.
Andrology
2023
Abstract
OBJECTIVE: To investigate the potential association between paternal health and male genital malformations in the offspring.MATERIALS AND METHODS: We analyzed data from 2007 to 2016 derived from the IBM MarketScan Research database, which reports on reimbursed private healthcare claims in the United States. The association between paternal comorbidities (defined as individual and combined measures) and genital malformations in male offspring was analyzed.RESULTS: Of 376,362 male births, 22% of fathers had at least one component of the metabolic syndrome (MetS ≥1) prior to conception. Totals of 2880 cases of cryptorchidism (0.77%) and 2651 cases of hypospadias (0.70%) were identified at birth. While 0.76% of sons born to fathers with no MetS components were diagnosed with cryptorchidism, 0.82% of sons with fathers with multiple MetS components had cryptorchidism. Similarly, 0.69% vs 0.88% of sons had hypospadias when fathers had 0 or 2+ components of MetS. After adjusting for maternal and paternal factors, the odds of a son diagnosed with hypospadias increased with two or more paternal MetS components (Odds ratio [95% confidence interval]: 1.27 [1.10 - 1.47]). Specific components of paternal MetS were not generally more associated with a son's genital malformations. When we performed a subgroup analysis where genital malformations were defined based on surgical correction, the association with hypospadias persisted.CONCLUSIONS: Fathers with multiple components of the metabolic syndrome in the preconception period were observed to be at increased risks for having sons born with hypospadias. The results support the association between a man's andrological and overall health. This article is protected by copyright. All rights reserved.
View details for DOI 10.1111/andr.13404
View details for PubMedID 36727635
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The impacts of ambient air pollution exposure during pregnancy on maternal and neonatal inflammatory biomarkers
MOSBY-ELSEVIER. 2023: AB119
View details for Web of Science ID 000991651900367
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Shorter maternal leukocyte telomere length following cesarean birth: Implications for future research
MOSBY-ELSEVIER. 2023: S456-S457
View details for Web of Science ID 000909337401260
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Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate.
HGG advances
2023; 4 (4): 100234
Abstract
Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n= 435), and subtype-specific risks for any cleft soft palate (CSP), (n= 259) and any cleft hard palate (CHP) (n= 125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p= 4.24*10-8) associated with CHP. One gene at this locus, angiopoietin-like 2 (ANGPTL2), plays a role in osteoblast differentiation. It is expressed both in craniofacial tissue of human embryos and developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p<5*10-6), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios for the 20 loci were most similar across all 3 groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either subtype. We also found nominal evidence of replication (p<0.05) for 22 SNPs previously associated with orofacial clefts. Our study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.
View details for DOI 10.1016/j.xhgg.2023.100234
View details for PubMedID 37719664
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Prefrontal activation in preschool children is associated with maternal adversity and child temperament: A preliminary fNIRS study of inhibitory control
DEVELOPMENTAL PSYCHOBIOLOGY
2023; 65 (1): e22351
Abstract
Exposure to adversity is a well-documented risk factor for cognitive, behavioral, and mental health problems. In fact, the consequences of adversity may be intergenerational. A growing body of research suggests that maternal exposures to adversity, including those prior to childbirth, are associated with offspring biobehavioral development. In a sample of 36 mothers and their preschool-age children (mean child age = 4.21 ± 0.92 years), we used functional near-infrared spectroscopy to replicate and extend this work to include brain activation during inhibitory control in young children. We found that measures of maternal exposure to adversity, including cumulative, childhood, and preconception exposures, were significantly and positively associated with activation in the right frontopolar prefrontal cortex (PFC) and in the left temporal and parietal clusters during inhibitory control. In addition, and consistent with previous findings, children's increased negative affect and decreased effortful control were associated with increased right PFC activation during inhibitory control. These findings provide preliminary evidence that maternal and dispositional risk factors are linked to alterations in PFC functioning during the preschool years. Children of mothers with a history of exposure to adversity, as well as children who are less temperamentally regulated, may require increased neural resources to meet the cognitive demands of inhibitory control.
View details for DOI 10.1002/dev.22351
View details for Web of Science ID 000895767900001
View details for PubMedID 36567657
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Antenatal wildfire smoke exposure and hypertensive disorders of pregnancy
MOSBY-ELSEVIER. 2023: S59-S60
View details for Web of Science ID 000909337400072
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The association of preconception paternal metabolic syndrome on early childhood emergency department visits and hospitalizations.
Andrology
2022
Abstract
Increasing preconception paternal comorbidity has been associated with adverse pregnancy outcomes. However, whether the father's health impacts the child after birth is uncertain.In the present study, we examined the association of preconception paternal metabolic syndrome status with childhood emergency department (ED) visits and hospitalizations.This is a longitudinal cohort study of children (295,355 boys and 278,735 girls) born to linked pairs of fathers and mothers in the United States between 2009 to 2016 within the IBM MarketScan® Research database. Associations between paternal and maternal metabolic syndrome (MetS) component diagnoses and subsequent hospitalizations and emergency department visits for offspring within the first two years of life were determined.35.5% (203,617/574,090) of children had at least one emergency room visit and 6.1% (35,141/574,090) of children had an inpatient admission. After adjustment, the odds of inpatient admission and emergency department visits increased in a dose-dependent fashion among fathers with higher comorbidities. Similar trends were seen for emergency department visit utilization.Increasing paternal preconception comorbidity is associated with a higher risk that a child requires emergency department and inpatient care in the first years of life. An opportunity exists to engage men in preconception counseling to optimize theirs and their offspring's health. This article is protected by copyright. All rights reserved.
View details for DOI 10.1111/andr.13370
View details for PubMedID 36542456
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Early prediction and longitudinal modeling of preeclampsia from multiomics.
Patterns (New York, N.Y.)
2022; 3 (12): 100655
Abstract
Preeclampsia is a complex disease of pregnancy whose physiopathology remains unclear. We developed machine-learning models for early prediction of preeclampsia (first 16weeks of pregnancy) and over gestation by analyzing six omics datasets from a longitudinal cohort of pregnant women. For early pregnancy, a prediction model using nine urine metabolites had the highest accuracy and was validated on an independent cohort (area under the receiver-operating characteristic curve [AUC]= 0.88, 95% confidence interval [CI] [0.76, 0.99] cross-validated; AUC= 0.83, 95% CI [0.62,1] validated). Univariate analysis demonstrated statistical significance of identified metabolites. An integrated multiomics model further improved accuracy (AUC= 0.94). Several biological pathways were identified including tryptophan, caffeine, and arachidonic acid metabolisms. Integration with immune cytometry data suggested novel associations between immune and proteomic dynamics. While further validation in a larger population is necessary, these encouraging results can serve as a basis for a simple, early diagnostic test for preeclampsia.
View details for DOI 10.1016/j.patter.2022.100655
View details for PubMedID 36569558
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Author Correction: Prediction of gestational age using urinary metabolites in term and preterm pregnancies.
Scientific reports
2022; 12 (1): 19753
View details for DOI 10.1038/s41598-022-23715-7
View details for PubMedID 36396676
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Assessing associations between residential proximity to greenspace and birth defects in the National Birth Defects Prevention Study.
Environmental research
2022: 114760
Abstract
BACKGROUND: Residential proximity to greenspace is associated with various health outcomes.OBJECTIVES: We estimated associations between maternal residential proximity to greenspace (based on an index of vegetation) and selected structural birth defects, including effect modification by neighborhood-level factors.METHODS: Data were from the National Birth Defects Prevention Study (1997-2011) and included 19,065 infants with at least one eligible birth defect (cases) and 8925 without birth defects (controls) from eight Centers throughout the United States. Maternal participants reported their addresses throughout pregnancy. Each address was systematically geocoded and residences around conception were linked to greenspace, US Census, and US Department of Agriculture data. Greenspace was estimated using the normalized difference vegetation index (NDVI); average maximum NDVI was estimated within 100 m and 500 m concentric buffers surrounding geocoded addresses to estimate residential NDVI. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals comparing those in the highest and lowest quartiles of residential NDVI and stratifying by rural/urban residence and neighborhood median income.RESULTS: After multivariable adjustment, for the 500 m buffer, inverse associations were observed for tetralogy of Fallot, secundum atrial septal defects, anencephaly, anotia/microtia, cleft lip ± cleft palate, transverse limb deficiency, and omphalocele, (aORs: 0.54-0.86). Results were similar for 100 m buffer analyses and similar patterns were observed for other defects, though results were not significant. Significant heterogeneity was observed after stratification by rural/urban for hypoplastic left heart, coarctation of the aorta, and cleft palate, with inverse associations only among participants residing in rural areas. Stratification by median income showed heterogeneity for atrioventricular and secundum atrial septal defects, anencephaly, and anorectal atresia, with inverse associations only among participants residing in a high-income neighborhood (aORs: 0.45-0.81).DISCUSSION: Our results suggest that perinatal residential proximity to more greenspace may contribute to a reduced risk of certain birth defects, especially among those living in rural or high-income neighborhoods.
View details for DOI 10.1016/j.envres.2022.114760
View details for PubMedID 36356662
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Reconciling Between Medication Orders and Medication Fills for Lupus in Pregnancy.
ACR open rheumatology
2022
Abstract
OBJECTIVE: Most studies consider either medications ordered or filled, but not both. Medication underuse based on filling data cannot necessarily be ascribed to patient nonadherence. Using both data sources, we quantified primary medication adherence in a cohort of prevalent systemic lupus erythematosus (SLE) pregnancies.METHODS: We identified 419 pregnancies in Kaiser Permanente Northern California in patients with prevalent SLE from 2011 to 2020. We calculated the number of physician-initiated orders or pharmacy-initiated reorders during pregnancy and a comparable 9-month window the year before (prepregnancy) and the proportion of orders ever filled and filled within 30days for hydroxychloroquine (HCQ), azathioprine, and corticosteroids. For pregnancies without an order or reorder, we identified the proportion with previous prescription fills overlapping into the respective study period.RESULTS: New orders for lupus medications were usually filled. HCQ was prescribed most often (45.8% pregnancies) and usually filled (89.7% in prepregnancy, 93.2% during pregnancy). The majority filled within 30days (80.5% prepregnancy, 83.3% pregnancy). Some pregnancies without new HCQ orders had continuous refills from prior orders; 53% of 2011-2015 pregnancies either had a new order or fill coverage from a previous period, compared to 63.2% of pregnancies delivering in 2016-2019. Corticosteroid fill frequencies were 90.6% in prepregnancy and 83.6% during pregnancy. Fewer patients used azathioprine; however, most new orders were filled (94.3% prepregnancy, 91.7% pregnancy). For azathioprine and corticosteroids, fill rates were modestly higher in prepregnancy compared to pregnancy.CONCLUSION: We observed that patients have high adherence to filling new orders for lupus medications, such as HCQ and azathioprine, in pregnancy.
View details for DOI 10.1002/acr2.11501
View details for PubMedID 36252776
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Differential newborn DNA methylation among individuals with complex congenital heart defects and childhood lymphoma.
Birth defects research
2022
Abstract
BACKGROUND: There is emerging evidence that children with complex congenital heart defects (CHDs) are at increased risk for childhood lymphoma, but the mechanisms underlying this association are unclear. Thus, we sought to evaluate the role of DNA methylation patterns on "CHD-lymphoma" associations.METHODS: From >3 million live births (1988-2004) in California registry linkages, we obtained newborn dried bloodspots from eight children with CHD-lymphoma through the California BioBank. We performed case-control epigenome-wide association analyses (EWAS) using two comparison groups with reciprocal discovery and validation to identify differential methylation associated with CHD-lymphoma.RESULTS: After correction for multiple testing at the discovery and validation stages, individuals with CHD-lymphoma had differential newborn methylation at six sites relative to two comparison groups. Our top finding was significant in both EWAS and indicates PPFIA1 cg25574765 was hypomethylated among individuals with CHD-lymphoma (mean beta=0.04) relative to both unaffected individuals (mean beta=0.93, p=1.5*10-12 ) and individuals with complex CHD (mean beta=0.95, p=3.8*10-8 ). PPFIA1 encodes a ubiquitously expressed liprin protein in one of the most commonly amplified regions in many cancers (11q13). Further, cg25574765 is a proposed marker of pre-eclampsia, a maternal CHD risk factor that has not been fully evaluated for lymphoma risk in offspring, and the tumor microenvironment that may drive immune cell malignancies.CONCLUSIONS: We identified associations between molecular changes present in the genome at birth and risk of childhood lymphoma among those with CHD. Our findings also highlight novel perinatal exposures that may underlie methylation changes in CHD predisposing to lymphoma.
View details for DOI 10.1002/bdr2.2105
View details for PubMedID 36226634
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LEVERAGING ELECTRONIC HEALTH RECORD DATA TO IDENTIFY PHENOTYPES ASSOCIATED WITH PREGNANCY LOSS MAY LEAD TO IMPROVED UNDERSTANDING OF RECURRENT PREGNANCY LOSS
ELSEVIER SCIENCE INC. 2022: E107
View details for Web of Science ID 000891804600262
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Preconception paternal comorbidities and offspring birth defects: Analysis of a large national data set.
Birth defects research
2022
Abstract
BACKGROUND: Despite the fact that the father contributes half the genome to a child, associations between paternal factors and birth defects are poorly understood.OBJECTIVES: To investigate the association between preconception paternal health and birth defects in the offspring.MATERIALS AND METHODS: We conducted analysis of a national cohort study utilizing the IBM Marketscan Research Database, which includes data on reimbursed private healthcare claims in the United States from 2007 to 2016. The potential association between paternal comorbidities, as measured by the components of metabolic syndrome (MetS), and any birth defect in the offspring was analyzed.RESULTS: Of the 712,774 live births identified, 21.2% of children were born to fathers with at least one component of the metabolic syndrome (MetS ≥1) prior to conception. Compared to infants born to fathers with no components of the metabolic syndrome, a modestly higher percentage of infants with cardiac birth defects were born to fathers with more components of MetS (MetS=1, OR [95% CI]: 1.07 [1.01-1.13]; MetS ≥2, 1.17 [1.08-1.26], in comparison to MetS=0) after adjusting for maternal and paternal factors. Similarly, a higher percentage of infants with respiratory defects were born to fathers with two or more components of metabolic syndrome (MetS ≥2, OR [95% CI]: 1.45 [1.22-1.71]).DISCUSSION AND CONCLUSION: In this private insurance claims-based study, we found that fathers with metabolic syndrome-related diseases before conception were at increased risk for having a child affected by birth defects, especially cardiac and respiratory defects, and this association was not influenced by paternal age or assessed maternal factors.
View details for DOI 10.1002/bdr2.2082
View details for PubMedID 36106720
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Hospital variation in extremely preterm birth.
Journal of perinatology : official journal of the California Perinatal Association
2022
Abstract
Given that regionalization of extremely preterm births (EPTBs) is associated with improved infant outcomes, we assessed between-hospital variation in EPTB stratified by hospital level of neonatal care, and determined the proportion of variance explained by differences in maternal and hospital factors.We assessed 7,046,253 births in California from 1997 to 2011, using hospital discharge, birth, and death certificate data. We estimated the association between maternal and hospital factors and EPTB using multivariable regression, calculated hospital-specific EPTB frequencies, and estimated between-hospital variances and median odds ratios, stratified by hospital level of care.Hospital frequencies of EPTB ranged from 0% to 2.5%. Between-hospital EPTB frequencies varied substantially, despite stratifying by hospital level of care and accounting for confounding factors.Our results demonstrate differences in EPTBs among hospitals with level 1 and 2 neonatal care, an area to target for future research and quality improvement.
View details for DOI 10.1038/s41372-022-01505-3
View details for PubMedID 36104499
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CIC missense variants contribute to susceptibility for spina bifida.
Human mutation
2022
Abstract
Neural Tube Defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to the cerebral folate deficiency syndrome by downregulating folate receptor 1 (FOLR1) expression. Given the importance of folate transport in neural tube formation, we hypothesized that CIC variants could contribute to increased risk for NTDs by depressing embryonic folate concentrations. In this study, we examined CIC variants from whole genome sequencing (WGS) data of 140 isolated spina bifida cases and identified 8 missense variants of CIC gene. We tested the pathogenicity of the observed variants through multiple in vitro experiments. We determined that CIC variants decreased FOLR1 protein level and planar cell polarity (PCP) pathway signaling in a human cell line (HeLa). In a murine cell line (NIH3T3), CIC loss of function variants down regulated PCP signaling. Taken together, this study provides evidence supporting CIC as a risk gene for human NTD. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/humu.24460
View details for PubMedID 36054333
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Primary hydroxychloroquine adherence in lupus pregnancy
WILEY. 2022: 125
View details for Web of Science ID 000859084400242
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Increased Risk of Preterm Delivery Phenotypes and Hypertensive Disorders of Pregnancy in First Deliveries of Patients with Systemic Vasculitis
WILEY. 2022: 1880-1881
View details for Web of Science ID 000877386501467
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Assessing the Association Between Hydroxychloroquine and Preeclampsia Risk in SLE Pregnancies Using Administrative Claims Data
WILEY. 2022: 1890-1893
View details for Web of Science ID 000877386501473
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Pregnancy Outcomes in a Diverse Lupus Cohort
WILEY. 2022: 1905-1906
View details for Web of Science ID 000877386501479
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Progressive Metabolic Abnormalities Associated with the Development of Neonatal Bronchopulmonary Dysplasia.
Nutrients
2022; 14 (17)
Abstract
Objective: To assess the longitudinal metabolic patterns during the evolution of bronchopulmonary dysplasia (BPD) development. Methods: A case-control dataset of preterm infants (<32-week gestation) was obtained from a multicenter database, including 355 BPD cases and 395 controls. A total of 72 amino acid (AA) and acylcarnitine (AC) variables, along with infants' calorie intake and growth outcomes, were measured on day of life 1, 7, 28, and 42. Logistic regression, clustering methods, and random forest statistical modeling were utilized to identify metabolic variables significantly associated with BPD development and to investigate their longitudinal patterns that are associated with BPD development. Results: A panel of 27 metabolic variables were observed to be longitudinally associated with BPD development. The involved metabolites increased from 1 predominant different AC by day 7 to 19 associated AA and AC compounds by day 28 and 16 metabolic features by day 42. Citrulline, alanine, glutamate, tyrosine, propionylcarnitine, free carnitine, acetylcarnitine, hydroxybutyrylcarnitine, and most median-chain ACs (C5:C10) were the most associated metabolites down-regulated in BPD babies over the early days of life, whereas phenylalanine, methionine, and hydroxypalmitoylcarnitine were observed to be up-regulated in BPD babies. Most calorie intake and growth outcomes revealed similar longitudinal patterns between BPD cases and controls over the first 6 weeks of life, after gestational adjustment. When combining with birth weight, the derived metabolic-based discriminative model observed some differences between those with and without BPD development, with c-statistics of 0.869 and 0.841 at day 7 and 28 of life on the test data. Conclusions: The metabolic panel we describe identified some metabolic differences in the blood associated with BPD pathogenesis. Further work is needed to determine whether these compounds could facilitate the monitoring and/or investigation of early-life metabolic status in the lung and other tissues for the prevention and management of BPD.
View details for DOI 10.3390/nu14173547
View details for PubMedID 36079804
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Exome sequencing identifies genetic variants in anophthalmia and microphthalmia.
American journal of medical genetics. Part A
2022
Abstract
Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.
View details for DOI 10.1002/ajmg.a.62874
View details for PubMedID 35716026
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Population-based associations between maternal pre-pregnancy body mass index and spontaneous and medically indicated preterm birth using restricted cubic splines in California.
Annals of epidemiology
2022
Abstract
The literature pertaining to risk of spontaneous preterm birth (sPTB) as related to body mass index (BMI), specifically high BMI, is conflicting.To assess the relationships between maternal pre-pregnancy BMI and sPTB separately for Non-Hispanic Whites, Non-Hispanic Blacks, Hispanics, and Asians.Population-based cohort study of mothers who delivered a singleton livebirth in California from 2007-2012. Associations between BMI and sPTB were estimated from Cox proportional hazard models. BMI was modelled with restricted cubic splines to account for non-linear relationships.A total of 2,645,950 births were included in the analysis, 135,357 (5.12%) in which the mother had a sPTB. Compared to mothers within the same race/ethnicity and a BMI of 26 kg/m2, all mothers with a BMI 28 kg/m2 or higher had significantly elevated adjusted hazard ratios sPTB. Asian mothers with a BMI between 16 to 25 kg/m2 had significantly decreased hazard ratios for sPTB while a of BMI 20 kg/m2 or less among Non-Hispanic White, Non-Hispanic Black, and Hispanic mothers showed increased hazard ratios.This study observed that mothers with high pre-pregnancy BMIs were more likely to experience sPTB across all race/ethnicities.
View details for DOI 10.1016/j.annepidem.2022.05.009
View details for PubMedID 35667536
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Prediction of gestational age using urinary metabolites in term and preterm pregnancies.
Scientific reports
2022; 12 (1): 8033
Abstract
Assessment of gestational age (GA) is key to provide optimal care during pregnancy. However, its accurate determination remains challenging in low- and middle-income countries, where access to obstetric ultrasound is limited. Hence, there is an urgent need to develop clinical approaches that allow accurate and inexpensive estimations of GA. We investigated the ability of urinary metabolites to predict GA at time of collection in a diverse multi-site cohort of healthy and pathological pregnancies (n=99) using a broad-spectrum liquid chromatography coupled with mass spectrometry (LC-MS) platform. Our approach detected a myriad of steroid hormones and their derivatives including estrogens, progesterones, corticosteroids, and androgens which were associated with pregnancy progression. We developed a restricted model that predicted GA with high accuracy using three metabolites (rho=0.87, RMSE=1.58weeks) that was validated in an independent cohort (n=20). The predictions were more robust in pregnancies that went to term in comparison to pregnancies that ended prematurely. Overall, we demonstrated the feasibility of implementing urine metabolomics analysis in large-scale multi-site studies and report a predictive model of GA with a potential clinical value.
View details for DOI 10.1038/s41598-022-11866-6
View details for PubMedID 35577875
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Leukocyte telomere dynamics across gestation in uncomplicated pregnancies and associations with stress.
BMC pregnancy and childbirth
2022; 22 (1): 381
Abstract
Short leukocyte telomere length is a biomarker associated with stress and morbidity in non-pregnant adults. Little is known, however, about maternal telomere dynamics in pregnancy. To address this, we examined changes in maternal leukocyte telomere length (LTL) during uncomplicated pregnancies and explored correlations with perceived stress.In this pilot study, maternal LTL was measured in blood collected from nulliparas who delivered live, term, singleton infants between 2012 and 2018 at a single institution. Participants were excluded if they had diabetes or hypertensive disease. Samples were collected over the course of pregnancy and divided into three time periods: < 200/7 weeks (Timepoint 1); 201/7 to 366/7 weeks (Timepoint 2); and 370/7 to 9-weeks postpartum (Timepoint 3). All participants also completed a survey assessing a multivariate profile of perceived stress at the time of enrollment in the first trimester. LTL was measured using quantitative polymerase chain reaction (PCR). Wilcoxon signed-rank tests were used to compare LTL differences within participants across all timepoint intervals. To determine whether mode of delivery affected LTL, we compared postpartum Timepoint 3 LTLs between participants who had vaginal versus cesarean birth. Secondarily, we evaluated the association of the assessed multivariate stress profile and LTL using machine learning analysis.A total of 115 samples from 46 patients were analyzed. LTL (mean ± SD), expressed as telomere to single copy gene (T/S) ratios, were: 1.15 ± 0.26, 1.13 ± 0.23, and 1.07 ± 0.21 for Timepoints 1, 2, and 3, respectively. There were no significant differences in LTL between Timepoints 1 and 2 (LTL T/S change - 0.03 ± 0.26, p = 0.39); 2 and 3 (- 0.07 ± 0.29, p = 0.38) or Timepoints 1 and 3 (- 0.07 ± 0.21, p = 0.06). Participants who underwent cesareans had significantly shorter postpartum LTLs than those who delivered vaginally (T/S ratio: 0.94 ± 0.12 cesarean versus 1.12 ± 0.21 vaginal, p = 0.01). In secondary analysis, poor sleep quality was the main stress construct associated with shorter Timepoint 1 LTLs (p = 0.02) and shorter mean LTLs (p = 0.03).In this cohort of healthy pregnancies, maternal LTLs did not significantly change across gestation and postpartum LTLs were shorter after cesarean than after vaginal birth. Significant associations between sleep quality and short LTLs warrant further investigation.
View details for DOI 10.1186/s12884-022-04693-0
View details for PubMedID 35501726
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Validation of the Assessment of Parent and Child Adversity (APCA) in Mothers and Young Children.
Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53
2022: 1-16
Abstract
Advancing understanding of how early adversity arises, manifests, and contributes to health difficulties depends on accurate measurement of children's experiences. In early life, exposure to adversity is often intertwined with that of one's caregivers. We present preliminary psychometric properties of a novel measure of adversity, the Assessment of Parent and Child Adversity (APCA), which simultaneously characterizes parents' and children's adversity.During pregnancy, women reported their past adverse experiences. When their children were ages 3-5 years (47% female), 97 mothers (71% White, 17% Hispanic/Latinx) completed the APCA, the Childhood Trauma Questionnaire, and the Benevolent Childhood Experiences scale. They reported their current symptoms of depression and anxiety and their child's emotional and behavioral problems. Using the APCA, we distinguished between maternal adversity during different life periods and obtained metrics of child witnessing of and direct exposure to adversity.The APCA demonstrated validity with other measures of maternal adverse experiences, maternal positive childhood experiences, and maternal symptoms of psychopathology. Children whose mothers experienced greater adversity, particularly in the prenatal period, had more emotional and behavioral problems, as did children who were directly exposed to greater adversity.The APCA has good usability and validity. Leveraging the ability of the APCA to distinguish between adversity during different life stages and originating from different sources, our findings highlight potentially distinct effects of different aspects of maternal and child adversity on difficulties in maternal and child mental health.
View details for DOI 10.1080/15374416.2022.2042696
View details for PubMedID 35500216
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Distance from home to birth hospital, transfer, and mortality in neonates with hypoplastic left heart syndrome in California.
Birth defects research
2022
Abstract
BACKGROUND: Prior studies report a lower risk of mortality among neonates with hypoplastic left heart syndrome (HLHS) who are born at a cardiac surgical center, but many neonates with HLHS are born elsewhere and transferred for repair. We investigated the associations between the distance from maternal home to birth hospital, the need for transfer after birth, sociodemographic factors, and mortality in infants with HLHS in California from 2006 to 2011.METHODS: We used linked data from two statewide databases to identify neonates for this study. Three groups were included in the analysis: "lived close/not transferred," "lived close/transferred," and "lived far/not transferred." We defined "lived close" versus "lived far" as 11miles, the median distance from maternal residence to birth hospital. Log-binomial regression models were used to identify the association between sociodemographic variables, distance to birth hospital and transfer. Cox proportional hazards models were used to identify the association between mortality and distance to birth hospital and transfer. Models were adjusted for sociodemographic variables.RESULTS: Infants in the lived close/not transferred and the lived close/transferred groups (vs. the lived far/not transferred group) were more likely to live in census tracts above the 75th percentile for poverty with relative risks 1.94 (95% confidence interval [CI] 1.41-2.68) and 1.21 (95% CI 1.05-1.40), respectively. Neonatal mortality was higher among the lived close/not transferred group compared with the lived far/not transferred group (hazard ratio 1.77, 95% CI 1.17-2.67).CONCLUSIONS: Infants born to mothers experiencing poverty were more likely to be born close to home. Infants with HLHS who were born close to home and not transferred to a cardiac center had a higher risk of neonatal mortality than infants who were delivered far from home and not transferred. Future studies should identify the barriers to delivery at a cardiac center for mothers experiencing poverty.
View details for DOI 10.1002/bdr2.2020
View details for PubMedID 35488460
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Gestational Dating by Urine Metabolic Profile at High Resolution Weekly Sampling Timepoints: Discovery and Validation.
Frontiers in molecular medicine
2022; 2: 844280
Abstract
Background: Pregnancy triggers longitudinal metabolic alterations in women to allow precisely-programmed fetal growth. Comprehensive characterization of such a "metabolic clock" of pregnancy may provide a molecular reference in relation to studies of adverse pregnancy outcomes. However, a high-resolution temporal profile of metabolites along a healthy pregnancy remains to be defined. Methods: Two independent, normal pregnancy cohorts with high-density weekly urine sampling (discovery: 478 samples from 19 subjects at California; validation: 171 samples from 10 subjects at Alabama) were studied. Urine samples were profiled by liquid chromatography-mass spectrometry (LC-MS) for untargeted metabolomics, which was applied for gestational age dating and prediction of time to delivery. Results: 5,473 urinary metabolic features were identified. Partial least-squares discriminant analysis on features with robust signals (n = 1,716) revealed that the samples were distributed on the basis of the first two principal components according to their gestational age. Pathways of bile secretion, steroid hormone biosynthesis, pantohenate, and CoA biosynthesis, benzoate degradation, and phenylpropanoid biosynthesis were significantly regulated, which was collectively applied to discover and validate a predictive model that accurately captures the chronology of pregnancy. With six urine metabolites (acetylcholine, estriol-3-glucuronide, dehydroepiandrosterone sulfate, α-lactose, hydroxyexanoy-carnitine, and l-carnitine), models were constructed based on gradient-boosting decision trees to date gestational age in high accordance with ultrasound results, and to accurately predict time to delivery. Conclusion: Our study characterizes the weekly baseline profile of the human pregnancy metabolome, which provides a high-resolution molecular reference for future studies of adverse pregnancy outcomes.
View details for DOI 10.3389/fmmed.2022.844280
View details for PubMedID 39086969
View details for PubMedCentralID PMC11285704
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A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study.
American journal of medical genetics. Part A
2022
Abstract
Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (Ndiscovery =3978; Nreplication =2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (Ndiscovery_TDT =440; Nreplication_TDT =275) and case-control analyses separately in infants (Ndiscovery_CCI =1635; Nreplication_CCI =990) and mothers (case status defined by infant; Ndiscovery_CCM =1703; Nreplication_CCM =1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (pdiscovery =4.08*10-9 ; preplication =2.44*10-4 ). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (pdiscovery =1.61*10-7 ; preplication =0.0016). Two other SNPs were suggestively associated (p<1*10-6 ) with OHD in only the discovery sample. In the case-control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds (*discovery <1*10-5 and preplication <0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (pdiscovery =1.42*10-6 ; preplication =0.04). Additional SNPs with pdiscovery <1*10-5 were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings.
View details for DOI 10.1002/ajmg.a.62759
View details for PubMedID 35451555
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A data-driven health index for neonatal morbidities.
iScience
2022; 25 (4): 104143
Abstract
Whereas prematurity is a major cause of neonatal mortality, morbidity, and lifelong impairment, the degree of prematurity is usually defined by the gestational age (GA) at delivery rather than by neonatal morbidity. Here we propose a multi-task deep neural network model that simultaneously predicts twelve neonatal morbidities, as the basis for a new data-driven approach to define prematurity. Maternal demographics, medical history, obstetrical complications, and prenatal fetal findings were obtained from linked birth certificates and maternal/infant hospitalization records for 11,594,786 livebirths in California from 1991 to 2012. Overall, our model outperformed traditional models to assess prematurity which are based on GA and/or birthweight (area under the precision-recall curve was 0.326 for our model, 0.229 for GA, and 0.156 for small for GA). These findings highlight the potential of using machine learning techniques to predict multiple prematurity phenotypes and inform clinical decisions to prevent, diagnose and treat neonatal morbidities.
View details for DOI 10.1016/j.isci.2022.104143
View details for PubMedID 35402862
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Frequency of cerclage in consecutive pregnancies of women with history of preterm birth.
Journal of neonatal-perinatal medicine
2022
Abstract
BACKGROUND: Serial cervical length screening is performed in women with a history of preterm birth to determine indication for cerclage placement. Our aim is to evaluate the frequency of cerclage placement in consecutive pregnancies with preterm birth history to determine whether performing serial cervical length screening for women with a history of late (34-36 6/7 weeks) spontaneous preterm birth (SPTB) should be reconsidered.METHODS: Retrospective evaluation of cerclage frequency and gestational age of delivery for consecutive singleton births for 69,671 women whose first birth was a SPTB.RESULTS: History of late SPTB was associated with a lower frequency of cerclage than history of early SPTB (0.83% vs 4.88%, OR 0.16, 95% CI 0.14-0.18). Rates of recurrent SPTB were lower for women with history of late SPTB than those with history of early SPTB (13.45%, 3.74% early, 9.71% late vs 20.69%, 9.12% early, 11.57% late).CONCLUSION: Women with a history of late PTB have a lower risk of recurrent PTB than those with a history of early PTB but constitute most of those undergoing serial cervical length screening for potential cerclage placement. Practice guidelines for screening women with a history of late PTB should be re-evaluated.
View details for DOI 10.3233/NPM-210834
View details for PubMedID 35404291
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Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study.
Annals of internal medicine
2022
Abstract
Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown.To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes.Nationwide prospective registry-based cohort study.Denmark from 1997 to 2016.All liveborn singletons from mothers without histories of diabetes or essential hypertension.Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings.Of 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073).Information on underlying disease status was limited.Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation.National Institutes of Health.
View details for DOI 10.7326/M21-4389
View details for PubMedID 35344380
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Exome sequencing identifies variants in infants with sacral agenesis.
Birth defects research
2022
Abstract
BACKGROUND: Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA.METHODS: Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child-parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child-father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced.RESULTS: Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N=1) and SPTBN5 (Spectrin Beta, Non-erythrocytic 5; N=2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X-linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children.CONCLUSIONS: To our knowledge, this is the first study reporting a possible association between ID1 and non-syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non-syndromic SA and provide data for future studies.
View details for DOI 10.1002/bdr2.1987
View details for PubMedID 35274497
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Multiomics Modeling of Preterm Birth in Low- and Middle-Income Countries
SPRINGER HEIDELBERG. 2022: 49-50
View details for Web of Science ID 000762765300020
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Early prediction of preeclampsia in pregnancy with cell-free RNA.
Nature
2022
Abstract
Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an opportunity to study the development of pregnancy-related complications in a non-invasive manner and to bridge gaps in clinical care1-4. Here we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia, a multi-organ syndrome that is the second largest cause of maternal death globally5. We find that changes in cfRNA gene expression between normotensive and preeclamptic mothers are marked and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial and immune cell types and tissues that reflect key aspects of preeclampsia physiology6-9, suggest new hypotheses for disease progression and correlate with maternal organ health. This enabled the identification and independent validation of a panel of 18 genes that when measured between 5 and 16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of preeclampsia long before clinical symptoms manifest themselves. Tests based on these observations could help predict and manage who is at risk for preeclampsia-an important objective for obstetric care10,11.
View details for DOI 10.1038/s41586-022-04410-z
View details for PubMedID 35140405
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Upstream oil and gas production and ambient air pollution in California.
The Science of the total environment
2022; 806 (Pt 1): 150298
Abstract
Prior studies have found that residential proximity to upstream oil and gas production is associated with increased risk of adverse health outcomes. Emissions of ambient air pollutants from oil and gas wells in the preproduction and production stages have been proposed as conferring risk of adverse health effects, but the extent of air pollutant emissions and resulting nearby pollution concentrations from wells is not clear.We examined the effects of upstream oil and gas preproduction (count of drilling sites) and production (total volume of oil and gas) activities on concentrations of five ambient air pollutants in California.We obtained data on approximately 1 million daily observations from 314 monitors in the EPA Air Quality System, 2006-2019, including daily concentrations of five routinely monitored ambient air pollutants: PM2.5, CO, NO2, O3, and VOCs. We obtained data on preproduction and production operations from Enverus and the California Geographic Energy Management Division (CalGEM) for all wells in the state. For each monitor and each day, we assessed exposure to upwind preproduction wells and total oil and gas production volume within 10 km. We used a panel regression approach in the analysis and fit adjusted fixed effects linear regression models for each pollutant, controlling for geographic, seasonal, temporal, and meteorological factors.We observed higher concentrations of PM2.5 and CO at monitors within 3 km of preproduction wells, NO2 at monitors at 1-2 km, and O3 at 2-4 km from the wells. Monitors with proximity to increased production volume observed higher concentrations of PM2.5, NO2, and VOCs within 1 km and higher O3 concentrations at 1-2 km. Results were robust to sensitivity analyses.Adjusting for geographic, meteorological, seasonal, and time-trending factors, we observed higher concentrations of ambient air pollutants at air quality monitors in proximity to preproduction wells within 4 km and producing wells within 2 km.
View details for DOI 10.1016/j.scitotenv.2021.150298
View details for PubMedID 34844318
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Upstream oil and gas production and ambient air pollution in California
SCIENCE OF THE TOTAL ENVIRONMENT
2022; 806
View details for DOI 10.1016/j.scitotenv.2021.150298
View details for Web of Science ID 000709731100002
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Cellular aging and pregnancy complications: Examining maternal leukocyte telomere length in two diverse cohorts.
MOSBY-ELSEVIER. 2022: S646
View details for Web of Science ID 000737459401371
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Revealing the impact of lifestyle stressors on the risk of adverse pregnancy outcomes with multitask machine learning.
Frontiers in pediatrics
2022; 10: 933266
Abstract
Psychosocial and stress-related factors (PSFs), defined as internal or external stimuli that induce biological changes, are potentially modifiable factors and accessible targets for interventions that are associated with adverse pregnancy outcomes (APOs). Although individual APOs have been shown to be connected to PSFs, they are biologically interconnected, relatively infrequent, and therefore challenging to model. In this context, multi-task machine learning (MML) is an ideal tool for exploring the interconnectedness of APOs on the one hand and building on joint combinatorial outcomes to increase predictive power on the other hand. Additionally, by integrating single cell immunological profiling of underlying biological processes, the effects of stress-based therapeutics may be measurable, facilitating the development of precision medicine approaches.Objectives: The primary objectives were to jointly model multiple APOs and their connection to stress early in pregnancy, and to explore the underlying biology to guide development of accessible and measurable interventions.Materials and Methods: In a prospective cohort study, PSFs were assessed during the first trimester with an extensive self-filled questionnaire for 200 women. We used MML to simultaneously model, and predict APOs (severe preeclampsia, superimposed preeclampsia, gestational diabetes and early gestational age) as well as several risk factors (BMI, diabetes, hypertension) for these patients based on PSFs. Strongly interrelated stressors were categorized to identify potential therapeutic targets. Furthermore, for a subset of 14 women, we modeled the connection of PSFs to the maternal immune system to APOs by building corresponding ML models based on an extensive single cell immune dataset generated by mass cytometry time of flight (CyTOF).Results: Jointly modeling APOs in a MML setting significantly increased modeling capabilities and yielded a highly predictive integrated model of APOs underscoring their interconnectedness. Most APOs were associated with mental health, life stress, and perceived health risks. Biologically, stressors were associated with specific immune characteristics revolving around CD4/CD8 T cells. Immune characteristics predicted based on stress were in turn found to be associated with APOs.Conclusions: Elucidating connections among stress, multiple APOs simultaneously, and immune characteristics has the potential to facilitate the implementation of ML-based, individualized, integrative models of pregnancy in clinical decision making. The modifiable nature of stressors may enable the development of accessible interventions, with success tracked through immune characteristics.
View details for DOI 10.3389/fped.2022.933266
View details for PubMedID 36582513
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Maternal stress and its consequences - biological strain.
American journal of perinatology
2022
Abstract
Understanding the role of stress in pregnancy and its consequences is important, particularly given documented associations between maternal stress and preterm birth and other pathologic outcomes. Physical and psychological stressors can elicit the same biological responses, known as biological strain. Chronic stressors, like poverty and racism (race-based discriminatory treatment), may create a legacy or trajectory of biological strain that no amount of coping can relieve in the absence of larger-scale socio-behavioral or societal changes. An integrative approach that takes into consideration simultaneously social and biological determinants of stress may provide the best insights into risk for preterm birth. The most successful computational approaches and the most predictive machine-learning models are likely to be those that combine information about the stressors and the biological strain (for example, as measured by different omics) experienced during pregnancy.
View details for DOI 10.1055/a-1798-1602
View details for PubMedID 35292943
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HOSPITAL VARIATION IN EXTREMELY PRETERM BIRTH
BMJ PUBLISHING GROUP. 2022: 215
View details for DOI 10.1136/jim-2022-WRMC.205
View details for Web of Science ID 000737295900226
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Perinatal infection, inflammation, preterm birth, and brain injury: A review with proposals for future investigations.
Experimental neurology
2022: 113988
Abstract
Preterm newborns are exposed to several risk factors for developing brain injury. Clinical studies have suggested that the presence of intrauterine infection is a consistent risk factor for preterm birth and white matter injury. Animal models have confirmed these associations by identifying inflammatory cascades originating at the maternofetal interface that penetrate the fetal blood-brain barrier and result in brain injury. Acquired diseases of prematurity further potentiate the risk for cerebral injury. Systems biology approaches incorporating ante- and post-natal risk factors and analyzing omic and multiomic data using machine learning are promising methodologies for further elucidating biologic mechanisms of fetal and neonatal brain injury.
View details for DOI 10.1016/j.expneurol.2022.113988
View details for PubMedID 35081400
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Systems biology analysis of human genomes points to key pathways conferring spina bifida risk.
Proceedings of the National Academy of Sciences of the United States of America
1800; 118 (51)
Abstract
Spina bifida (SB) is a debilitating birth defect caused by multiple gene and environment interactions. Though SB shows non-Mendelian inheritance, genetic factors contribute to an estimated 70% of cases. Nevertheless, identifying human mutations conferring SB risk is challenging due to its relative rarity, genetic heterogeneity, incomplete penetrance, and environmental influences that hamper genome-wide association studies approaches to untargeted discovery. Thus, SB genetic studies may suffer from population substructure and/or selection bias introduced by typical candidate gene searches. We report a population based, ancestry-matched whole-genome sequence analysis of SB genetic predisposition using a systems biology strategy to interrogate 298 case-control subject genomes (149 pairs). Genes that were enriched in likely gene disrupting (LGD), rare protein-coding variants were subjected to machine learning analysis to identify genes in which LGD variants occur with a different frequency in cases versus controls and so discriminate between these groups. Those genes with high discriminatory potential for SB significantly enriched pathways pertaining to carbon metabolism, inflammation, innate immunity, cytoskeletal regulation, and essential transcriptional regulation consistent with their having impact on the pathogenesis of human SB. Additionally, an interrogation of conserved noncoding sequences identified robust variant enrichment in regulatory regions of several transcription factors critical to embryonic development. This genome-wide perspective offers an effective approach to the interrogation of coding and noncoding sequence variant contributions to rare complex genetic disorders.
View details for DOI 10.1073/pnas.2106844118
View details for PubMedID 34916285
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Modeling complex effects of exposure to particulate matter and extreme heat during pregnancy on congenital heart defects: A U.S. population-based case-control study in the National Birth Defects Prevention Study.
The Science of the total environment
2021: 152150
Abstract
BACKGROUND/OBJECTIVE: Research suggests gestational exposure to particulate matter ≤2.5 mum (PM2.5) and extreme heat may independently increase risk of birth defects. We investigated whether duration of gestational extreme heat exposure modifies associations between PM2.5 exposure and specific congenital heart defects (CHDs). We also explored nonlinear exposure-outcome relationships.METHODS: We identified CHD case children (n = 2824) and non-malformed live-birth control children (n = 4033) from pregnancies ending between 1999 and 2007 in the National Birth Defects Prevention Study, a U.S. population-based multicenter case-control study. We assigned mothers 6-week averages of PM2.5 exposure during the cardiac critical period (postconceptional weeks 3-8) using the closest monitor within 50 km of maternal residence. We assigned a count of extreme heat days (EHDs, days above the 90th percentile of daily maximum temperature for year, season, and weather station) during this period using the closest weather station. Using generalized additive models, we explored logit-nonlinear exposure-outcome relationships, concluding logistic models were reasonable. We estimated joint effects of PM2.5 and EHDs on six CHDs using logistic regression models adjusted for mean dewpoint and maternal age, education, and race/ethnicity. We assessed multiplicative and additive effect modification.RESULTS: Conditional on the highest observed EHD count (15) and at least one critical period day during spring/summer, each 5 mug/m3 increase in average PM2.5 exposure was significantly associated with perimembranous ventricular septal defects (VSDpm; OR: 1.54 [95% CI: 1.01, 2.41]). High EHD counts (8+) in the same population were positively, but non-significantly, associated with both overall septal defects and VSDpm. Null or inverse associations were observed for lower EHD counts. Multiplicative and additive effect modification estimates were consistently positive in all septal models.CONCLUSIONS: Results provide limited evidence that duration of extreme heat exposure modifies the PM2.5-septal defects relationship. Future research with enhanced exposure assessment and modeling techniques could clarify these relationships.
View details for DOI 10.1016/j.scitotenv.2021.152150
View details for PubMedID 34864029
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Early-pregnancy prediction of risk for pre-eclampsia using maternal blood leptin/ceramide ratio: discovery and confirmation.
BMJ open
2021; 11 (11): e050963
Abstract
OBJECTIVE: This study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation.STUDY DESIGN: Retrospective discovery and longitudinal confirmation.SETTING: Maternity units from two US hospitals.PARTICIPANTS: Six previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation.OUTCOME MEASURES: Biomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays.RESULTS: Our discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks' gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation.CONCLUSIONS: Our study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.
View details for DOI 10.1136/bmjopen-2021-050963
View details for PubMedID 34824115
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Trends in eclampsia in the United States, 2009-2017: a population-based study.
Journal of hypertension
2021
Abstract
BACKGROUND: Reducing the prevalence of eclampsia, a major cause of maternal and perinatal morbidity, is a maternal health priority. However, sparse data exist examining trends in the USA prevalence of eclampsia.OBJECTIVE: The aim of this study was to assess temporal trends in the prevalence of eclampsia among live births in the United States from 2009 to 2017.STUDY DESIGN: This population-based cross-sectional study included live births in 41 USA states and the District of Columbia between 2009 and 2017. The prevalence of eclampsia among all women, women with chronic hypertension and hypertensive disorders of pregnancy were reported by 1000 live births. Risk ratios adjusted for maternal characteristics were used to assess temporal trends.RESULTS: Of 27 866 714 live births between 2009 and 2017, 83 000 (0.30%) were associated with eclampsia. The adjusted risk of eclampsia decreased 10% during the 7 most recent years of the cohort, with an adjusted risk ratio of 0.90 [95% confidence interval (95% CI): 0.87-0.93] in 2017 relative to 2009. Relative to 2009, the adjusted risk of eclampsia in 2017 was substantially lower among women with chronic hypertension (adjusted risk ratio: 0.51; 95% CI: 0.46-0.57) and women with hypertensive pregnancy disorders (adjusted risk ratio: 0.43; 95% CI: 0.40-0.47). Among nonhypertensive women, there was a slight increase in the adjusted risk of eclampsia in 2017 relative to 2009 (adjusted risk ratio: 1.14; 95% CI: 1.10-1.17).CONCLUSION: Despite reductions in the eclampsia prevalence among women with chronic hypertension and hypertensive disorders of pregnancy, public health initiatives are needed to reduce the overall eclampsia prevalence, especially in nonhypertensive women.
View details for DOI 10.1097/HJH.0000000000003037
View details for PubMedID 34751169
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Newborn screen metabolic panels reflect the impact of common disorders of pregnancy.
Pediatric research
2021
Abstract
BACKGROUND: Hypertensive disorders of pregnancy and maternal diabetes profoundly affect fetal and newborn growth, yet disturbances in intermediate metabolism and relevant mediators of fetal growth alterations remain poorly defined. We sought to determine whether there are distinct newborn screen metabolic patterns among newborns affected by maternal hypertensive disorders or diabetes in utero.METHODS: A retrospective observational study investigating distinct newborn screen metabolites in conjunction with data linked to birth and hospitalization records in the state of California between 2005 and 2010.RESULTS: A total of 41,333 maternal-infant dyads were included. Infants of diabetic mothers demonstrated associations with short-chain acylcarnitines and free carnitine. Infants born to mothers with preeclampsia with severe features and chronic hypertension with superimposed preeclampsia had alterations in acetylcarnitine, free carnitine, and ornithine levels. These results were further accentuated by size for gestational age designations.CONCLUSIONS: Infants of diabetic mothers demonstrate metabolic signs of incomplete beta oxidation and altered lipid metabolism. Infants of mothers with hypertensive disorders of pregnancy carry analyte signals that may reflect oxidative stress via altered nitric oxide signaling. The newborn screen analyte composition is influenced by the presence of these maternal conditions and is further associated with the newborn size designation at birth.IMPACT: Substantial differences in newborn screen analyte profiles were present based on the presence or absence of maternal diabetes or hypertensive disorder of pregnancy and this finding was further influenced by the newborn size designation at birth. The metabolic health of the newborn can be examined using the newborn screen and is heavily impacted by the condition of the mother during pregnancy. Utilizing the newborn screen to identify newborns affected by common conditions of pregnancy may help relate an infant's underlying biological disposition with their clinical phenotype allowing for greater risk stratification and intervention.
View details for DOI 10.1038/s41390-021-01753-7
View details for PubMedID 34671094
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Black swans and ambitious overgeneralization in newborn intensive care.
Pediatric research
2021
View details for DOI 10.1038/s41390-021-01771-5
View details for PubMedID 34601493
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THE ASSOCIATION OF PRECONCEPTION PATERNAL METABOLIC SYNDROME ON EARLY CHILDHOOD EMERGENCY DEPARTMENT VISITS AND HOSPITALIZATION: ANALYSIS OF US CLAIMS DATA
LIPPINCOTT WILLIAMS & WILKINS. 2021: E526
View details for Web of Science ID 000693688500311
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Homelessness in pregnancy: perinatal outcomes.
Journal of perinatology : official journal of the California Perinatal Association
2021
Abstract
OBJECTIVE: Investigate the association between maternal homelessness at the time of delivery and perinatal outcomes, with a focus on neonatal health outcomes.STUDY DESIGN: Population-based cohort using California's statewide database included 1,520,253 women with linked birth and maternal discharge data, 2008-2012. Multivariable analysis assessed homelessness at time of delivery on perinatal outcomes, preterm delivery, and neonatal intensive care unit admission.RESULT: A total of 672 women (0.05%) were homeless at the time of delivery. Homelessness was associated with premature delivery at multiple gestational age cutoffs (34w0d-36w6d; 32w0d-33w6d; 28w0d-31w6d; <28w0d) (range of aORs:1.62-2.19), and neonatal intensive care unit admission (aOR=1.66, 95% CI:1.31-2.09). Among term infants, homelessness remained associated with increased odds of neonatal intensive care unit admission (aOR=1.84, 95% CI:1.34-2.53), low birthweight (aOR=1.99, 95% CI:1.36-2.90), neonatal abstinence syndrome (aOR=2.13, 95% CI:1.35-2.53), hypoxic-ischemic encephalopathy (aOR=14.38, 95% CI:3.90-53.01), and necrotizing enterocolitis (aOR=14.94, 95% CI:2.68-83.20).CONCLUSION: Homelessness in pregnancy was associated with adverse perinatal outcomes including increased odds of preterm delivery across all gestational ages, and increased risk of neonatal intensive care unit admission and low birth weight independent of preterm delivery.
View details for DOI 10.1038/s41372-021-01187-3
View details for PubMedID 34404925
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Associations between wildfire smoke exposure during pregnancy and risk of preterm birth in California.
Environmental research
2021: 111872
Abstract
There is limited population-scale evidence on the burden of exposure to wildfire smoke during pregnancy and its impacts on birth outcomes. In order to investigate this relationship, data on every singleton birth in California 2006-2012 were combined with satellite-based estimates of wildfire smoke plume boundaries and high-resolution gridded estimates of surface PM2.5 concentrations and a regression model was used to estimate associations with preterm birth risk. Results suggest that each additional day of exposure to any wildfire smoke during pregnancy was associated with an 0.49 % (95 % CI: 0.41-0.59 %) increase in risk of preterm birth (<37 weeks). At sample median smoke exposure (7 days) this translated to a 3.4 % increase in risk, relative to an unexposed mother. Estimates by trimester suggest stronger associations with exposure later in pregnancy and estimates by smoke intensity indicate that observed associations were driven by higher intensity smoke-days. Exposure to low intensity smoke-days had no association with preterm birth while an additional medium (smoke PM2.5 5-10 mug/m3) or high (smoke PM2.5 > 10 mug/m3) intensity smoke-day was associated with an 0.95 % (95 % CI: 0.47-1.42 %) and 0.82 % (95 % CI: 0.41-1.24 %) increase in preterm risk, respectively. In contrast to previous findings for other pollution types, neither exposure to smoke nor the relative impact of smoke on preterm birth differed by race/ethnicity or income in our sample. However, impacts differed greatly by baseline smoke exposure, with mothers in regions with infrequent smoke exposure experiencing substantially larger impacts from an additional smoke-day than mothers in regions where smoke is more common. We estimate 6,974 (95 % CI: 5,513-8,437) excess preterm births attributable to wildfire smoke exposure 2007-2012, accounting for 3.7 % of observed preterm births during this period. Our findings have important implications for understanding the costs of growing wildfire smoke exposure, and for understanding the benefits of smoke mitigation measures.
View details for DOI 10.1016/j.envres.2021.111872
View details for PubMedID 34403668
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Exome sequencing of child-parent trios with bladder exstrophy: Findings in 26 children.
American journal of medical genetics. Part A
2021
Abstract
Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency≤0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect.
View details for DOI 10.1002/ajmg.a.62439
View details for PubMedID 34355505
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Stillbirth as left truncation for early neonatal death in California, 1989-2015: a time-series study.
BMC pregnancy and childbirth
2021; 21 (1): 478
Abstract
BACKGROUND: Some scholars posit that attempts to avert stillbirth among extremely preterm gestations may result in a live birth but an early neonatal death. The literature, however, reports no empirical test of this potential form of left truncation. We examine whether annual cohorts delivered at extremely preterm gestational ages show an inverse correlation between their incidence of stillbirth and early neonatal death.METHODS: We retrieved live birth and infant death information from the California Linked Birth and Infant Death Cohort Files for years 1989 to 2015. We defined the extremely preterm period as delivery from 22 to <28weeks of gestation and early neonatal death as infant death at less than 7days of life. We calculated proportions of stillbirth and early neonatal death separately by cohort year, race/ethnicity, and sex. Our correlational analysis controlled for well-documented declines in neonatal mortality over time.RESULTS: California reported 89,276 extremely preterm deliveries (live births and stillbirths) to Hispanic, non-Hispanic (NH) Black, and NH white mothers from 1989 to 2015. Findings indicate an inverse correlation between stillbirth and early neonatal death in the same cohortyear (coefficient: -0.27, 95% CI of -0.11; -0.42). Results remain robust to alternative specifications and falsification tests.CONCLUSIONS: Findings support the notion that cohorts with an elevated risk of stillbirth also show a reduced risk of early neonatal death among extremely preterm deliveries. Results add to the evidence base that selection in utero may influence the survival characteristics of live-born cohorts.
View details for DOI 10.1186/s12884-021-03852-z
View details for PubMedID 34215208
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Noninvasive Prediction of Preeclampsia in Pregnancy with Circulating RNA.
SPRINGER HEIDELBERG. 2021: 75A
View details for Web of Science ID 000675441000068
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Multi-Omic, Longitudinal Profile of Third-Trimester Pregnancies Identifies a Molecular Switch That Predicts the Onset of Labor.
SPRINGER HEIDELBERG. 2021: 233A-234A
View details for Web of Science ID 000675441000486
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Association of Gestational Age with Postpartum Hemorrhage: An International Cohort Study
ANESTHESIOLOGY
2021; 134 (6): 874-886
Abstract
Risk factors for postpartum hemorrhage, such as chorioamnionitis and multiple gestation, have been identified in previous epidemiologic studies. However, existing data describing the association between gestational age at delivery and postpartum hemorrhage are conflicting. The aim of this study was to assess the association between gestational age at delivery and postpartum hemorrhage.The authors conducted a population-based retrospective cohort study of women who underwent live birth delivery in Sweden between 2014 and 2017 and in California between 2011 and 2015. The primary exposure was gestational age at delivery. The primary outcome was postpartum hemorrhage, classified using International Classification of Diseases, Ninth Revision-Clinical Modification codes for California births and a blood loss greater than 1,000 ml for Swedish births. The authors accounted for demographic and obstetric factors as potential confounders in the analyses.The incidences of postpartum hemorrhage in Sweden (23,323/328,729; 7.1%) and in California (66,583/2,079,637; 3.2%) were not comparable. In Sweden and California, the incidence of postpartum hemorrhage was highest for deliveries between 41 and 42 weeks' gestation (7,186/75,539 [9.5%] and 8,921/160,267 [5.6%], respectively). Compared to deliveries between 37 and 38 weeks, deliveries between 41 and 42 weeks had the highest adjusted odds of postpartum hemorrhage (1.62 [95% CI, 1.56 to 1.69] in Sweden and 2.04 [95% CI, 1.98 to 2.09] in California). In both cohorts, the authors observed a nonlinear (J-shaped) association between gestational age and postpartum hemorrhage risk, with 39 weeks as the nadir. In the sensitivity analyses, similar findings were observed among cesarean deliveries only, when postpartum hemorrhage was classified only by International Classification of Diseases, Tenth Revision-Clinical Modification codes, and after excluding women with abnormal placentation disorders.The postpartum hemorrhage incidence in Sweden and California was not comparable. When assessing a woman's risk for postpartum hemorrhage, clinicians should be aware of the heightened odds in women who deliver between 41 and 42 weeks' gestation.
View details for DOI 10.1097/ALN.0000000000003730
View details for Web of Science ID 000648691100012
View details for PubMedID 33760074
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Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset.
Science translational medicine
2021; 13 (592)
Abstract
Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 * 10-40, N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 * 10-7, N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies.
View details for DOI 10.1126/scitranslmed.abd9898
View details for PubMedID 33952678
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Trends in Spontaneous and Medically Indicated Preterm Birth in Twins versus Singletons: A California Cohort 2007 to 2011.
American journal of perinatology
2021
Abstract
OBJECTIVE: The study aimed to describe preterm birth (PTB) rates, subtypes, and risk factors in twins compared with singletons to better understand reasons for the decline in PTB rate between 2007 and 2011.STUDY DESIGN: This was a retrospective population-based analysis using the California linked birth certificates and maternal-infant hospital discharge records from 2007 to 2011. The main outcomes were overall, spontaneous (following spontaneous labor or preterm premature rupture of membranes), and medically indicated PTB at various gestational age categories: <37, <32, and 34 to 36 weeks in twins and singletons.RESULTS: Among the 2,290,973 singletons and 28,937 twin live births pairs included, overall PTB <37 weeks decreased by 8.46% (6.77-6.20%) in singletons and 7.17% (55.31-51.35%) in twins during the study period. In singletons, this was primarily due to a 24.91% decrease in medically indicated PTB with almost no change in spontaneous PTB, whereas in twins indicated PTB declined 7.02% and spontaneous PTB by 7.39%.CONCLUSION: Recent declines in PTB in singletons appear to be largely due to declines in indicated PTB, whereas both spontaneous and indicated PTB declined in twins.KEY POINTS: · The declines in PTB noted between 2006 and 2014 occurred in both singleton and twins.. · Declines were mostly in medically indicated PTB.. · Interventions proposed as causing the declines in singletons would not apply to twins..
View details for DOI 10.1055/s-0041-1729161
View details for PubMedID 33934321
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Nitrate in Drinking Water during Pregnancy and Spontaneous Preterm Birth: A Retrospective Within-Mother Analysis in California.
Environmental health perspectives
2021; 129 (5): 57001
Abstract
BACKGROUND: Nitrate is a widespread groundwater contaminant and a leading cause of drinking water quality violations in California. Associations between nitrate exposure and select adverse birth outcomes have been suggested, but few studies have examined gestational exposures to nitrate and risk of preterm birth (before 37 wk gestation).OBJECTIVE: We investigated the association between elevated nitrate in drinking water and spontaneous preterm birth through a within-mother retrospective cohort study of births in California.METHODS: We acquired over 6 million birth certificate records linked with Office of Statewide Health Planning and Development hospital discharge data for California births from 2000-2011. We used public water system monitoring records to estimate nitrate concentrations in drinking water for each woman's residence during gestation. After exclusions, we constructed a sample of 1,443,318 consecutive sibling births in order to conduct a within-mother analysis. We used separate conditional logistic regression models to estimate the odds of preterm birth at 20-31 and 32-36 wk, respectively, among women whose nitrate exposure changed between consecutive pregnancies.RESULTS: Spontaneous preterm birth at 20-31 wk was increased in association with tap water nitrate concentrations during pregnancy of 5 to <10mg/L [odds ratio (OR)=1.47; 95% confidence interval (CI): 1.29, 1.67] and ≥10mg/L (OR=2.52; 95% CI: 1.49, 4.26) compared with <5mg/L (as nitrogen). Corresponding estimates for spontaneous preterm birth at 32-36 wk were positive but close to the null for 5 to <10mg/L nitrate (OR=1.08; 95% CI: 1.02, 1.15) and for ≥10mg/L nitrate (OR=1.05; 95% CI: 0.85, 1.31) vs. <5mg/L nitrate. Our findings were similar in several secondary and sensitivity analyses, including in a conventional individual-level design.DISCUSSION: The results suggest that nitrate in drinking water is associated with increased odds of spontaneous preterm birth. Notably, we estimated modestly increased odds associated with tap water nitrate concentrations of 5 to <10mg/L (below the federal drinking water standard of 10mg/L) relative to <5mg/L. https://doi.org/10.1289/EHP8205.
View details for DOI 10.1289/EHP8205
View details for PubMedID 33949893
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Greenspace, Air Pollution, Neighborhood Factors, and Preeclampsia in a Population-Based Case-Control Study in California
INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH
2021; 18 (10)
Abstract
To investigate preeclampsia etiologies, we examined relationships between greenspace, air pollution, and neighborhood factors. Data were from hospital records and geocoded residences of 77,406 women in San Joaquin Valley, California from 2000 to 2006. Preeclampsia was divided into mild, severe, or superimposed onto pre-existing hypertension. Greenspace within 100 and 500 m residential buffers was estimated from satellite data using normalized difference vegetation index (NDVI). Air quality data were averaged over pregnancy from daily 24-h averages of nitrogen dioxide, particulate matter <10 µm (PM10) and <2.5 µm (PM2.5), and carbon monoxide. Neighborhood socioeconomic (SES) factors included living below the federal poverty level and median annual income using 2000 US Census data. Odds of preeclampsia were estimated using logistic regression. Effect modification was assessed using Wald tests. More greenspace (500 m) was inversely associated with superimposed preeclampsia (OR = 0.57). High PM2.5 and low SES were associated with mild and severe preeclampsia. We observed differences in associations between greenspace (500 m) and superimposed preeclampsia by neighborhood income and between greenspace (500 m) and severe preeclampsia by PM10, overall and among those living in higher SES neighborhoods. Less greenspace, high particulate matter, and high-poverty/low-income neighborhoods were associated with preeclampsia, and effect modification was observed between these exposures. Further research into exposure combinations and preeclampsia is warranted.
View details for DOI 10.3390/ijerph18105127
View details for Web of Science ID 000654887800001
View details for PubMedID 34066190
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The relationship between air pollutants and maternal socioeconomic factors on preterm birth in California urban counties.
Journal of exposure science & environmental epidemiology
2021
Abstract
BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality in the U.S. and disparities among racial and ethnic groups persist. While etiologies of preterm birth have not been fully elucidated, it is probable that environmental and social factors play a role.OBJECTIVE: We hypothesized that there is an interactive association between exposure to fine particulate matter (PM2.5) or ozone (O3) and neighborhood socioeconomic factors that increase the risk of preterm birth.METHODS: We conducted a retrospective study using geocoded birth certificate data between 2007 and 2011, daily ambient air quality data on PM2.5 and O3, and American Community Survey (2007-2011 5-year estimates) data to assess census tract-level socioeconomic factors in California urban counties.RESULTS: Our study found a small positive association between maternal exposures to PM2.5 and O3 and preterm birth that varied by gestational exposure period. In mixed-effects models, we found an increase in the risk of preterm birth for a one-unit change in PM2.5 averaged across the entire pregnancy (AOR=1.02, 95% CI: 1.01, 1.02) and O3 during 3-months pre-pregnancy (AOR=1.03, 95% CI: 1.02, 1.04). Interaction between census tract-level factors and air pollutants showed an increase in the risk of preterm birth among mothers living in higher socioeconomic areas, though, a fixed cohort bias sensitivity analysis showed these associations were not significant.SIGNIFICANCE: These findings substantiate previous studies that showed associations between air pollution and preterm birth, even as pollution levels have decreased. This study has important implications for policy decisions and may help inform research on potential mechanisms of preterm birth.
View details for DOI 10.1038/s41370-021-00323-7
View details for PubMedID 33859340
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African American Unemployment and the Disparity in Periviable Births.
Journal of racial and ethnic health disparities
2021
Abstract
Periviable infants (i.e., born before 26 complete weeks of gestation) represent fewer than .5% of births in the US but account for 40% of infant mortality and 20% of billed hospital obstetric costs. African American women contribute about 14% of live births in the US, but these include nearly a third of the country's periviable births. Consistent with theory and with periviable births among other race/ethnicity groups, males predominate among African American periviable births in stressed populations. We test the hypothesis that the disparity in periviable male births among African American and non-Hispanic white populations responds to the African American unemployment rate because that indicator not only traces, but also contributes to, the prevalence of stress in the population. We use time-series methods that control for autocorrelation including secular trends, seasonality, and the tendency to remain elevated or depressed after high or low values. The racial disparity in male periviable birth increases by 4.45% for each percentage point increase in the unemployment rate of African Americans above its expected value. We infer that unemployment-a population stressor over which our institutions exercise considerable control-affects the disparity between African American and non-Hispanic white periviable births in the US.
View details for DOI 10.1007/s40615-021-01022-7
View details for PubMedID 33783756
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Understanding how biologic and social determinants affect disparities in preterm birth and outcomes of preterm infants in the NICU.
Seminars in perinatology
2021: 151408
Abstract
To understand the disparities in spontaneous preterm birth (sPTB) and/or its outcomes, biologic and social determinants as well as healthcare practice (such as those in neonatal intensive care units) should be considered. They have been largely intractable and remain obscure in most cases, despite a myriad of identified risk factors for and causes of sPTB. We still do not know how they might actually affect and lead to the different outcomes at different gestational ages and if they are independent of NICU practices. Here we describe an integrated approach to study the interplay between the genome and exposome, which may drive biochemistry and physiology, with health disparities.
View details for DOI 10.1016/j.semperi.2021.151408
View details for PubMedID 33875265
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Interdisciplinary Data Science to Advance Environmental Health Research and Improve Birth Outcomes.
Environmental research
2021: 111019
Abstract
Rates of preterm birth and low birthweight continue to rise in the United States and pose a significant public health problem. Although a variety of environmental exposures are known to contribute to these and other adverse birth outcomes, there has been a limited success in developing policies to prevent these outcomes. A better characterization of the complexities between multiple exposures and their biological responses can provide the evidence needed to inform public health policy and strengthen preventative population-level interventions. In order to achieve this, we encourage the establishment of an interdisciplinary data science framework that integrates epidemiology, toxicology and bioinformatics with biomarker-based research to better define how population-level exposures contribute to these adverse birth outcomes. The proposed interdisciplinary research framework would 1) facilitate data-driven analyses using existing data from health registries and environmental monitoring programs; 2) develop novel algorithms with the ability to predict which exposures are driving, in this case, adverse birth outcomes in simultaneous exposures; and 3) refine biomarker-based research, ultimately leading to new policies and interventions to reduce the incidence of adverse birth outcomes.
View details for DOI 10.1016/j.envres.2021.111019
View details for PubMedID 33737076
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Genome-wide investigation identifies a rare copy-number variant burden associated with human spina bifida.
Genetics in medicine : official journal of the American College of Medical Genetics
2021
Abstract
PURPOSE: Next-generation sequencing has implicated some risk variants for human spina bifida (SB), but the genome-wide contribution of structural variation to this complex genetic disorder remains largely unknown. We examined copy-number variant (CNV) participation in the genetic architecture underlying SB risk.METHODS: A high-confidence ensemble approach to genome sequences (GS) was benchmarked and employed for systematic detection of common and rare CNVs in two separate ancestry-matched SB case-control cohorts.RESULTS: SB cases were enriched with exon disruptive rare CNVs, 44% of which were under 10 kb, in both ancestral populations (P=6.75 * 10-7; P=7.59 * 10-4). Genes containing these disruptive CNVs fall into molecular pathways, supporting a role for these genes in SB. Our results expand the catalog of variants and genes with potential contribution to genetic and gene-environment interactions that interfere with neurulation, useful for further functional characterization.CONCLUSION: This study underscores the need for genome-wide investigation and extends our previous threshold model of exonic, single-nucleotide variation toward human SB risk to include structural variation. Since GS data afford detection of CNVs with greater resolution than microarray methods, our results have important implications toward a more comprehensive understanding of the genetic risk and mechanisms underlying neural tube defect pathogenesis.
View details for DOI 10.1038/s41436-021-01126-9
View details for PubMedID 33686259
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Gene-environment interactions between air pollution and biotransformation enzymes and risk of birth defects.
Birth defects research
2021
Abstract
Genetic and environmental factors have been observed to influence risks for birth defects, though few studies have investigated gene-environment interactions. Our aim was to examine the interaction terms of gene variants in biotransformation enzyme pathways and air pollution exposures in relation to risk of several structural birth defects. We evaluated the role of ambient air pollutant exposure (nitrogen dioxide [NO2 ], nitrogen oxide, carbon monoxide, particulate matter <10 [PM10 ] and <2.5 [PM2.5 ] microns) during pregnancy and 104 gene variants of biotransformation enzymes from infant bloodspots or buccal cells in a California population-based case-control study in 1997-2006. Cases included cleft lip with or without cleft palate (N = 206), gastroschisis (N = 94), tetralogy of Fallot (N = 69), and dextro-transposition of the great arteries (d-TGA; N = 40) and were compared to 208 nonmalformed controls. Overall, the results were not consistent, though did highlight some associations for further investigation as indicated by Wald chi-square test p value <.1. Increased risk of cleft lip was associated with exposure to high PM10 and two CYP gene variants. High PM2.5 and the variant of SLCO1B1 was associated with increased risk of teratology of Fallot. Higher NO2 and two gene variants, CYP2A6 and SLC01B1, were associated with increased risk of d-TGA. Results for gastroschisis were inconsistent in direction and across pollutants. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of air pollution.
View details for DOI 10.1002/bdr2.1880
View details for PubMedID 33569925
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Timing of Transfer and Mortality in Neonates with Hypoplastic Left Heart Syndrome in California.
Pediatric cardiology
2021
Abstract
Maternal race/ethnicity is associated with mortality in neonates with hypoplastic left heart syndrome (HLHS). We investigated whether maternal race/ethnicity and other sociodemographic factors affect timing of transfer after birth and whether timing of transfer impacts mortality in infants with HLHS. We linked two statewide databases, the California Perinatal Quality Care Collaborative and records from the Office of Statewide Health Planning and Development, to identify cases of HLHS born between 1/1/06 and 12/31/11. Cases were divided into three groups: birth at destination hospital, transfer on day of life 0-1 ("early transfer"), or transfer on day of life≥2 ("late transfer"). We used log-binomial regression models to estimate relative risks (RR) for timing of transfer and Cox proportional hazard models to estimate hazard ratios (HR) for mortality. We excluded infants who died within 60days of life without intervention from the main analyses of timing of transfer, since intervention may not have been planned in these infants. Of 556 cases, 107 died without intervention (19%) and another 52 (9%) died within 28days. Of the 449 included in analyses of timing of transfer, 28% were born at the destination hospital, 49% were transferred early, and 23% were transferred late. Late transfer was more likely for infants of low birthweight (RR 1.74) and infants born to US-born Hispanic (RR 1.69) and black (RR 2.45) mothers. Low birthweight (HR 1.50), low 5-min Apgar score (HR 4.69), and the presence of other major congenital anomalies (HR 3.41), but not timing of transfer, predicted neonatal mortality. Late transfer was more likely in neonates born to US-born Hispanic and black mothers but was not associated with higher mortality.
View details for DOI 10.1007/s00246-021-02561-w
View details for PubMedID 33533967
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Proteomic signatures predict preeclampsia in individual cohorts but not across cohorts - implications for clinical biomarker studies.
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
2021: 1–8
Abstract
Early identification of pregnant women at risk for preeclampsia (PE) is important, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analyses of plasma proteins feature prominently among molecular approaches used for risk prediction. However, derivation of protein signatures of sufficient predictive power has been challenging. The recent availability of platforms simultaneously assessing over 1000 plasma proteins offers broad examinations of the plasma proteome, which may enable the extraction of proteomic signatures with improved prognostic performance in prenatal care.The primary aim of this study was to examine the generalizability of proteomic signatures predictive of PE in two cohorts of pregnant women whose plasma proteome was interrogated with the same highly multiplexed platform. Establishing generalizability, or lack thereof, is critical to devise strategies facilitating the development of clinically useful predictive tests. A second aim was to examine the generalizability of protein signatures predictive of gestational age (GA) in uncomplicated pregnancies in the same cohorts to contrast physiological and pathological pregnancy outcomes.Serial blood samples were collected during the first, second, and third trimesters in 18 women who developed PE and 18 women with uncomplicated pregnancies (Stanford cohort). The second cohort (Detroit), used for comparative analysis, consisted of 76 women with PE and 90 women with uncomplicated pregnancies. Multivariate analyses were applied to infer predictive and cohort-specific proteomic models, which were then tested in the alternate cohort. Gene ontology (GO) analysis was performed to identify biological processes that were over-represented among top-ranked proteins associated with PE.The model derived in the Stanford cohort was highly significant (p = 3.9E-15) and predictive (AUC = 0.96), but failed validation in the Detroit cohort (p = 9.7E-01, AUC = 0.50). Similarly, the model derived in the Detroit cohort was highly significant (p = 1.0E-21, AUC = 0.73), but failed validation in the Stanford cohort (p = 7.3E-02, AUC = 0.60). By contrast, proteomic models predicting GA were readily validated across the Stanford (p = 1.1E-454, R = 0.92) and Detroit cohorts (p = 1.1.E-92, R = 0.92) indicating that the proteomic assay performed well enough to infer a generalizable model across studied cohorts, which makes it less likely that technical aspects of the assay, including batch effects, accounted for observed differences.Results point to a broader issue relevant for proteomic and other omic discovery studies in patient cohorts suffering from a clinical syndrome, such as PE, driven by heterogeneous pathophysiologies. While novel technologies including highly multiplex proteomic arrays and adapted computational algorithms allow for novel discoveries for a particular study cohort, they may not readily generalize across cohorts. A likely reason is that the prevalence of pathophysiologic processes leading up to the "same" clinical syndrome can be distributed differently in different and smaller-sized cohorts. Signatures derived in individual cohorts may simply capture different facets of the spectrum of pathophysiologic processes driving a syndrome. Our findings have important implications for the design of omic studies of a syndrome like PE. They highlight the need for performing such studies in diverse and well-phenotyped patient populations that are large enough to characterize subsets of patients with shared pathophysiologies to then derive subset-specific signatures of sufficient predictive power.
View details for DOI 10.1080/14767058.2021.1888915
View details for PubMedID 33653202
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Deleterious and Protective Psychosocial and Stress-Related Factors Predict Risk of Spontaneous Preterm Birth.
American journal of perinatology
2021
Abstract
The aim of the study was to: (1) Identify (early in pregnancy) psychosocial and stress-related factors that predict risk of spontaneous preterm birth (PTB, gestational age <37 weeks); (2) Investigate whether "protective" factors (e.g., happiness/social support) decrease risk; (3) Use the Dhabhar Quick-Assessment Questionnaire for Stress and Psychosocial Factors™ (DQAQ-SPF™) to rapidly quantify harmful or protective factors that predict increased or decreased risk respectively, of PTB. This is a prospective cohort study. Relative risk (RR) analyses investigated association between individual factors and PTB. Machine learning-based interdependency analysis (IDPA) identified factor clusters, strength, and direction of association with PTB. A nonlinear model based on support vector machines was built for predicting PTB and identifying factors that most strongly predicted PTB. Higher levels of deleterious factors were associated with increased RR for PTB: General anxiety (RR = 8.9; 95% confidence interval or CI = 2.0,39.6), pain (RR = 5.7; CI = 1.7,17.0); tiredness/fatigue (RR = 3.7; CI = 1.09,13.5); perceived risk of birth complications (RR = 4; CI = 1.6,10.01); self-rated health current (RR = 2.6; CI = 1.0,6.7) and previous 3 years (RR = 2.9; CI = 1.1,7.7); and divorce (RR = 2.9; CI = 1.1,7.8). Lower levels of protective factors were also associated with increased RR for PTB: low happiness (RR = 9.1; CI = 1.25,71.5); low support from parents/siblings (RR = 3.5; CI = 0.9,12.9), and father-of-baby (RR = 3; CI = 1.1,9.9). These factors were also components of the clusters identified by the IDPA: perceived risk of birth complications (p < 0.05 after FDR correction), and general anxiety, happiness, tiredness/fatigue, self-rated health, social support, pain, and sleep (p < 0.05 without FDR correction). Supervised analysis of all factors, subject to cross-validation, produced a model highly predictive of PTB (AUROC or area under the receiver operating characteristic = 0.73). Model reduction through forward selection revealed that even a small set of factors (including those identified by RR and IDPA) predicted PTB. These findings represent an important step toward identifying key factors, which can be assessed rapidly before/after conception, to predict risk of PTB, and perhaps other adverse pregnancy outcomes. Quantifying these factors, before, or early in pregnancy, could identify women at risk of delivering preterm, pinpoint mechanisms/targets for intervention, and facilitate the development of interventions to prevent PTB.· Newly designed questionnaire used for rapid quantification of stress and psychosocial factors early during pregnancy.. · Deleterious factors predict increased preterm birth (PTB) risk.. · Protective factors predict decreased PTB risk..
View details for DOI 10.1055/s-0041-1729162
View details for PubMedID 34015838
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Interpregnancy intervals and adverse birth outcomes in high-income countries: An international cohort study.
PloS one
2021; 16 (7): e0255000
Abstract
BACKGROUND: Most evidence for interpregnancy interval (IPI) and adverse birth outcomes come from studies that are prone to incomplete control for confounders that vary between women. Comparing pregnancies to the same women can address this issue.METHODS: We conducted an international longitudinal cohort study of 5,521,211 births to 3,849,193 women from Australia (1980-2016), Finland (1987-2017), Norway (1980-2016) and the United States (California) (1991-2012). IPI was calculated based on the time difference between two dates-the date of birth of the first pregnancy and the date of conception of the next (index) pregnancy. We estimated associations between IPI and preterm birth (PTB), spontaneous PTB, and small-for-gestational age births (SGA) using logistic regression (between-women analyses). We also used conditional logistic regression comparing IPIs and birth outcomes in the same women (within-women analyses). Random effects meta-analysis was used to calculate pooled adjusted odds ratios (aOR).RESULTS: Compared to an IPI of 18-23 months, there was insufficient evidence for an association between IPI <6 months and overall PTB (aOR 1.08, 95% CI 0.99-1.18) and SGA (aOR 0.99, 95% CI 0.81-1.19), but increased odds of spontaneous PTB (aOR 1.38, 95% CI 1.21-1.57) in the within-women analysis. We observed elevated odds of all birth outcomes associated with IPI ≥60 months. In comparison, between-women analyses showed elevated odds of adverse birth outcomes for <12 month and >24 month IPIs.CONCLUSIONS: We found consistently elevated odds of adverse birth outcomes following long IPIs. IPI shorter than 6 months were associated with elevated risk of spontaneous PTB, but there was insufficient evidence for increased risk of other adverse birth outcomes. Current recommendations of waiting at least 24 months to conceive after a previous pregnancy, may be unnecessarily long in high-income countries.
View details for DOI 10.1371/journal.pone.0255000
View details for PubMedID 34280228
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Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach.
PLoS genetics
2021; 17 (3): e1009413
Abstract
Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways.
View details for DOI 10.1371/journal.pgen.1009413
View details for PubMedID 33684136
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Explaining the Black-White Disparity in Preterm Birth: A Consensus Statement From a Multi-Disciplinary Scientific Work Group Convened by the March of Dimes.
Frontiers in reproductive health
2021; 3: 684207
Abstract
In 2017-2019, the March of Dimes convened a workgroup with biomedical, clinical, and epidemiologic expertise to review knowledge of the causes of the persistent Black-White disparity in preterm birth (PTB). Multiple databases were searched to identify hypothesized causes examined in peer-reviewed literature, 33 hypothesized causes were reviewed for whether they plausibly affect PTB and either occur more/less frequently and/or have a larger/smaller effect size among Black women vs. White women. While definitive proof is lacking for most potential causes, most are biologically plausible. No single downstream or midstream factor explains the disparity or its social patterning, however, many likely play limited roles, e.g., while genetic factors likely contribute to PTB, they explain at most a small fraction of the disparity. Research links most hypothesized midstream causes, including socioeconomic factors and stress, with the disparity through their influence on the hypothesized downstream factors. Socioeconomic factors alone cannot explain the disparity's social patterning. Chronic stress could affect PTB through neuroendocrine and immune mechanisms leading to inflammation and immune dysfunction, stress could alter a woman's microbiota, immune response to infection, chronic disease risks, and behaviors, and trigger epigenetic changes influencing PTB risk. As an upstream factor, racism in multiple forms has repeatedly been linked with the plausible midstream/downstream factors, including socioeconomic disadvantage, stress, and toxic exposures. Racism is the only factor identified that directly or indirectly could explain the racial disparities in the plausible midstream/downstream causes and the observed social patterning. Historical and contemporary systemic racism can explain the racial disparities in socioeconomic opportunities that differentially expose African Americans to lifelong financial stress and associated health-harming conditions. Segregation places Black women in stressful surroundings and exposes them to environmental hazards. Race-based discriminatory treatment is a pervasive stressor for Black women of all socioeconomic levels, considering both incidents and the constant vigilance needed to prepare oneself for potential incidents. Racism is a highly plausible, major upstream contributor to the Black-White disparity in PTB through multiple pathways and biological mechanisms. While much is unknown, existing knowledge and core values (equity, justice) support addressing racism in efforts to eliminate the racial disparity in PTB.
View details for DOI 10.3389/frph.2021.684207
View details for PubMedID 36303973
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Corrigendum: Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation.
Frontiers in pediatrics
2021; 9: 680201
Abstract
[This corrects the article DOI: 10.3389/fped.2020.605219.].
View details for DOI 10.3389/fped.2021.680201
View details for PubMedID 33903851
View details for PubMedCentralID PMC8065098
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Measuring Variation in Interpregnancy Interval: Identifying Hotspots for Improvement Initiatives.
American journal of perinatology
2021
Abstract
The study aimed to determine if single year birth certificate data can be used to identify regional and hospital variation in rates of short interpregnancy interval (IPI < 6 months). IPI was estimated for multiparous women ages 15 to 44 years with singleton live births between 2015 and 2016. Perinatal outcomes, place of birth, maternal race, and data for IPI calculations were obtained by using birth certificates. IPI frequencies are presented as observed rates. The cohort included 562,039 multiparous women. Short IPI rates were similar to those obtained with analyses by using linked longitudinal data and confirmed the association with preterm birth. Short IPI rates varied by race and Hispanic nativity. There was substantial hospital (0.8-9%) and regional (2.9-6.2%) variation in short IPI rates. IPI rates can be reliably obtained from current year birth certificate data. This can be a useful tool for quality improvement projects targeting interventions and rapidly assessing their progress to promote optimal birth spacing.· Near-real time regional and hospital IPI rates can be reliably obtained from current year birth certificate data.. · Substantial variations in rates of short IPI exist between hospital and perinatal regions.. · IPI rates from individual birth certificates can be a tool to target and assess interventions..
View details for DOI 10.1055/s-0041-1728819
View details for PubMedID 33940645
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Decreased Mortality Rate Among COVID-19 Patients Prescribed Statins: Data From Electronic Health Records in the US.
Frontiers in medicine
2021; 8: 639804
Abstract
The severe respiratory illness due to SARS-CoV-2, the virus responsible for coronavirus disease 2019 (COVID-19), is triggered by an intense pro-inflammatory host response. Statins, prescribed primarily for lipid reduction, are known to have anti-inflammatory and immunomodulatory properties and have been associated with a reduced mortality rate among COVID-19 patients taking statins as reported in two recent retrospective studies. However, a meta-analysis that included nine studies showed that statin use did not improve in-hospital outcomes of those with COVID-19. In addition, concerns regarding the use of statins and an increase in COVID-19 infections have been raised, as statins may increase the expression of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the SARS-CoV-2 virus. Our goal was to investigate the effect of statins in COVID-19 patients in a large, diverse patient population across the United States containing nearly 120,000 patients diagnosed with COVID-19. We used propensity score matching of demographics, comorbidities, and medication indication to compare statin-treated patients (N = 2,297) with matched controls (N = 4,594). We observed a small, but statistically significant, decrease in mortality among patients prescribed statins (16.1%) when compared with matched COVID-19-positive controls (18.0 to 20.6%). These results support previous evidence that statins do not increase COVID-19-related mortality and may, in fact, have a mitigating effect on severity of the disease reflected in a slight reduction in mortality. Mixed findings on effects of statins in COVID-19 patients reported in the literature should prompt prospective randomized controlled trials in order to define better who might be advantaged with respect to clinical outcomes.
View details for DOI 10.3389/fmed.2021.639804
View details for PubMedID 33614688
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Data-Driven Modeling of Pregnancy-Related Complications.
Trends in molecular medicine
2021
Abstract
A healthy pregnancy depends on complex interrelated biological adaptations involving placentation, maternal immune responses, and hormonal homeostasis. Recent advances in high-throughput technologies have provided access to multiomics biological data that, combined with clinical and social data, can provide a deeper understanding of normal and abnormal pregnancies. Integration of these heterogeneous datasets using state-of-the-art machine-learning methods can enable the prediction of short- and long-term health trajectories for a mother and offspring and the development of treatments to prevent or minimize complications. We review advanced machine-learning methods that could: provide deeper biological insights into a pregnancy not yet unveiled by current methodologies; clarify the etiologies and heterogeneity of pathologies that affect a pregnancy; and suggest the best approaches to address disparities in outcomes affecting vulnerable populations.
View details for DOI 10.1016/j.molmed.2021.01.007
View details for PubMedID 33573911
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Maternal Exposure to Disinfection By-Products and Risk of Hypospadias in the National Birth Defects Prevention Study (2000-2005).
International journal of environmental research and public health
2020; 17 (24)
Abstract
The purpose of this study was to estimate the association between 2nd and 3rd degree hypospadias and maternal exposure to disinfection by-products (DBPs) using data from a large case-control study in the United States. Concentration estimates for total trihalomethanes (TTHMs), the sum of the five most prevalent haloacetic acids (HAA5), and individual species of each were integrated with data on maternal behaviors related to water use from the National Birth Defects Prevention Study (NBDPS) to create three different exposure metrics: (1) household DBP concentrations; (2) estimates of DBP ingestion; (3) predicted uptake (i.e., internal dose) of trihalomethanes (THMs) via ingestion, showering, and bathing. The distribution of DBP exposure was categorized as follows: (Q1/referent) < 50%; (Q2) ≥ 50% to < 75%; and (Q3) ≥ 75%. Logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Generally, null associations were observed with increasing TTHM or HAA5 exposure. An increased risk was observed among women with household bromodichloromethane levels in the second quantile (aOR: 1.8; 95% CI: 1.2, 2.7); however, this association did not persist after the inclusion of individual-level water-use data. Findings from the present study do not support the hypothesis that maternal DBP exposures are related to the occurrence of hypospadias.
View details for DOI 10.3390/ijerph17249564
View details for PubMedID 33371304
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Parental age and preterm birth: a population-based cohort of nearly 3 million California livebirths from 2007 to 2012.
Journal of perinatology : official journal of the California Perinatal Association
2020
Abstract
PURPOSE: To assess the relationships between parental ages and preterm birth subtypes.METHODS: A population-based cohort analysis of California livebirths 2007-2012. Associations between maternal and paternal age with spontaneous and medically indicated preterm birth were estimated from Cox proportional hazard models. Parental age was modeled with restricted cubic splines to account for nonlinear relationships.RESULTS: Young paternal age was associated with increased hazard ratios for spontaneous and medically indicated preterm birth. Older fathers showed elevated hazards for preterm birth in crude analysis but after adjustment the relationship was generally not observed. Aging mothers showed increased hazard ratios for both preterm birth phenotypes.CONCLUSIONS: After adjusting for parental demographics, births to younger fathers and older mothers had the highest risks for spontaneous preterm birth. The paternal influence on preterm birth was observed to be independent of maternal factors.
View details for DOI 10.1038/s41372-020-00894-7
View details for PubMedID 33293667
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Maternal metabolic profiling to assess fetal gestational age and predict preterm delivery: a two-centre retrospective cohort study in the US.
BMJ open
2020; 10 (12): e040647
Abstract
OBJECTIVES: The aim of this study was to develop a single blood test that could determine gestational age and estimate the risk of preterm birth by measuring serum metabolites. We hypothesised that serial metabolic modelling of serum analytes throughout pregnancy could be used to describe fetal gestational age and project preterm birth with a high degree of precision.STUDY DESIGN: A retrospective cohort study.SETTING: Two medical centres from the USA.PARTICIPANTS: Thirty-six patients (20 full-term, 16 preterm) enrolled at Stanford University were used to develop gestational age and preterm birth risk algorithms, 22 patients (9 full-term, 13 preterm) enrolled at the University of Alabama were used to validate the algorithms.OUTCOME MEASURES: Maternal blood was collected serially throughout pregnancy. Metabolic datasets were generated using mass spectrometry.RESULTS: A model to determine gestational age was developed (R2=0.98) and validated (R2=0.81). 66.7% of the estimates fell within ±1week of ultrasound results during model validation. Significant disruptions from full-term pregnancy metabolic patterns were observed in preterm pregnancies (R2=-0.68). A separate algorithm to predict preterm birth was developed using a set of 10 metabolic pathways that resulted in an area under the curve of 0.96 and 0.92, a sensitivity of 0.88 and 0.86, and a specificity of 0.96 and 0.92 during development and validation testing, respectively.CONCLUSIONS: In this study, metabolic profiling was used to develop and test a model for determining gestational age during full-term pregnancy progression, and to determine risk of preterm birth. With additional patient validation studies, these algorithms may be used to identify at-risk pregnancies prompting alterations in clinical care, and to gain biological insights into the pathophysiology of preterm birth. Metabolic pathway-based pregnancy modelling is a novel modality for investigation and clinical application development.
View details for DOI 10.1136/bmjopen-2020-040647
View details for PubMedID 33268420
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Reproductive sequelae of parental severe illness before the pandemic: implications for the COVID-19 pandemic.
Fertility and sterility
2020; 114 (6): 1242–49
Abstract
OBJECTIVE: To investigate, with pre-COVID-19 data, whether parental exposure to severe systemic infections near the time of conception is associated with pregnancy outcomes.DESIGN: Retrospective cohort study.SETTING: Population-based study covering births within the United States from 2009 to2016.PARTICIPANTS: The IBM MarketScan Research database covers reimbursed health care claims data on inpatient and outpatient encounters that are privately insured through employment-sponsored health insurance. Our analytic sample included pregnancies to paired fathers and mothers.INTERVENTIONS(S): Parental preconception exposure (0-6 months before conception) to severe systemic infection (e.g., sepsis, hypotension, respiratory failure, critical care evaluation).MAIN OUTCOME MEASURE(S): Preterm birth (i.e., live birth before 37 weeks) and pregnancy loss.RESULT(S): A total of 999,866 pregnancies were recorded with 214,057 pregnancy losses (21.4%) and 51,759 preterm births (5.2%). Mothers receiving intensive care in the preconception period had increased risk of pregnancy loss, as did fathers. Mothers with preconception sepsis had higher risk of preterm birth and pregnancy loss, and paternal sepsis exposure was associated with an increased risk of pregnancy loss. Similar results were noted for hypotension. In addition, a dose response was observed for both mothers and fathers between preconception time in intensive care and the risk of preterm birth and pregnancy loss.CONCLUSION(S): In a pre-COVID-19 cohort, parental preconception severe systemic infection was associated with increased odds of preterm birth and pregnancy loss when conception was soon after the illness.
View details for DOI 10.1016/j.fertnstert.2020.09.153
View details for PubMedID 33280730
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Infant Allergy Testing and Food Allergy Diagnoses Before and After Guidelines for Early Peanut Introduction.
The journal of allergy and clinical immunology. In practice
2020
Abstract
BACKGROUND: A landmark 2015 trial on early exposure to peanuts led to expert recommendations for screening and early peanut introduction in high-risk (severe eczema and/or egg allergy) infants, but the impact of this paradigm shift on allergy testing and diagnosis is unknown.OBJECTIVE: We assessed the effects of the Learning Early About Peanut Allergy (LEAP) trial and guideline publications on allergy testing and food allergy diagnoses in infants.METHODS: In this retrospective cohort study, de-identified administrative health claims from a commercial and Medicare advantage claims database were used. Infants with at least one year of continuous coverage were selected using newborn codes for birth hospitalizations from January 2010 to June 2018. Interrupted time series models were used to compare the prevalence of allergy testing before and after LEAP publication in February 2015 and formal guideline publication in January 2017.RESULTS: For 487,533 included infants, allergy testing increased after LEAP (risk ratio [RR]: 1.11 [95% CI, 1.07-1.15]) and guidelines (1.21 [1.18-1.23]). This increase of testing was also seen in infants not considered high-risk, both after LEAP (1.12 [1.08-1.17]) and guidelines (1.20 [1.16, 1.23]). For first-time allergy tests, post-guideline median number of allergens tested was 9 for serum tests and 10 for skin tests. Post-guidelines there was a significant increase in diagnosis of peanut (RR: 1.08 [1.00, 1.16]), egg (1.12 [1.05, 1.20]), and other food allergies (excluding milk) (1.22 [1.14, 1.31]).CONCLUSION: Allergy testing has increased, including in non-high-risk infants. Multi-allergen testing may be contributing to an increase in the diagnosis of other food allergies.
View details for DOI 10.1016/j.jaip.2020.10.060
View details for PubMedID 33186769
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Singleton preterm birth rates for racial and ethnic groups during the coronavirus disease 2019 pandemic in California.
American journal of obstetrics and gynecology
2020
View details for DOI 10.1016/j.ajog.2020.10.033
View details for PubMedID 33203528
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Integration of mechanistic immunological knowledge into a machine learning pipeline improves predictions
NATURE MACHINE INTELLIGENCE
2020
View details for DOI 10.1038/s42256-020-00232-8
View details for Web of Science ID 000579336000001
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Integration of mechanistic immunological knowledge into a machine learning pipeline improves predictions.
Nature machine intelligence
2020; 2 (10): 619-628
Abstract
The dense network of interconnected cellular signalling responses that are quantifiable in peripheral immune cells provides a wealth of actionable immunological insights. Although high-throughput single-cell profiling techniques, including polychromatic flow and mass cytometry, have matured to a point that enables detailed immune profiling of patients in numerous clinical settings, the limited cohort size and high dimensionality of data increase the possibility of false-positive discoveries and model overfitting. We introduce a generalizable machine learning platform, the immunological Elastic-Net (iEN), which incorporates immunological knowledge directly into the predictive models. Importantly, the algorithm maintains the exploratory nature of the high-dimensional dataset, allowing for the inclusion of immune features with strong predictive capabilities even if not consistent with prior knowledge. In three independent studies our method demonstrates improved predictions for clinically relevant outcomes from mass cytometry data generated from whole blood, as well as a large simulated dataset. The iEN is available under an open-source licence.
View details for DOI 10.1038/s42256-020-00232-8
View details for PubMedID 33294774
View details for PubMedCentralID PMC7720904
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Congenital diaphragmatic hernia and maternal dietary nutrient pathways and diet quality.
Birth defects research
2020
Abstract
INTRODUCTION: We examined the association of congenital diaphragmatic hernia (CDH) with maternal dietary intake, using semi-Bayes hierarchical models and principal components analysis to consider intake of nutrients that contribute to one-carbon metabolism and oxidative stress pathways, and a diet quality index.METHODS: We included data on 825 cases and 11,108 nonmalformed controls born from 1997-2011 whose mother participated in the National Birth Defects Prevention Study (NBDPS), a multisite, population-based case-control study. Exposure data were from maternal telephone interviews, which included a food frequency questionnaire. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were generated from logistic regression models that included nutritional factors as continuous variables and were adjusted for maternal energy intake, race-ethnicity, parity, and vitamin supplement intake.RESULTS: In the semi-Bayes hierarchical model that included all nutrients and confounders, riboflavin was the only nutrient for which the 95% CI excluded 1.0; the aOR for a 1SD increase was 0.83. The aORs were 0.79 (95% CI 0.69-0.91) for the one-carbon metabolism pathway score, 0.90 (95% CI 0.80-1.01) for oxidative stress, and 0.85 (95% CI 0.77-0.93) for diet quality (the aORs correspond to a 1 SD increase).CONCLUSIONS: The findings from this study provide some support for the hypothesis that better prepregnancy nutrition is associated with reduced risk for CDH. These results provide etiologic clues but should be interpreted with caution given the novelty of the investigation.
View details for DOI 10.1002/bdr2.1770
View details for PubMedID 32744808
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Newborn Iodine Status Is Not Related to Congenital Hypothyroidism.
The Journal of nutrition
2020
Abstract
BACKGROUND: Severe iodine deficiency or excess during pregnancy can cause congenital hypothyroidism (CH). Iodine deficiency is common in pregnant women in the United States.OBJECTIVES: We conducted a nested case-control study in a cohort of 2.5 million births in California to determine whether iodine status is related to CH in a US population.METHODS: Dried blood spots from 907 newborns with CH identified by newborn screening and 909 unaffected controls matched by month of birth were obtained from the California Newborn Screening Program to measure whole-blood iodine concentration. Iodine status was compared between cases and controls, and logistic regression was used to assess the association between CH status and blood iodine concentrations. Iodine status was also compared between cases and controls among infants treated in a neonatal intensive care unit (NICU) because CH has been reported in infants exposed to high levels of iodine in the NICU.RESULTS: Blood iodine concentrations did not differ significantly between cases (median: 20.0 ng/mL; IQR: 12.1-29.8 ng/mL) and controls (median: 20.3 ng/mL; IQR: 12.5-30.9 ng/mL; P=0.59). Neither extremely high nor extremely low blood iodine concentrations (1st, 5th, 95th, and 99th percentiles of the distribution) were more common in cases. Among infants treated in NICUs, however, cases had significantly (P=0.01) higher iodine (median: 22.7 ng/mL; IQR: 16.4-32.1 ng/mL) compared with controls (median: 17.3 ng/mL; IQR: 8.3-26.6 ng/mL).CONCLUSIONS: CH cases did not have significantly higher or lower iodine in this population, which is reassuring given that maternal iodine deficiency is common in the United States. Among newborns in the NICU, CH cases had higher blood iodine concentrations compared with controls, suggesting that excess iodine exposure in the NICU could be causing CH. It may be beneficial to monitor iodine exposure from surgical procedures, imaging, and iodine-containing disinfectants and to consider non-iodine alternatives.
View details for DOI 10.1093/jn/nxaa178
View details for PubMedID 32633779
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Towards personalized medicine in maternal and child health: integrating biologic and social determinants.
Pediatric research
2020
View details for DOI 10.1038/s41390-020-0981-8
View details for PubMedID 32454518
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Effects of Selective Exclusion of Patients on Preterm Birth Test Performance
OBSTETRICS AND GYNECOLOGY
2020; 135 (5): 1228–29
View details for Web of Science ID 000570209400048
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Postpartum LARC Among the Privately Insured-Use After Preterm and Term Births
LIPPINCOTT WILLIAMS & WILKINS. 2020: 108S–109S
View details for Web of Science ID 000554572900377
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Early prediction of preeclampsia via machine learning.
American journal of obstetrics & gynecology MFM
2020; 2 (2): 100100
Abstract
BACKGROUND: Early prediction of preeclampsia is challenging because of poorly understood causes, various risk factors, and likely multiple pathogenic phenotypes of preeclampsia. Statistical learning methods are well-equipped to deal with a large number of variables, such as patients' clinical and laboratory data, and to select the most informative features automatically.OBJECTIVE: Our objective was to use statistical learning methods to analyze all available clinical and laboratory data that were obtained during routine prenatal visits in early pregnancy and to use them to develop a prediction model for preeclampsia.STUDY DESIGN: This was a retrospective cohort study that used data from 16,370 births at Lucile Packard Children Hospital at Stanford, CA, from April 2014 to January 2018. Two statistical learning algorithms were used to build a predictive model: (1) elastic net and (2) gradient boosting algorithm. Models for all preeclampsia and early-onset preeclampsia (<34 weeks gestation) were fitted with the use of patient data that were available at <16 weeks gestational age. The 67 variables that were considered in the models included maternal characteristics, medical history, routine prenatal laboratory results, and medication intake. The area under the receiver operator curve, true-positive rate, and false-positive rate were assessed via cross-validation.RESULTS: Using the elastic netalgorithm, we developed a prediction model that contained a subset of the most informative features from all variables. The obtained prediction model for preeclampsia yielded an area under the curve of 0.79 (95% confidence interval, 0.75-0.83), sensitivity of 45.2%, and false-positive rate of 8.1%. The prediction model for early-onset preeclampsia achieved an area under the curve of 0.89 (95% confidence interval, 0.84-0.95), true-positive rate of 72.3%, and false-positive rate of 8.8%.CONCLUSION: Statistical learning methods in a retrospective cohort study automatically identified a set of significant features for prediction and yielded high prediction performance for preeclampsia risk from routine early pregnancy information.
View details for DOI 10.1016/j.ajogmf.2020.100100
View details for PubMedID 33345966
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Progressive Metabolic Dysfunction and Nutritional Variability Precedes Necrotizing Enterocolitis.
Nutrients
2020; 12 (5)
Abstract
Necrotizing Enterocolitis (NEC) is associated with prematurity, enteral feedings, and enteral dysbiosis. Accordingly, we hypothesized that along with nutritional variability, metabolic dysfunction would be associated with NEC onset. Methods: We queried a multicenter longitudinal database that included 995 preterm infants (<32 weeks gestation) and included 73 cases of NEC. Dried blood spot samples were obtained on day of life 1, 7, 28, and 42. Metabolite data from each time point included 72 amino acid (AA) and acylcarnitine (AC) measures. Nutrition data were averaged at each of the same time points. Odds ratios and 95% confidence intervals were calculated using samples obtained prior to NEC diagnosis and adjusted for potential confounding variables. Nutritional and metabolic data were plotted longitudinally to determine relationship to NEC onset. Results: Day 1 analyte levels of alanine, phenylalanine, free carnitine, C16, arginine, C14:1/C16, and citrulline/phenylalanine were associated with the subsequent development of NEC. Over time, differences in individual analyte levels associated with NEC onset shifted from predominantly AAs at birth to predominantly ACs by day 42. Subjects who developed NEC received significantly lower weight-adjusted total calories (p < 0.001) overall, a trend that emerged by day of life 7 (p = 0.020), and persisted until day of life 28 (p < 0.001) and 42 (p < 0.001). Conclusion: Premature infants demonstrate metabolic differences at birth. Metabolite abnormalities progress in parallel to significant differences in nutritional delivery signifying metabolic dysfunction in premature newborns prior to NEC onset. These observations provide new insights to potential contributing pathophysiology of NEC and opportunity for clinical care-based prevention.
View details for DOI 10.3390/nu12051275
View details for PubMedID 32365850
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Maternal occupational exposure to polycyclic aromatic hydrocarbons and the risk of isolated congenital heart defects among offspring.
Environmental research
2020; 186: 109550
Abstract
BACKGROUND: Although there is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) is linked with congenital heart defects (CHDs), few studies have examined the association in humans. We conducted a case-control study to examine the association between maternal exposure to PAHs and CHDs in offspring using data from the National Birth Defects Prevention Study (NBDPS) (1997-2011).METHODS: We obtained detailed information on maternal occupation during the month before to three months after conception. Expert raters, masked to case-control status, assessed job descriptions to assign categorical levels of exposure. Categories were quantitatively mapped to estimate cumulative exposure to PAHs, incorporating exposure intensity, frequency, work duration, and work hours. Quartiles were generated for cumulative maternal exposure to PAHs. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression for quartiles of PAH exposure and six CHD groupings (e.g. conotruncal) and specific subtypes (e.g. tetralogy of Fallot [ToF]). Final models were adjusted for maternal age, race/ethnicity, education, smoking, anticonvulsant use, folic acid supplementation, and study center.RESULTS: There were 4,775 case and 7,734 control infants eligible for the study. The prevalence of occupational exposure to PAHs was 10.2% among both case and control mothers. In adjusted analysis, compared to mothers with no occupational PAH exposure, those in the highest quartile of exposure were more likely to have offspring in the conotruncal heart defects group (OR 1.41; 95% CI 1.00-2.00), and with ToF (OR 1.83; 95% CI 1.21-2.78).CONCLUSIONS: Women in the highest quartile of estimated cumulative occupational PAH exposure during early pregnancy were more likely to have offspring with conotruncal heart defects, specifically ToF, compared to women with no occupational PAH exposure. Other comparisons between PAHs and other CHDs subgroups did not show any statistically precise associations.
View details for DOI 10.1016/j.envres.2020.109550
View details for PubMedID 32335433
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Quantification of selection bias in studies of risk factors for birth defects among livebirths.
Paediatric and perinatal epidemiology
2020
Abstract
BACKGROUND: Risk factors for birth defects are frequently investigated using data limited to liveborn infants. By conditioning on survival, results of such studies may be distorted by selection bias, also described as "livebirth bias." However, the implications of livebirth bias on risk estimation remain poorly understood.OBJECTIVES: We sought to quantify livebirth bias and to investigate the conditions under which it arose.METHODS: We used data on 3994 birth defects cases and 11829 controls enrolled in the National Birth Defects Prevention Study to compare odds ratio (OR) estimates of the relationship between three established risk factors (antiepileptic drug use, smoking, and multifetal pregnancy) and four birth defects (anencephaly, spina bifida, omphalocele, and cleft palate) when restricted to livebirths as compared to among livebirths, stillbirths, and elective terminations. Exposures and birth defects represented varying strengths of association with livebirth; all controls were liveborn. We performed a quantitative bias analysis to evaluate the sensitivity of our results to excluding terminated and stillborn controls.RESULTS: Cases ranged from 33% liveborn (anencephaly) to 99% (cleft palate). Smoking and multifetal pregnancy were associated with livebirth among anencephaly (crude OR [cOR] 0.61 and cOR 3.15, respectively) and omphalocele cases (cOR 2.22 and cOR 5.22, respectively). For analyses of the association between exposures and birth defects, restricting to livebirths produced negligible differences in estimates except for anencephaly and multifetal pregnancy, which was twofold higher among livebirths (adjusted OR [aOR] 4.93) as among all pregnancy outcomes (aOR 2.44). Within tested scenarios, bias analyses suggested that results were not sensitive to the restriction to liveborn controls.CONCLUSIONS: Selection bias was generally limited except for high mortality defects in the context of exposures strongly associated with livebirth. Findings indicate that substantial livebirth bias is unlikely to affect studies of risk factors for most birth defects.
View details for DOI 10.1111/ppe.12650
View details for PubMedID 32249969
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Association of preconception paternal health on perinatal outcomes: analysis of U.S. claims data.
Fertility and sterility
2020
Abstract
OBJECTIVE: To assess whether paternal health is associated with maternal peripartum and neonatal outcomes.DESIGN: Retrospective cohort study.SETTING: University research departments.PATIENT(S): Analytic sample of children born to paired fathers and mothers covering live births within the United States between 2009-2016.INTERVENTION(S): Paternal health status (e.g., metabolic syndrome diagnoses, individual chronic disease diagnoses).MAIN OUTCOME MEASURE(S): Primary outcome of preterm birth (i.e., live birth before 37 weeks), and secondary outcomes of low birth weight, neonatal intensive care unit (NICU) stay, gestational diabetes, preeclampsia, eclampsia, and length of maternal stay.RESULT(S): The IBM Marketscan Research database covers reimbursed health care claims data on inpatient and outpatient encounters who are privately insured through employment-sponsored health insurance. We assessed 785,809 singleton live births, with 6.6% born preterm. The presence of paternal comorbidities was associated with higher odds of preterm birth, low birth weight (LBW), and NICU stay. After adjusting for maternal factors, fathers with most or all components of the metabolic syndrome had 19% higher odds of having a child born preterm (95% CI 1.11-1.28), 23% higher odds of LBW (95% CI 1.01-1.51), and 28% higher odds of NICU stay (95% CI 1.08-1.52). Maternal morbidity (e.g., gestational diabetes or preeclampsia) was also positively associated with preconception paternal health.CONCLUSION(S): Increased preconception paternal comorbidity may be associated with negative infant and maternal outcomes. Although the paternal effect remains modest, these findings highlight the importance of the health of both parents, particularly the mother, on healthy pregnancy.
View details for DOI 10.1016/j.fertnstert.2019.12.026
View details for PubMedID 32147174
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Maternal dietary fat intake and the risk of congenital heart defects in offspring.
Pediatric research
2020
Abstract
BACKGROUND: Fatty acids are crucial in embryologic development, including cardiogenesis. The impact of maternal periconceptional dietary fat intake on the risk of congenital heart defects (CHDs) has not been clearly elucidated. We hypothesized that maternal dietary fat intake during pregnancy is associated with risk of CHDs in offspring.METHODS: We analyzed CHD cases and nonmalformed controls from the National Birth Defects Prevention Study, a case-control, multicenter population-based study of birth defects. We used multivariable logistic regression to analyze the association between maternal periconceptional dietary fat intake and occurrence of CHDs.RESULTS: We examined 11,393 infants with CHDs (cases) and 11,029 infants without birth defects (controls). Multivariable analysis of maternal dietary fat intake adjusted for maternal energy intake demonstrated modest change in risk for 2 of the 25 CHDs analyzed; otherwise there was no association. Maternal dietary fat intake unadjusted for total energy was associated with increased risk for several CHDs.CONCLUSIONS: After adjusting for total energy intake, maternal periconceptional dietary fat intake has a modest association with risk of a few specific CHDs. If maternal dietary fat intake does impact CHD risk, the effect is minimal.IMPACT: In this large, case-control study, after adjusting for total caloric intake, maternal periconceptional dietary fat intake was not associated with increased odds of congenital heart defects.This study investigates the hypothesis that women's periconceptional fat intake alters the risk of congenital heart defects in offspring.Our results raise questions about the role maternal fat intake may play in cardiogenesis and risk of congenital heart defects. Additionally, they raise the question about whether maternal lipid metabolism, as opposed to fat intake, may influence cardiac development.
View details for DOI 10.1038/s41390-020-0813-x
View details for PubMedID 32120376
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Multi-Omic, Longitudinal Profile of Third-Trimester Pregnancies Identifies a Molecular Switch That Predicts the Onset of Labor.
SPRINGER HEIDELBERG. 2020: 89A
View details for Web of Science ID 000525432600082
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Survival of infants with congenital diaphragmatic hernia in California: impact of hospital, clinical, and sociodemographic factors.
Journal of perinatology : official journal of the California Perinatal Association
2020
Abstract
To understand factors associated with care and survival among babies with congenital diaphragmatic hernia (CDH).We used data on California births (2006-2011) to examine birth hospital level of care, hospital transfer before repair, and survival.Among 577 infants, 25% were born at lower-level hospitals, 62% were transferred, and 31% died during infancy. Late or no prenatal care had the strongest association with birth at lower-level hospitals (adjusted relative risk (ARR) = 1.9, 95% confidence interval (CI) = 1.0-3.6). Birth at lower-level hospitals was associated with transfer (ARR = 1.2, CI = 1.1-1.4), and transferred infants tended to be less clinically complex. Infants with low birthweight, other birth defects, low Apgar scores, and late or no prenatal care had two- to fourfold higher risk of mortality than their comparison groups.These data support the importance of prenatal care and delivery planning into higher-level hospitals for optimal care and outcomes for newborns with CDH.
View details for DOI 10.1038/s41372-020-0612-6
View details for PubMedID 32086437
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Associations between interpregnancy interval and preterm birth by previous preterm birth status in four high-income countries: a cohort study.
BJOG : an international journal of obstetrics and gynaecology
2020
Abstract
To investigate the effect of interpregnancy interval (IPI) on preterm birth (PTB) according to whether the previous birth was preterm or term.Cohort study.USA (California), Australia, Finland, Norway (1980-2017).Women who gave birth to first and second (N=3,213,855) singleton livebirths.Odds ratios (ORs) for PTB according to IPIs were modelled using logistic regression with prognostic score stratification for potential confounders. Within-site ORs were pooled by random-effects meta-analysis.PTB (gestational age<37 weeks).Absolute risk of PTB for each IPI ranged from 3-6% after previous term and 17-22% after previous PTB. ORs for PTB differed between previous term and preterm births in all countries (P-for-interaction≤0.001). For women with a previous term birth, pooled ORs were increased for IPI <6months (1.50, 95%CI 1.43-1.58); 6-11months (1.10, 95%CI 1.04-1.16); 24-59months (1.16, 95%CI 1.13-1.18); and ≥60months (1.72, 95%CI 1.60-1.86), compared to 18-23months. For previous PTB, ORs were increased for <6months (1.30, 95%CI 1.18-1.42) and ≥60months (1.29, 95%CI 1.17-1.42), but were less than ORs among women with a previous term birth (P<0.05).Associations between IPI and PTB are modified by whether the previous pregnancy was preterm. ORs for short and long IPIs were higher among women with a previous term birth than a previous PTB, which for short IPI is consistent with the maternal depletion hypothesis. Given high risk of recurrence and assuming a causal association between IPI and PTB, IPI remains a potentially modifiable risk factor for women with previous PTB.
View details for DOI 10.1111/1471-0528.16606
View details for PubMedID 33232573
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Male-to-female ratios among NTDs and women's periconceptional intake of folic acid.
Birth defects research
2020
Abstract
About a decade ago, a hypothesis was put forward to explain the preponderance of females among neural tube defect (NTD) fetuses. That hypothesis predicts that a woman's higher levels of early gestational intake of methyl groups, such as folic acid, will be associated with lesser male-to-female ratio differences in NTD-affected births, specifically less preponderance of females. We explored this hypothesis in four distinct studies that investigated human NTDs, obtained information on folic acid, and capitalized on timing of folic acid fortification by investigating data that were collected both prior to and after the 1998 initiation of U.S. mandatory folic acid fortification of grains.We analyzed data from four population-based case control studies conducted in California for birth years spanning 1987-2011. Two studies were conducted before folic acid fortification of the U.S. food supply. Each of the four studies included interviews of women who either had NTD-affected pregnancies (cases) or who did not have a pregnancy affected by a birth defect (controls). In each study, information on periconceptional supplement use was elicited. We explored male-to-female ratios and 95% binomial confidence limits in each data set.Our analyses of two case-control studies performed prior to and two performed post mandatory folate fortification in the United States showed that more NTD-affected fetuses were female in the first two studies. In the studies done before fortification, the frequency of females was even greater among those pregnancies without folic acid supplementation.Our findings suggest folic acid may differentially reduce risk of NTDs among female fetuses.
View details for DOI 10.1002/bdr2.1708
View details for PubMedID 32415919
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Periconceptional stressors and social support and risk for adverse birth outcomes.
BMC pregnancy and childbirth
2020; 20 (1): 487
Abstract
The prevalence of preterm birth and low birth weight has been increasing slightly in recent years. A few studies have suggested that psychosocial stress during pregnancy may increase risk for these adverse birth outcomes. To extend those observations, we analyzed various major life event stressors separately and cumulatively as potential risk factors for preterm birth and low birth weight using granular categories of each outcome in a large, population-based study. Additionally, we assessed if greater social support buffered any effects.Data were from a nested prevalence study of 4395 women in the National Birth Defects Prevention Study who delivered live-born non-malformed infants (controls) between 2006 and 2011. Participants completed a standardized, computer-assisted interview between 6 weeks and 24 months after delivery that included questions on stress and social support from 3 months before pregnancy to the 3rd month of pregnancy. Cumulative stress and support indices were also calculated. Preterm birth was divided into "early preterm" (< 32 weeks), "late preterm" (32-36 weeks) and "term." Low birthweight was divided into "very low birth weight" (< 1500 g), "low birth weight" (1500-2499 g) and "normal birth weight" (≥2500 g). Relative risks and 95% confidence intervals (95% CI) were calculated using Poisson regression.For women reporting relationship difficulties, there was a suggestive risk of early preterm birth (RR: 1.9, 95%CI: 0.9-3.9) and very low birthweight (RR: 2.0, 95%CI: 0.9-4.4). For women reporting that they or someone close to them were victims of abuse, violence, or crime, there was an increased risk of low birthweight (RR: 1.8, 95%CI: 1.1-2.7) and late preterm birth (RR: 1.5, 95%CI: 1.0-2.2). There were no strong associations observed between social support questions and the various outcomes.Our results add some support to prior evidence that certain stressors may be associated with increase selected adverse birth outcomes risk. We did not find strong evidence that social support buffered the observed risks in our study.
View details for DOI 10.1186/s12884-020-03182-6
View details for PubMedID 32831042
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FKBP8 variants are risk factors for spina bifida.
Human molecular genetics
2020
Abstract
Neural tube defects (NTDs) are a group of severe congenital malformations caused by a failure of neural tube closure during early embryonic development. Although extensively investigated, the genetic etiology of NTDs remains poorly understood. FKBP8 is critical for proper mammalian neural tube closure. Fkbp8-/- mouse embryos showed posterior NTDs consistent with a diagnosis of spina bifida (SB). To date, no publication has reported any association between FKBP8 and human NTDs. Using Sanger sequencing on genomic DNA samples from 472 SB and 565 control samples, we identified 5 rare (MAF < =0.001) deleterious variants in SB patients, while no rare deleterious variant was identified in the controls (p = 0.0191). p.Glu140* affected FKBP8 localization to the mitochondria and created a truncated form of the FKBP8 protein, thus impairing its interaction with BCL2 and ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein levels. p.Lys315Asn further increased the cellular apoptosis. RNA sequencing on anterior and posterior tissues isolated from Fkbp8-/- and wildtype mice at E9.5 and E10.5 showed that Fkbp8-/- embryos have an abnormal expression profile within tissues harvested at posterior sites, thus leading to a posterior NTD. Moreover, we found that Fkbp8 knockout mouse embryos have abnormal expression of Wnt3a and Nkx2.9 during the early stage of neural tube development, perhaps also contributing to caudal specific NTDs. These findings provide evidence that functional variants of FKBP8 are risk factors for SB, which may involve a novel mechanism by which Fkbp8 mutations specifically cause SB in mice.
View details for DOI 10.1093/hmg/ddaa211
View details for PubMedID 32969478
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Loss of RAD9B impairs early neural development and contributes to the risk for human spina bifida.
Human mutation
2020
Abstract
DNA damage response (DDR) genes orchestrating the network of DNA repair, cell cycle control, are essential for the rapid proliferation of neural progenitor cells (NPC). To date, the potential association between specific DDR genes and the risk of human neural tube defects (NTDs) has not been investigated. Using whole-genome sequencing (WGS) and targeted sequencing, we identified significant enrichment of rare deleterious RAD9B variants in spina bifida cases compared to controls (8/409 vs 0 /298, p=0.0241). Among the eight identified variants, the two frameshift mutants and p.Gln146Glu affected RAD9B nuclear localization. The two frameshift mutants also decreased the protein level of RAD9B. p.Ser354Gly, as well as the two frameshifts, affected the cell proliferation rate. Finally, p.Ser354Gly, p.Ser10Gly, p.Ile112Met, p.Gln146Glu and the two frameshift variants showed a decreased ability for activating JNK phosphorylation. RAD9B knockdowns in human embryonic stem cells (hESCs) profoundly affected early differentiation through impairing PAX6 and OCT4 expression. RAD9B deficiency impeded in vitro formation of neural organoids, a 3D cell culture model for human neural development. Furthermore, the RNA-seq data revealed that loss of RAD9B dysregulates cell adhesion genes during organoid formation. These results represent the first demonstration of a DDR gene as an NTD risk factor in humans. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/humu.23969
View details for PubMedID 31898828
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Racial/ethnic disparities and human milk use in necrotizing enterocolitis.
Pediatric research
2020; 88 (Suppl 1): 3–9
Abstract
The impact of human milk use on racial/ethnic disparities in necrotizing enterocolitis (NEC) incidence is unknown.Trends in NEC incidence and human milk use at discharge were evaluated by race/ethnicity among 47,112 very low birth weight infants born in California from 2008 to 2017. We interrogated the association between race/ethnicity and NEC using multilevel regression analysis, and evaluated the effect of human milk use at discharge on the relationship between race/ethnicity and NEC using mediation analysis.Annual NEC incidence declined across all racial/ethnic groups from an aggregate average of 4.8% in 2008 to 2.6% in 2017. Human milk use at discharge increased over the time period across all racial groups, and non-Hispanic (NH) black infants received the least human milk each year. In multivariable analyses, Hispanic ethnicity (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.02-1.57) and Asian or Pacific Islander race (OR 1.35, 95% CI 1.01-1.80) were each associated with higher odds of NEC, while the association of NH black race with NEC was attenuated after adding human milk use at discharge to the model. Mediation analysis revealed that human milk use at discharge accounted for 22% of the total risk of NEC in non-white vs. white infants, and 44% in black vs. white infants.Although NEC incidence has declined substantially over the past decade, a sizable racial/ethnic disparity persists. Quality improvement initiatives augmenting human milk use may further reduce the incidence of NEC in vulnerable populations.
View details for DOI 10.1038/s41390-020-1073-5
View details for PubMedID 32855505
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Outcome of cerclage in pregnancies without a prior preterm birth
MOSBY-ELSEVIER. 2020: S672–S673
View details for DOI 10.1016/j.ajog.2019.11.1103
View details for Web of Science ID 000504997301409
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Vaginal progesterone treatment is associated with intrahepatic cholestasis of pregnancy
MOSBY-ELSEVIER. 2020: S58–S59
View details for DOI 10.1016/j.ajog.2019.11.084
View details for Web of Science ID 000504997300069
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Do women who delivered at 34-36 weeks need serial transvaginal ultrasound cervical lengths?
MOSBY-ELSEVIER. 2020: S401
View details for DOI 10.1016/j.ajog.2019.11.644
View details for Web of Science ID 000504997300627
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Effects of Selective Exclusion of Patients on Preterm Birth Test Performance.
Obstetrics and gynecology
2020; 135 (5): 1228–29
View details for DOI 10.1097/AOG.0000000000003855
View details for PubMedID 32332399
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Residential proximity to green space and preeclampsia in California.
Environmental epidemiology (Philadelphia, Pa.)
2020; 4 (6): e120
Abstract
We investigated whether residing near more green space might reduce the risk of preeclampsia.Participants were women who delivered a live, singleton birth between 1998 and 2011 in eight counties of the San Joaquin Valley in California. There were 7276 cases of preeclampsia divided into mild, severe, or superimposed on preexisting hypertension. Controls were 197,345 women who did not have a hypertensive disorder and delivered between 37 and 41 weeks. Green space was estimated from satellite data using Normalized Difference Vegetation Index (NDVI), an index calculated from surface reflectance at the visible and near-infrared wavelengths. Values closer to 1 denote a higher density of green vegetation. Average NDVI was calculated within a 50 m, 100 m, and 500 m buffer around each woman's residence. Odds ratios and 95% confidence intervals were estimated comparing the lowest and highest quartiles of mean NDVI to the interquartile range comparing each preeclampsia phenotype, divided into early (20-31 weeks) and late (32-36 weeks) preterm birth, to full-term controls.We observed an inverse association in the 500 m buffer for women in the top quartile of NDVI and a positive association for women in the lowest quartile of NDVI for women with superimposed preeclampsia. There were no associations in the 50 and 100 m buffers.Within a 500 m buffer, more green space was inversely associated with superimposed preeclampsia. Future work should explore the mechanism by which green space may protect against preeclampsia.
View details for DOI 10.1097/EE9.0000000000000120
View details for PubMedID 33336135
View details for PubMedCentralID PMC7727466
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Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries.
JAMA network open
2020; 3 (12): e2029655
Abstract
Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies.To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB.This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019.Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites.The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation.Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways.This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB.
View details for DOI 10.1001/jamanetworkopen.2020.29655
View details for PubMedID 33337494
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Association between preconception paternal health and pregnancy loss in the USA: an analysis of US claims data.
Human reproduction (Oxford, England)
2020
Abstract
Is preconception paternal health associated with pregnancy loss?Poor preconception paternal health is associated with a higher risk of pregnancy loss as confirmed in sensitivity analyses accounting for maternal age and health.Preconception paternal health can negatively impact perinatal outcomes.Retrospective cohort study of US insurance claims database from 2009 to 2016 covering 958 804 pregnancies.US insurance claims database including women, men and pregnancies within the USA between 2007 and 2016. Paternal preconception health status (e.g. metabolic syndrome diagnoses (MetS), Charlson comorbidity index (CCI) and individual chronic disease diagnoses) was examined in relation to pregnancy loss (e.g. ectopic pregnancy, miscarriage and stillbirth).In all, 958 804 pregnancies were analyzed. The average paternal age was 35.3 years (SD 5.3) and maternal age was 33.1 years (SD 4.4). Twenty-two percent of all pregnancies ended in a loss. After adjusting for maternal factors, the risk of pregnancy loss increased with increasing paternal comorbidity. For example, compared to men with no components of MetS, the risk of pregnancy loss increased for men with one (relative risk (RR) 1.10, 95% CI 1.09-1.12), two (RR 1.15, 95% CI 1.13-1.17) or three or more (RR 1.19, 95% CI 1.14-1.24) components. Specifically, less healthy men had a higher risk of siring a pregnancy ending in spontaneous abortion, stillbirth and ectopic pregnancies. Similar patterns remained with other measures of paternal health (e.g. CCI, chronic diseases, etc.). When stratifying by maternal age as well as maternal health, a similar pattern of increasing pregnancy loss risk for men with 1, 2 or 3+ MetS was observed. A statistically significant but weak association between timing of pregnancy loss and paternal health was found.Retrospective study design covering only employer insured individuals may limit generalizability.Optimization of a father's health may improve pregnancy outcomes.National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085). M.L.E. is an advisor for Sandstone Diagnostics, Dadi, Hannah and Underdog. No other competing interests were declared.N/A.
View details for DOI 10.1093/humrep/deaa332
View details for PubMedID 33336240
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Oil and gas production and spontaneous preterm birth in the San Joaquin Valley, CA: A case-control study.
Environmental epidemiology (Philadelphia, Pa.)
2020; 4 (4): e099
Abstract
Recent studies report an association between preterm birth and exposure to unconventional oil and gas wells. There has been limited previous study on exposure to conventional wells, which are common in California. Our objective was to determine whether exposure to well sites was associated with increased odds of spontaneous preterm birth (delivery at <37 weeks).We conducted a case-control study using data on 27,913 preterm birth cases and 197,461 term birth controls. All births were without maternal comorbidities and were located in the San Joaquin Valley, CA, between 1998 and 2011. We obtained data for 83,559 wells in preproduction or production during the study period. We assessed exposure using inverse distance-squared weighting and, for each birth and trimester, we assigned an exposure tertile. Using logistic regression, we estimated adjusted odds ratios (ORs) for the association between exposure to well sites and preterm birth at 20-27, 28-31, and 32-36 weeks.We observed increased ORs for preterm birth with high exposure to wells in the first and second trimesters for births delivered at ≤31 weeks (adjusted ORs, 1.08-1.14). In stratified analyses, the associations were confined to births to Hispanic and non-Hispanic Black women and to women with ≤12 years of educational attainment. In a secondary analysis, we found evidence that exposure to wells in preproduction is associated with higher concentrations of particulate matter.We found evidence that exposure to oil and gas well sites is associated with increased risk of spontaneous preterm birth.
View details for DOI 10.1097/EE9.0000000000000099
View details for PubMedID 32832838
View details for PubMedCentralID PMC7423522
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Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia.
PloS one
2020; 15 (3): e0230000
Abstract
Placental protein expression plays a crucial role during pregnancy. We hypothesized that: (1) circulating levels of pregnancy-associated, placenta-related proteins throughout gestation reflect the temporal progression of the uncomplicated, full-term pregnancy, and can effectively estimate gestational ages (GAs); and (2) preeclampsia (PE) is associated with disruptions in these protein levels early in gestation; and can identify impending PE. We also compared gestational profiles of proteins in the human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms.Serum levels of placenta-related proteins-leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)-were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 subjects who developed PE with 61 samples). Multivariate analysis was performed to estimate the GA in normal pregnancy. Mean-squared errors of GA estimations were used to identify impending PE. The human protein profiles were then compared with those in the pregnant HO-1 Het mice.An elastic net-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using serum levels of the 6 proteins measured at various GAs from women with normal uncomplicated pregnancies. In women who developed PE, the model was not (R2 = -0.17) associated with GA. Deviations from the model estimations were observed in women who developed PE (P = 0.01). The model developed with 5 proteins (ELA excluded) performed similarly from sera from normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (R2 = 0.27) and mouse HO-1 Het (R2 = 0.30) pregnancies. LEP outperformed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse GAs.Serum placenta-related protein profiles are temporally regulated throughout normal pregnancies and significantly disrupted in women who develop PE. LEP changes earlier than the well-established biomarkers (sFlt-1 and PlGF). There may be evidence of a causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model.
View details for DOI 10.1371/journal.pone.0230000
View details for PubMedID 32126118
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Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation.
Frontiers in pediatrics
2020; 8: 605219
Abstract
In recent years, there have been major advances in the application of non-invasive techniques to predict pregnancy-related complications, for example by measuring cell-free RNA (cfRNA) in maternal blood. In contrast to cell-free DNA (cfDNA), which is already in clinical use to diagnose fetal aneuploidy, circulating RNA levels can correspond with tissue-specific gene expression and provide a snapshot of prenatal health across gestation. Here, we review the physiologic origins of cfRNA and its novel applications and corresponding challenges to monitor fetal and maternal health and predict pregnancy-related complications.
View details for DOI 10.3389/fped.2020.605219
View details for PubMedID 33381480
View details for PubMedCentralID PMC7767905
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VoPo leverages cellular heterogeneity for predictive modeling of single-cell data.
Nature communications
2020; 11 (1): 3738
Abstract
High-throughput single-cell analysis technologies produce an abundance of data that is critical for profiling the heterogeneity of cellular systems. We introduce VoPo (https://github.com/stanleyn/VoPo), a machine learning algorithm for predictive modeling and comprehensive visualization of the heterogeneity captured in large single-cell datasets. In three mass cytometry datasets, with the largest measuring hundreds of millions of cells over hundreds of samples, VoPo defines phenotypically and functionally homogeneous cell populations. VoPo further outperforms state-of-the-art machine learning algorithms in classification tasks, and identified immune-correlates of clinically-relevant parameters.
View details for DOI 10.1038/s41467-020-17569-8
View details for PubMedID 32719375
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Mid-gestation serum lipidomic profile associations with spontaneous preterm birth are influenced by body mass index.
PloS one
2020; 15 (11): e0239115
Abstract
Spontaneous preterm birth (sPTB) is a major cause of infant morbidity and mortality. While metabolic changes leading to preterm birth are unknown, several factors including dyslipidemia and inflammation have been implicated and paradoxically both low (<18.5 kg/m2) and high (>30 kg/m2) body mass indices (BMIs) are risk factors for this condition. The objective of the study was to identify BMI-associated metabolic perturbations and potential mid-gestation serum biomarkers of preterm birth in a cohort of underweight, normal weight and obese women experiencing either sPTB or full-term deliveries (n = 102; n = 17/group). For this purpose, we combined untargeted metabolomics and lipidomics with targeted metabolic profiling of major regulators of inflammation and metabolism, including oxylipins, endocannabinoids, bile acids and ceramides. Women who were obese and had sPTB showed elevated oxidative stress and dyslipidemia characterized by elevated serum free fatty acids. Women who were underweight-associated sPTB also showed evidence of dyslipidemia characterized by elevated phospholipids, unsaturated triglycerides, sphingomyelins, cholesteryl esters and long-chain acylcarnitines. In normal weight women experiencing sPTB, the relative abundance of 14(15)-epoxyeicosatrienoic acid and 14,15-dihydroxyeicosatrienoic acids to other regioisomers were altered at mid-pregnancy. This phenomenon is not yet associated with any biological process, but may be linked to estrogen metabolism. These changes were differentially modulated across BMI groups. In conclusion, using metabolomics we observed distinct BMI-dependent metabolic manifestations among women who had sPTB. These observations suggest the potential to predict sPTB mid-gestation using a new set of metabolomic markers and BMI stratification. This study opens the door to further investigate the role of cytochrome P450/epoxide hydrolase metabolism in sPTB.
View details for DOI 10.1371/journal.pone.0239115
View details for PubMedID 33201881
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Defining critical factors in multi-country studies of assisted reproductive technologies (ART): data from the US and UK health systems.
Journal of assisted reproduction and genetics
2020
Abstract
As the worldwide use of assisted reproductive technologies (ART) continues to grow, there is a critical need to assess the safety of these treatment parameters and the potential adverse health effects of their use in adults and their offspring. While key elements remain similar across nations, geographic variations both in treatments and populations make generalizability challenging. We describe and compare the demographic factors between the USA and the UK related to ART use and discuss implications for research. The USA and the UK share some common elements of ART practice and in how data are collected regarding long-term outcomes. However, the monitoring of ART in these two countries each brings strengths that complement each other's limitations.
View details for DOI 10.1007/s10815-020-01951-y
View details for PubMedID 32995971
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Preterm birth outcomes among Asian women by maternal place of birth.
Journal of perinatology : official journal of the California Perinatal Association
2020
Abstract
To investigate overall, spontaneous, and medically indicated preterm birth (PTB) rates between US-born and non-US-born Asian women living in California.Nulliparous women with a singleton livebirth and Asian race in California between 2007 and 2011 were investigated. The prevalence of overall (<37 weeks), spontaneous, and medically indicated PTB was examined by self-reported race and place of birth among ten Asian subgroups.There were marked differences in PTB rates between the individual Asian subgroups. After adjustments, non-US-born Chinese, Japanese, Vietnamese, and Indian women had lower odds of overall PTB and Chinese, Vietnamese, Cambodian, and Indian women had lower odds of spontaneous PTB compared with their US-born counterparts.Further investigation of biological and social factors contributing to these lower odds of spontaneous PTB among the non-US-born Asian population could potentially offer clues for reducing the burden of PTB among the US born.
View details for DOI 10.1038/s41372-020-0633-1
View details for PubMedID 32094480
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Still- and Live Births in the Periviable Period.
Annals of epidemiology
2020
Abstract
We use data from California, where 13% of US births occur, to address two questions arising from efforts in the first decade of this century to avoid stillbirth before 25 6/7 weeks of gestation (i.e., in the periviable period). First, did stillbirths decline in the first decade of this century? Second, if stillbirths did decline, did periviable live births increase simultaneously? Answering these questions would seem important given that periviable infants represent <1% of live births but account for roughly 40% of infant mortality and 20% of hospital-based obstetric costs in the US.We constructed 240 monthly conception cohorts, starting with that conceived in January 1991, from 9,880,536 singleton pregnancies that reached the 20 0/7 week of gestation. We used time-series design and Box-Jenkins methods that address confounding by autocorrelation, including secular trends and seasonality to answer our questions.We detected a downward shift in stillbirths in April 2007 that coincided with an upward shift in periviable live births.Our findings imply that, since 2007, fewer Californians than expected from history and from the size of conception cohorts reaching 20 0/7 weeks of gestation, have had to contend with the sequelae of stillbirth, but more than expected likely have had to contend with those of periviable birth.
View details for DOI 10.1016/j.annepidem.2020.07.002
View details for PubMedID 32648545
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Evaluation of US State-Level Variation in Hypertensive Disorders of Pregnancy.
JAMA network open
2020; 3 (10): e2018741
Abstract
Hypertensive disorders of pregnancy are important causes of maternal and perinatal morbidity in the US. However, the extent of statewide variation in the prevalence of chronic hypertension, pregnancy-induced hypertension or preeclampsia, and eclampsia in the US remains unknown.To examine the extent of statewide variation in the prevalence of chronic hypertension, hypertensive disorders of pregnancy (including pregnancy-induced hypertension or preeclampsia), and eclampsia in the US.A cross-sectional study using 2017 US birth certificate data was conducted from September 1, 2019, to February 1, 2020. A population-based sample of 3 659 553 women with a live birth delivery was included.State-specific prevalence of chronic hypertension, hypertensive disorders of pregnancy, and eclampsia was assessed using multilevel multivariable logistic regression, with the median odds ratio (MOR) to evaluate statewide variation.Of the 3 659 553 women, 185 932 women (5.1%) were younger than 20 years, 727 573 women (19.9%) were aged between 20 and 24 years, 1 069 647 women (29.2%) were aged between 25 and 29 years, 1 037 307 women (28.3%) were aged between 30 and 34 years, 523 607 women (14.3%) were aged between 35 and 39 years, and 115 487 women (3.2%) were 40 years or older. Most women had Medicaid (42.8%) or private insurance (49.4%). Hawaii had the lowest adjusted prevalence of chronic hypertension (1.0%; 95% CI, 0.9%-1.2%), and Alaska had the highest (3.4%; 95% CI, 3.0%-3.9%). Massachusetts had the lowest adjusted prevalence of hypertensive disorders of pregnancy (4.3%; 95% CI, 4.1%-4.6%), and Louisiana had the highest (9.3%; 95% CI, 8.9%-9.8%). Delaware had the lowest adjusted prevalence of eclampsia (0.03%; 95% CI, 0.01%-0.09%), and Hawaii had the highest (2.8%; 95% CI, 2.2%-3.4%). The degree of statewide variation was high for eclampsia (MOR, 2.36; 95% CI, 1.88-2.82), indicating that the median odds of eclampsia were 2.4-fold higher if the same woman delivered in a US state with a higher vs lower prevalence of eclampsia. Modest variation between states was observed for chronic hypertension (MOR, 1.27; 95% CI, 1.20-1.33) and hypertensive disorders of pregnancy (MOR, 1.17; 95% CI, 1.13-1.21).The findings of this study suggest that after accounting for patient-level and state-level variables, substantial state-level variation exists in the prevalence of eclampsia. These data can inform future public-health inquiries to identify reasons for the eclampsia variability.
View details for DOI 10.1001/jamanetworkopen.2020.18741
View details for PubMedID 33001203
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High-throughput quantitation of serological ceramides/dihydroceramides by LC/MS/MS: Pregnancy baseline biomarkers and potential metabolic messengers.
Journal of pharmaceutical and biomedical analysis
2020; 192: 113639
Abstract
Ceramides and dihydroceramides are sphingolipids that present in abundance at the cellular membrane of eukaryotes. Although their metabolic dysregulation has been implicated in many diseases, our knowledge about circulating ceramide changes during the pregnancy remains limited. In this study, we present the development and validation of a high-throughput liquid chromatography-tandem mass spectrometric method for simultaneous quantification of 16 ceramides and 10 dihydroceramides in human serum within 5 min. by using stable isotope-labeled ceramides as internal standards. This method employs a protein precipitation method for high throughput sample preparation, reverse phase isocratic elusion for chromatographic separation, and Multiple Reaction Monitoring for mass spectrometric detection. To qualify for clinical applications, our assay has been validated against the FDA guidelines for Lower Limit of Quantitation (1 nM), linearity (R2>0.99), precision (imprecision<15 %), accuracy (inaccuracy<15 %), extraction recovery (>90 %), stability (>85 %), and carryover (<0.01 %). With enhanced sensitivity and specificity from this method, we have, for the first time, determined the serological levels of ceramides and dihydroceramides to reveal unique temporal gestational patterns. Our approach could have value in providing insights into disorders of pregnancy.
View details for DOI 10.1016/j.jpba.2020.113639
View details for PubMedID 33017796
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Multiomic immune clockworks of pregnancy.
Seminars in immunopathology
2020
Abstract
Preterm birth is the leading cause of mortality in children under the age of five worldwide. Despite major efforts, we still lack the ability to accurately predict and effectively prevent preterm birth. While multiple factors contribute to preterm labor, dysregulations of immunological adaptations required for the maintenance of a healthy pregnancy is at its pathophysiological core. Consequently, a precise understanding of these chronologically paced immune adaptations and of the biological pacemakers that synchronize the pregnancy "immune clock" is a critical first step towards identifying deviations that are hallmarks of peterm birth. Here, we will review key elements of the fetal, placental, and maternal pacemakers that program the immune clock of pregnancy. We will then emphasize multiomic studies that enable a more integrated view of pregnancy-related immune adaptations. Such multiomic assessments can strengthen the biological plausibility of immunological findings and increase the power of biological signatures predictive of preterm birth.
View details for DOI 10.1007/s00281-019-00772-1
View details for PubMedID 32020337
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A Genome-Wide Analysis of Clinical Chorioamnionitis among Preterm Infants
AMERICAN JOURNAL OF PERINATOLOGY
2019; 36 (14): 1453–58
View details for DOI 10.1055/s-0038-1677503
View details for Web of Science ID 000499481500005
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Associations between fine particulate matter, extreme heat events, and congenital heart defects.
Environmental epidemiology (Philadelphia, Pa.)
2019; 3 (6): e071
Abstract
Previous research reports associations between air pollution measured during pregnancy and the occurrence of congenital heart defects (CHDs) in offspring. The objective of this research was to assess if exposure to extreme heat events (EHEs) during pregnancy may modify this association.Methods: The study population consisted of 4,033 controls and 2,632 cases with dates of delivery between 1999 and 2007 who participated in the National Birth Defects Prevention Study, a multi-site case-control study in the United States. Daily data from the closest stationary fine particulate matter (PM2.5) monitor within 50 km from the maternal residence were averaged across weeks 3-8 post-conception. EHEs were defined as maximum ambient temperature in the upper 95th percentile for at least 2 consecutive days or the upper 90th percentile for 3 consecutive days. Logistic regression models were adjusted for maternal age, ethnicity, education, and average humidity. Relative excess risks due to interaction (RERI) were calculated.Results: Compared with women with low PM2.5 exposure and no exposure to an EHE, the odds of a ventricular septal defect in offspring associated with high PM2.5 exposure was elevated only among women who experienced an EHE (odds ratio [OR] 2.14 95% confidence interval [CI] 1.19, 3.38 vs. OR 0.97 95% CI 0.49, 1.95; RERI 0.82 95% CI -0.39, 2.17). The majority of observed associations and interactions for other heart defects were null and/or inconclusive due to lack of precision.Conclusions: This study provides limited evidence that EHEs may modify the association between prenatal exposure to PM2.5 and CHD occurrence.
View details for DOI 10.1097/EE9.0000000000000071
View details for PubMedID 32091506
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Male-to-Female Ratios, Race/Ethnicity, and Spontaneous Preterm Birth among 11 Million California Infants.
American journal of perinatology
2019
Abstract
OBJECTIVE: An observed disparity in population-scale data are a larger number of males among preterm births (PTBs). We investigated spontaneous PTB risk among women of various race/ethnic groups in combination with infants' sex.STUDY DESIGN: This observational study was conducted in>10 million California births (1991-2012) using birth certificates linked with maternal and infant hospital discharge data.RESULTS: Male-to-female ratios among term (37-42 weeks) infants exhibited the narrow ratio range 1.02 to 1.06 across race/ethnic groups. Such ratios among spontaneous PTBs were generally larger for all race/ethnic groups except non-Hispanic blacks. For blacks, ratios tended to be lower and similar to their term birth counterpart, 1.03. Hazard ratios adjusted for maternal age and education for non-Hispanic blacks were 0.99 (95% confidence interval [CI] 0.90-1.09), 1.01 (95% CI 0.95-1.08), 0.98 (95% CI 0.94-1.03), and 1.03 (95% CI 1.01-1.05), respectively, for gestational week groupings of 20 to 23, 24 to 27, 28 to 321, and 32 to 36. Hazard ratios for non-Hispanic whites for the same groupings were 1.08 (95% CI 0.98-1.18), 1.13 (95% CI 1.07-1.19), 1.21 (95% CI 1.17-1.25), and 1.18 (95% CI 1.17-1.19).CONCLUSION: Why male-to-female ratios are similar across gestational ages in blacks but substantially higher in other race/ethnic groups is theoretically considered relative to inflammation, stress, and other influences.
View details for DOI 10.1055/s-0039-3400449
View details for PubMedID 31756757
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Failed umbilical artery catheterization and adverse outcomes in extremely low birth weight infants
JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
2019; 32 (21): 3566–70
View details for DOI 10.1080/14767058.2018.1468430
View details for Web of Science ID 000478069900010
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Single Cell Transcriptomes Derived from Human Cervical and Uterine Tissue during Pregnancy
ADVANCED BIOSYSTEMS
2019; 3 (11)
View details for DOI 10.1002/adbi.201800336
View details for Web of Science ID 000498192300005
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Single Cell Transcriptomes Derived from Human Cervical and Uterine Tissue during Pregnancy.
Advanced biosystems
2019; 3 (11): e1800336
Abstract
This work presents the workflow for generating single cell transcriptomes derived from primary human uterine and cervical tissue obtained during planned cesarean hysterectomies. In total, a catalogue of 310 single cell transcriptomes are obtained, cell types present in these biopsies are inferred, and specific genes defining each of the cellular types present in the tissue are identified. Further validation of the inferred cell identity is also demonstrated via meta-analysis of independent repositories in literature generated by bulk sequenced data of fluorescence-activated cell sorting sorted cells.
View details for DOI 10.1002/adbi.201800336
View details for PubMedID 32648692
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Associations between PM2.5 and risk of preterm birth among liveborn infants.
Annals of epidemiology
2019
Abstract
PURPOSE: Studies suggest exposure to ambient particulate matter less than 2.5mug/m3 in aerodynamic diameter (PM2.5) may be associated with preterm birth (PTB), but few have evaluated how this is modified by ambient temperature. We investigated the relationship between PM2.5 exposure during pregnancy and PTB in infants without birth defects (1999-2006) and enrolled in the National Birth Defects Prevention Study and how it is modified by concurrent temperature.METHODS: PTB was defined as spontaneous or iatrogenic delivery before 37weeks. Exposure was assigned using inverse distance weighting with up to four monitors within 50kilometers of maternal residence. To account for state-level variations, a Bayesian two-level hierarchal model was developed.RESULTS: PTB was associated with PM2.5 during the third and fourth months of pregnancy (range: (odds ratio (95% confidence interval)=1.00 (0.35, 2.15) to 1.49 (0.82, 2.68) and 1.31 (0.56, 2.91) to 1.62 (0.7, 3.32), respectively); no week of exposure conveyed greater risk. Temperature may modify this relationship; higher local average temperatures during pregnancy yielded stronger positive relationships between PM2.5 and PTB compared to nonstratified results.CONCLUSIONS: Results add to literature on associations between PM2.5 and PTB, underscoring the importance of considering co-exposures when estimating effects of PM2.5 exposure during pregnancy.
View details for DOI 10.1016/j.annepidem.2019.09.008
View details for PubMedID 31678056
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Air Pollution, Maternal Hypertensive Disorders, and Preterm Birth.
Environmental epidemiology (Philadelphia, Pa.)
2019; 3 (5)
Abstract
Background: Air pollution has been associated with hypertension and preterm birth. We examined if prenatal exposure to air pollutants was associated with gestational hypertension and if its association with preterm birth was modified by maternal hypertension.Methods: Data were from birth certificates and hospital discharge records of 252,205 women in San Joaquin Valley of California from 2000-2006. Air quality data were assigned from 24-hour averages of nitrogen dioxide (NO2), particulate matter <10mum (PM10) and <2.5mum (PM2.5), and carbon monoxide (CO) for different averaging periods over pregnancy. We estimated odds of preterm birth and multiplicative interaction between each pollutant and hypertensive disorder.Results: Among normotensive women, odds of preterm birth were slightly higher for higher exposure to all pollutants over the entire pregnancy. Patterns were similar among women with a hypertensive disorder. Among 32-36 week births there was effect modification for exposure to NO2 and CO during the first trimester with higher odds among hypertensive women, and PM2.5 and CO during the last six weeks with higher odds among normotensive women. For 28-31 week births, there was effect modification by hypertensive status for PM10 exposure for entire pregnancy, first, and second trimester with hypertensive women consistently having lower odds of preterm birth than normotensive.Conclusion: There was some evidence of effect modification in the direction counter to our hypothesis for exposure to PM10 and early preterm birth, and CO and PM2.5 at the end of pregnancy, but overall, hypertension did not modify the relationship between pollution and preterm birth.
View details for DOI 10.1097/ee9.0000000000000062
View details for PubMedID 32051927
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Preterm birth phenotypes in women with autoimmune rheumatic diseases: A population based cohort study.
BJOG : an international journal of obstetrics and gynaecology
2019
Abstract
OBJECTIVE: To investigate preterm birth (PTB) phenotypes in women with different autoimmune rheumatic diseases in a large population-based cohort.DESIGN: Retrospective cohort study.SETTING: California, USA.POPULATION: All live singleton births in California between 2007 and 2011 were analyzed. Patients with autoimmune disease at delivery were identified by ICD-9 codes for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and juvenile idiopathic arthritis (JIA).METHODS: Maternally linked hospital and birth certificate records of 2,481,516 deliveries were assessed (SLE n=2,272, RA n=1,501, SSc n=88, JIA n=187, DM/PM n=38). Multivariable Poisson regression models estimated risk ratios (RRs) for different PTB phenotypes (relative to term deliveries) for each autoimmune disease compared to the general obstetric population adjusting for maternal age, race/ethnicity, body mass index, smoking, education, payer, parity, and prenatal care.MAIN OUTCOME MEASURES: PTB was assessed overall (20-36 weeks) and by subphenotype: pre-term premature rupture of membranes (PPROM), spontaneous, or medically indicated PTB. Risk of PTB overall and each phenotype was partitioned by gestational age: early (20-31 weeks) and late (32-36 weeks).RESULTS: Risks for PTB were elevated for each autoimmune disease evaluated: SLE (RR 3.27 95%CI 3.01-3.56), RA (RR 2.04 95%CI 1.79-2.33), SSc (RR 3.74 95%CI 2.51-5.58), JIA (RR 2.23 95%CI 1.54-3.23), and DM/PM (RR 5.26 95%CI 3.12-8.89). These elevated risks were observed for the majority of PTB phenotypes as well.CONCLUSIONS: Women with systemic autoimmune diseases appear to have an elevated risk of various PTB phenotypes. Therefore, preconception counseling and close monitoring during pregnancy is crucial.
View details for DOI 10.1111/1471-0528.15970
View details for PubMedID 31571337
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Maternal exposure to outdoor air pollution and congenital limb deficiencies in the National Birth Defects Prevention Study.
Environmental research
2019; 179 (Pt A): 108716
Abstract
BACKGROUND: Congenital limb deficiencies (CLDs) are a relatively common group of birth defects whose etiology is mostly unknown. Recent studies suggest maternal air pollution exposure as a potential risk factor.AIM: To investigate the relationship between ambient air pollution exposure during early pregnancy and offspring CLDs.METHODS: The study population was identified from the National Birth Defects Prevention Study, a population-based multi-center case-control study, and consisted of 615 CLD cases and 5,701 controls with due dates during 1997 through 2006. Daily averages and/or maxima of six criteria air pollutants (particulate matter <2.5 mum [PM2.5], particulate matter <10 mum [PM10], nitrogen dioxide [NO2], sulfur dioxide [SO2], carbon monoxide [CO], and ozone [O3]) were averaged over gestational weeks 2-8, as well as for individual weeks during this period, using data from EPA air monitors nearest to the maternal address. Logistic regression was used to estimate odds ratios (aORs) and 95% confidence intervals (CIs) adjusted for maternal age, race/ethnicity, education, and study center. We estimated aORs for any CLD and CLD subtypes (i.e., transverse, longitudinal, and preaxial). Potential confounding by co-pollutant was assessed by adjusting for one additional air pollutant. Using the single pollutant model, we further investigated effect measure modification by body mass index, cigarette smoking, and folic acid use. Sensitivity analyses were conducted restricting to those with a residence closer to an air monitor.RESULTS: We observed near-null aORs for CLDs per interquartile range (IQR) increase in PM10, PM2.5, and O3. However, weekly averages of the daily average NO2 and SO2, and daily max NO2, SO2, and CO concentrations were associated with increased odds of CLDs. The crude ORs ranged from 1.03 to 1.12 per IQR increase in these air pollution concentrations, and consistently elevated aORs were observed for CO. Stronger associations were observed for SO2 and O3 in subtype analysis (preaxial). In co-pollutant adjusted models, associations with CO remained elevated (aORs: 1.02-1.30); but aORs for SO2 and NO2 became near-null. The aORs for CO remained elevated among mothers who lived within 20 km of an air monitor. The aORs varied by maternal BMI, smoking status, and folic acid use.CONCLUSION: We observed modest associations between CLDs and air pollution exposures during pregnancy, including CO, SO2, and NO2, though replication through further epidemiologic research is warranted.
View details for DOI 10.1016/j.envres.2019.108716
View details for PubMedID 31546130
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Reply to: Transpyloric feeds and bronchopulmonary dysplasia.
Journal of perinatology : official journal of the California Perinatal Association
2019
View details for DOI 10.1038/s41372-019-0458-y
View details for PubMedID 31431655
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Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data.
Birth defects research
2019
Abstract
BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens.METHODS: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA.RESULTS: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol.CONCLUSIONS: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers.
View details for DOI 10.1002/bdr2.1554
View details for PubMedID 31328417
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Factors Associated with Timeliness of Surgical Repair among Infants with Myelomeningocele: California Perinatal Quality Care Collaborative, 2006 to 2011.
American journal of perinatology
2019
Abstract
OBJECTIVE: To examine factors associated with timely (0-2 days after birth) myelomeningocele surgical repair.STUDY DESIGN: We examined 2006 to 2011 births from the California Perinatal Quality Care Collaborative, linking to hospital discharge and vital records. Selected maternal, infant, and delivery hospital characteristics were evaluated to understand disparities in timely repair. Poisson regression was used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs).RESULTS: Overall, 399 of the 450 (89%) infants had a timely repair and approximately 80% of them were delivered in level III/IV hospitals. Infants with hydrocephalus were significantly less likely to have a delayed myelomeningocele repair compared with those without (aRR=0.22; 95% CI=0.13, 0.39); infants whose medical care was paid by Medi-Cal or other nonprivate insurance were 2.2 times more likely to have a delayed repair compared with those covered by a private insurance (aRR=2.23; 95% CI=1.17, 4.27). Low birth weight was a significant predictor for delayed repair (aRR=2.06; 95% CI=1.10, 3.83).CONCLUSION: There was a significant disparity in myelomenigocele repair based on medical care payer. Families and hospitals should work together for timely repair in hospitals having specialized multidisciplinary teams. Findings from the study can be used to follow best clinical practices for myelomeningocele repair.
View details for DOI 10.1055/s-0039-1693127
View details for PubMedID 31307103
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Maternal Height and Risk of Preeclampsia among Race/Ethnic Groups
AMERICAN JOURNAL OF PERINATOLOGY
2019; 36 (8): 864–71
View details for DOI 10.1055/s-0038-1675205
View details for Web of Science ID 000474763600013
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Risk factors associated with the development of double-inlet ventricle congenital heart disease
BIRTH DEFECTS RESEARCH
2019; 111 (11): 640–48
View details for DOI 10.1002/bdr2.1501
View details for Web of Science ID 000473561000003
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Accumulation of rare coding variants in genes implicated in risk of human cleft lip with or without cleft palate
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2019; 179 (7): 1260–69
View details for DOI 10.1002/ajmg.a.61183
View details for Web of Science ID 000471068000019
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Sociodemographic, health behavioral, and clinical risk factors for anotia/microtia in a population-based case-control study
INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY
2019; 122: 18–26
View details for DOI 10.1016/j.ijporl.2019.03.026
View details for Web of Science ID 000471738900004
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Preterm Delivery Phenotypes in Systemic Lupus Erythematosus Pregnancies
AMERICAN JOURNAL OF PERINATOLOGY
2019; 36 (9): 964–68
View details for DOI 10.1055/s-0038-1675648
View details for Web of Science ID 000477661000014
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Reply to: 'Early transyploric feeding: an old wine in a new bottle'.
Journal of perinatology : official journal of the California Perinatal Association
2019
View details for DOI 10.1038/s41372-019-0418-6
View details for PubMedID 31222155
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Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia.
Frontiers in immunology
2019; 10: 1305
Abstract
Preeclampsia is one of the most severe pregnancy complications and a leading cause of maternal death. However, early diagnosis of preeclampsia remains a clinical challenge. Alterations in the normal immune adaptations necessary for the maintenance of a healthy pregnancy are central features of preeclampsia. However, prior analyses primarily focused on the static assessment of select immune cell subsets have provided limited information for the prediction of preeclampsia. Here, we used a high-dimensional mass cytometry immunoassay to characterize the dynamic changes of over 370 immune cell features (including cell distribution and functional responses) in maternal blood during healthy and preeclamptic pregnancies. We found a set of eight cell-specific immune features that accurately identified patients well before the clinical diagnosis of preeclampsia (median area under the curve (AUC) 0.91, interquartile range [0.82-0.92]). Several features recapitulated previously known immune dysfunctions in preeclampsia, such as elevated pro-inflammatory innate immune responses early in pregnancy and impaired regulatory T (Treg) cell signaling. The analysis revealed additional novel immune responses that were strongly associated with, and preceded the onset of preeclampsia, notably abnormal STAT5ab signaling dynamics in CD4+T cell subsets (AUC 0.92, p = 8.0E-5). These results provide a global readout of the dynamics of the maternal immune system early in pregnancy and lay the groundwork for identifying clinically-relevant immune dysfunctions for the prediction and prevention of preeclampsia.
View details for DOI 10.3389/fimmu.2019.01305
View details for PubMedID 31263463
View details for PubMedCentralID PMC6584811
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Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia
FRONTIERS IN IMMUNOLOGY
2019; 10
View details for DOI 10.3389/fimmu.2019.01305
View details for Web of Science ID 000470999000001
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Developing evidence-based recommendations for optimal interpregnancy intervals in high-income countries: protocol for an international cohort study
BMJ OPEN
2019; 9 (1)
View details for DOI 10.1136/bmjopen-2018-027941
View details for Web of Science ID 000471116800279
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Maternal genetic markers for risk of celiac disease and their potential association with neural tube defects in offspring
MOLECULAR GENETICS & GENOMIC MEDICINE
2019; 7 (6)
View details for DOI 10.1002/mgg3.688
View details for Web of Science ID 000476745400037
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Early transpyloric vs gastric feeding in preterm infants: a retrospective cohort study
JOURNAL OF PERINATOLOGY
2019; 39 (6): 837–41
View details for DOI 10.1038/s41372-019-0372-3
View details for Web of Science ID 000468895300010
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The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation
HUMAN MOLECULAR GENETICS
2019; 28 (10): 1726–37
View details for DOI 10.1093/hmg/ddz010
View details for Web of Science ID 000475882600012
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Accumulation of rare coding variants in genes implicated in risk of human cleft lip with or without cleft palate.
American journal of medical genetics. Part A
2019
Abstract
Cleft lip with/without cleft palate (CLP) is a common craniofacial malformation with complex etiologies, reflecting both genetic and environmental factors. Most of the suspected genetic risk for CLP has yet to be identified. To further classify risk loci and estimate the contribution of rare variants, we sequenced the exons in 49 candidate genes in 323 CLP cases and 211 nonmalformed controls. Our findings indicated that rare, protein-altering variants displayed markedly higher burdens in CLP cases at relevant loci. First, putative loss-of-function mutations (nonsense, frameshift) were significantly enriched among cases: 13 of 323 cases (~4%) harbored such alleles within these 49 genes, versus one such change in controls (p = 0.01). Second, in gene-level analyses, the burden of rare alleles showed greater case-association for several genes previously implicated in cleft risk. For example, BHMT displayed a 10-fold increase in protein-altering variants in CLP cases (p = .03), including multiple case occurrences of a rare frameshift mutation (K400fs). Other loci with greater rare, coding allele burdens in cases were in signaling pathways relevant to craniofacial development (WNT9B, BMP4, BMPR1B) as well as the methionine cycle (MTRR). We conclude that rare coding variants may confer risk for isolated CLP.
View details for PubMedID 31063268
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Substantial Cardiovascular Morbidity in Adults With Lower-Complexity Congenital Heart Disease
CIRCULATION
2019; 139 (16): 1889–99
View details for DOI 10.1161/CIRCULATIONAHA.118.037064
View details for Web of Science ID 000469321500006
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Early transpyloric vs gastric feeding in preterm infants: a retrospective cohort study.
Journal of perinatology : official journal of the California Perinatal Association
2019
Abstract
BACKGROUND: Neonatal transpyloric feeding (TPF) has not been rigorously studied since the 1980s. Our objective was to evaluate early TPF, defined as TPF initiated within the first week after birth, among preterm infants in the setting of modern neonatal practice.STUDY DESIGN: A retrospective cohort study was conducted between 2013 and 2017 for all extremely low birth weight (ELBW) infants born in a tertiary neonatal intensive care unit where early TPF is a common practice. Infants were excluded if they did not receive enteral feeding within the first week after birth or if they died prior to initiation of enteral feeding. The primary outcome was death or bronchopulmonary dysplasia (BPD). The association between early TPF and the primary outcome was assessed using multivariable logistic regression, with adjustment for gestational age, birth weight, and intubation status.RESULT: The study sample included 368 ELBW infants. Twenty-seven percent received early TPF. Death or BPD occurred in 58% of infants who received early TPF compared with 67% of infants who received gastric feeding, adjusted odds ratio 0.6, 95% confidence interval 0.3-0.9. Growth and adverse gastrointestinal outcomes did not differ between the two groups.CONCLUSION: Early TPF is associated with reduced risk of death or BPD among ELBW infants. Further investigation in the form of a randomized controlled trial is required to confirm a causal association between early TPF and improved clinical outcomes.
View details for PubMedID 30967655
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Maternal genetic markers for risk of celiac disease and their potential association with neural tube defects in offspring.
Molecular genetics & genomic medicine
2019: e688
Abstract
BACKGROUND: We examined the association between the maternal genotype for celiac disease-associated variants and risk of neural tube defects (NTDs).METHODS: We conducted a case-control study, using data from the National Birth Defects Prevention Study. We evaluated 667 cases (women with an offspring with NTD) and 743 controls (women with an offspring without a birth defect). We classified women as having low, intermediate, or high risk of celiac disease based on human leukocyte antigen (HLA) variants. We used logistic regression to assess the relationship between HLA celiac risk group (low, intermediate, high) and risk of NTDs. Fifteen non-HLA variants (identified from genome-wide association studies of celiac disease) were individually evaluated and modeled additively.RESULTS: There was no association between HLA celiac risk group and NTDs (intermediate vs. low risk: aOR, 1.0; 95% CI, 0.8-1.3; high vs. low risk: aOR, 0.8; 95% CI, 0.5-1.3). Of the fifteen non-HLA variants, we observed five significant associations after accounting for multiple comparisons. Three negative associations were observed with rs10903122, rs13314993, rs13151961 (aOR range: 0.69-0.81), and two positive associations were observed with rs13003464 and rs11221332 (aOR range: 1.27-1.73).CONCLUSION: If confirmed, our results suggest that the maternal variants related to celiac disease may be involved in the risk of NTDs.
View details for PubMedID 30968606
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A pilot study showing a stronger H1N1 influenza vaccination response during pregnancy in women who subsequently deliver preterm
JOURNAL OF REPRODUCTIVE IMMUNOLOGY
2019; 132: 16–20
View details for DOI 10.1016/j.jri.2019.02.004
View details for Web of Science ID 000466622600003
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Variants identified in PTK7 associated with neural tube defects
MOLECULAR GENETICS & GENOMIC MEDICINE
2019; 7 (4)
View details for DOI 10.1002/mgg3.584
View details for Web of Science ID 000465102200008
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Stillbirth and Live Birth at Periviable Gestational Age: A Comparison of Prevalence and Risk Factors
AMERICAN JOURNAL OF PERINATOLOGY
2019; 36 (5): 537–44
View details for DOI 10.1055/s-0038-1670633
View details for Web of Science ID 000463944600016
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Risk factors associated with the development of double-inlet ventricle congenital heart disease.
Birth defects research
2019
Abstract
BACKGROUND: Congenital heart disease (CHD) is the most common birth defect group and a significant contributor to neonatal and infant death. CHD with single ventricle anatomy, including hypoplastic left heart syndrome (HLHS), tricuspid atresia (TA), and various double-inlet ventricle (DIV) malformations, is the most complex with the highest mortality. Prenatal risk factors associated with HLHS have been studied, but such data for DIV are lacking.METHODS: We analyzed DIV cases and nonmalformed controls in the National Birth Defects Prevention Study, a case-control, multicenter population-based study of birth defects. Random forest analysis identified potential predictor variables for DIV, which were included in multivariable models to estimate effect magnitude and directionality.RESULTS: Random forest analysis identified pre-pregnancy diabetes, history of maternal insulin use, maternal total lipid intake, paternal race, and intake of several foods and nutrients as potential predictors of DIV. Logistic regression confirmed pre-pregnancy diabetes, maternal insulin use, and paternal race as risk factors for having a child with DIV. Additionally, higher maternal total fat intake was associated with a reduced risk.CONCLUSIONS: Maternal pre-pregnancy diabetes and history of insulin use were associated with an increased risk of having an infant with DIV, while maternal lipid intake had an inverse association. These novel data provide multiple metabolic pathways for investigation to identify better the developmental etiologies of DIV and suggest that public health interventions targeting diabetes prevention and management in women of childbearing age could reduce CHD risk.
View details for PubMedID 30920163
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Sociodemographic, health behavioral, and clinical risk factors for anotia/microtia in a population-based case-control study.
International journal of pediatric otorhinolaryngology
2019; 122: 18–26
Abstract
OBJECTIVE: Anotia and microtia are congenital malformations of the external ear with few known risk factors. We conducted a comprehensive assessment of a wide range of potential risk factors using data from the National Birth Defects Prevention Study (NBDPS), a population-based case-control study of non-chromosomal structural birth defects in the United States.METHODS: Mothers of 699 infants with anotia or microtia (cases) and 11,797 non-malformed infants (controls) delivered between 1997 and 2011 were interviewed to obtain information about sociodemographic, health behavioral, and clinical characteristics. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated with logistic regression.RESULTS: Infants with anotia/microtia were more likely to be male (aOR, 1.29; 95% CI, 1.10-1.50) and from a multifetal pregnancy (aOR, 1.68; 95% CI, 1.16-2.42). Cases were also more likely to have parents of Hispanic ethnicity (maternal aOR, 3.19; 95% CI, 2.61-3.91; paternal aOR, 2.11; 95% CI, 1.54-2.88), and parents born outside the United States (maternal aOR, 1.29; 95% CI, 1.06-1.57; paternal aOR, 1.92; 95% CI, 1.53-2.41). Maternal health conditions associated with increased odds of anotia/microtia included obesity (aOR, 1.31; 95% CI, 1.06-1.61) and pre-pregnancy diabetes (type I aOR, 9.89; 95% CI, 5.46-17.92; type II aOR, 4.70; 95% CI, 2.56-8.63). Reduced odds were observed for black mothers (aOR, 0.57; 95% CI, 0.38-0.85) and mothers reporting daily intake of folic acid-containing supplements (aOR, 0.59; 95% CI, 0.46-0.76).CONCLUSION: We identified several risk factors for anotia/microtia, some which have been previously reported (e.g., diabetes) and others which we investigate for perhaps the first time (e.g., binge drinking) that warrant further investigation. Our findings point to some potentially modifiable risk factors and provide further leads toward understanding the etiology of anotia/microtia.
View details for PubMedID 30928866
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Women's periconceptional lowered carbohydrate intake and NTD-affected pregnancy risk in the era of prefortification with folic acid
BIRTH DEFECTS RESEARCH
2019; 111 (5): 248–53
View details for DOI 10.1002/bdr2.1466
View details for Web of Science ID 000460569200002
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Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk.
Epigenetics
2019: 1–16
Abstract
Cleft lip with or without cleft palate (CL/P) is a common human birth defect whose etiologies remain largely unknown. Several studies have demonstrated that periconceptional supplementation of folic acid can reduce risk of CL/P in offspring. In this study, we tested the hypothesis that the preventive effect of folic acid is manifested through epigenetic modifications by determining whether DNA methylation changes are associated with CL/P. To more readily observe the potential effects of maternal folate on the offspring epigenome, we focused on births prior to mandatory dietary folate fortification in the United States (i.e. birth year 1997 or earlier). Genomic DNA methylation levels were assessed from archived newborn bloodspots in a 182-member case-control study using the Illumina Human Beadchip 450K array. CL/P cases displayed striking epigenome-wide hypomethylation relative to controls: 63% of CpGs interrogated had lower methylation levels in case newborns, a trend which held up in racially stratified sub-groups. 28 CpG sites reached epigenome-wide significance and all were case-hypomethylated. The most significant CL/P-associated differentially methylated region encompassed the VTRNA2-1 gene, which was also hypomethylated in cases (FWER p =0.014). This region has been previously characterized as a nutritionally-responsive, metastable epiallele and CL/P-associated methylation changes, in general, were greater at or near putative metastable epiallelic regions. Gene Set Enrichment Analysis of CL/P-associated DMRs showed an over-representation of genes involved in palate development such as WNT9B, MIR140 and LHX8. CL/P-associated DNA methylation changes may partly explain the mechanism by which orofacial clefts are responsive to maternal folate levels.
View details for PubMedID 30870065
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NEUROCOGNITIVE DEFICITS IN ADULT CONGENITAL HEART DISEASE: DOES CORONARY ARTERY DISEASE ADD INSULT TO INJURY?
ELSEVIER SCIENCE INC. 2019: 566
View details for Web of Science ID 000460565900566
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Parental age and stillbirth: a population-based cohort of nearly 10 million California deliveries from 1991 to 2011
ANNALS OF EPIDEMIOLOGY
2019; 31: 32–37
View details for DOI 10.1016/j.annepidem.2018.12.001
View details for Web of Science ID 000462806400007
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A machine learning approach to investigate potential risk factors for gastroschisis in California
BIRTH DEFECTS RESEARCH
2019; 111 (4): 212–21
View details for DOI 10.1002/bdr2.1441
View details for Web of Science ID 000461575000004
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Prenatal exposure to air pollution, maternal diabetes and preterm birth
ENVIRONMENTAL RESEARCH
2019; 170: 160–67
View details for DOI 10.1016/j.envres.2018.12.031
View details for Web of Science ID 000458710800020
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Comparing Usual Dietary Intakes Among Subgroups of Mothers in the Year Before Pregnancy
PUBLIC HEALTH REPORTS
2019; 134 (2): 155–63
View details for DOI 10.1177/0033354918821078
View details for Web of Science ID 000460640500009
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The contributions of genetics to premature birth
PEDIATRIC RESEARCH
2019; 85 (4): 416–17
View details for DOI 10.1038/s41390-019-0292-0
View details for Web of Science ID 000460127000003
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Vasa previa and extreme prematurity: a population-based study
JOURNAL OF PERINATOLOGY
2019; 39 (3): 475–80
View details for DOI 10.1038/s41372-019-0319-8
View details for Web of Science ID 000459549600018
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Understanding health disparities
JOURNAL OF PERINATOLOGY
2019; 39 (3): 354–58
View details for DOI 10.1038/s41372-018-0298-1
View details for Web of Science ID 000459549600003
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Preeclampsia and Preterm Birth Risk in Women Receiving Dialysis During Pregnancy: A Population-Based Cohort Study.
SAGE PUBLICATIONS INC. 2019: 178A–179A
View details for Web of Science ID 000459610400342
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Data-Driven Queries between Medications and Spontaneous Preterm Birth among 2.5 Million Pregnancies: Association with Genital Herpes and Antiviral Drugs.
SAGE PUBLICATIONS INC. 2019: 389A
View details for Web of Science ID 000459610400965
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Substantial Cardiovascular Morbidity in Adults with Lower-Complexity Congenital Heart Disease.
Circulation
2019
Abstract
BACKGROUND: Although lower-complexity cardiac malformations constitute the majority of adult congenital heart disease (ACHD), the long-term risks of adverse cardiovascular events and relationship with conventional risk factors in this population are poorly understood. We aimed to quantify the risk of adverse cardiovascular events associated with lower-complexity ACHD that is unmeasured by conventional risk factors.METHODS: A multi-tiered classification algorithm was used to select individuals with lower-complexity ACHD and individuals without ACHD for comparison amongst >500,000 British adults in the UK Biobank (UKB). ACHD diagnoses were sub-classified as "isolated aortic valve (AoV)" and "non-complex" defects. Time-to-event analyses were conducted for primary endpoints of fatal or non-fatal acute coronary syndrome (ACS), ischemic stroke, heart failure (HF), and atrial fibrillation, and a secondary combined endpoint for major adverse cardiovascular event (MACE). Maximum follow-up time for the study period was 22 years using retrospectively and prospectively collected data from the UKB.RESULTS: We identified 2,006 individuals with lower-complexity ACHD and 497,983 unexposed individuals in the UKB (median [IQR] age at enrollment 58 [51,63]). Of the ACHD-exposed group, 59% were male; 51% were current or former smokers; 30% were obese; 69%, 41%, and 7% were diagnosed or treated for hypertension, hyperlipidemia, and diabetes respectively. After adjustment for 12 measured cardiovascular risk factors, ACHD remained strongly associated with the primary endpoints, with hazard ratios (HR) ranging from 2.0 (95% confidence interval [CI] 1.5-2.8, p<0.001) for ACS to 13.0 (95% CI 9.4-18.1, p<0.001) for HF. ACHD-exposed individuals with ≤2 cardiovascular risk factors had a 29% age-adjusted incidence rate of MACE in contrast to 13% in non-ACHD individuals with ≥5 risk factors.CONCLUSIONS: Individuals with lower-complexity ACHD had higher burden of adverse cardiovascular events relative to the general population that was unaccounted for by conventional cardiovascular risk factors. These findings highlight the need for closer surveillance of patients with mild to moderate ACHD and further investigation into management and mechanisms of cardiovascular risk unique to this growing population of high-risk adults.
View details for PubMedID 30813762
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A pilot study showing a stronger H1N1 influenza vaccination response during pregnancy in women who subsequently deliver preterm.
Journal of reproductive immunology
2019; 132: 16–20
Abstract
PROBLEM: Preterm birth (PTB), or the delivery of an infant prior to 37 weeks of gestation, is a major health concern. Although a variety of social, environmental, and maternal factors have been implicated in PTB, causes of preterm labor have remained largely unknown. There is evidence of effectiveness and safety of influenza vaccination during pregnancy, however fewer studies have looked at vaccination response as an indicator of an innate host response that may be associated with adverse pregnancy outcomes. We carried out a pilot study to analyze the flu vaccine response during pregnancy of women who later deliver preterm or term.METHOD OF STUDY: We performed a secondary analysis of the individual-level data from an influenza vaccination response study (openly available from ImmPort) measured by hemagglutination inhibition assay of 91 pregnant women with term deliveries and 11 women who went on to deliver preterm. Flu vaccination responses for H1N1 and H3N2 influenza strains were compared between term and preterm deliveries.RESULTS: Women who went on to deliver preterm showed a significantly (P< 0.001) greater flu vaccine response for the H1N1 strain than women who delivered at term. The vaccine response for H3N2 was not significantly different between these two groups (P= 0.97).CONCLUSIONS: Although the sample size is limited and additional validation is required, our findings suggest an increased activation of the maternal immune system as shown by the stronger vaccination response to H1N1 in women who subsequently delivered preterm, in comparison to women who delivered at term.
View details for PubMedID 30852461
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Projected Changes in Maternal Heat Exposure During Early Pregnancy and the Associated Congenital Heart Defect Burden in the United States.
Journal of the American Heart Association
2019; 8 (3): e010995
Abstract
Background More intense and longer-lasting heat events are expected in the United States as a consequence of climate change. This study aimed to project the potential changes in maternal heat exposure during early pregnancy (3-8weeks post conception) and the associated burden of congenital heart defects ( CHD s) in the future. Methods and Results This study expanded on a prior nationwide case-control study that evaluated the association between CHD s and maternal heat exposure during early pregnancy in summer and spring. We defined multiple indicators of heat exposure, and applied published odds ratios obtained for the matching season of the baseline (1995-2005) into the projection period (2025-2035) to estimate potential changes in CHD burden throughout the United States. Increases in maternal heat exposure were projected across the United States and to be larger in the summer. The Midwest will potentially have the highest increase in summer maternal exposure to excessively hot days (3.42; 95% CI, 2.99-3.88 per pregnancy), heat event frequency (0.52; 95% CI, 0.44-0.60) and heat event duration (1.73; 95% CI, 1.49-1.97). We also found large increases in specific CHD subtypes during spring, including a 34.0% (95% CI, 4.9%-70.8%) increase in conotruncal CHD in the South and a 38.6% (95% CI , 9.9%-75.1%) increase in atrial septal defect in the Northeast. Conclusions Projected increases in maternal heat exposure could result in an increased CHD burden in certain seasons and regions of the United States.
View details for PubMedID 30696385
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Projected Changes in Maternal Heat Exposure During Early Pregnancy and the Associated Congenital Heart Defect Burden in the United States
JOURNAL OF THE AMERICAN HEART ASSOCIATION
2019; 8 (3)
View details for DOI 10.1161/JAHA.118.010995
View details for Web of Science ID 000460106400018
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Maternal Lactase Polymorphism (rs4988235) Is Associated with Neural Tube Defects in Offspring in the National Birth Defects Prevention Study
JOURNAL OF NUTRITION
2019; 149 (2): 295–303
View details for DOI 10.1093/jn/nxy246
View details for Web of Science ID 000458632000015
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Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk
EPIGENETICS
2019; 14 (2): 198–213
View details for DOI 10.1080/15592294.2019.1581591
View details for Web of Science ID 000463795900008
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Developing evidence-based recommendations for optimal interpregnancy intervals in high-income countries: protocol for an international cohort study.
BMJ open
2019; 9 (1): e027941
Abstract
INTRODUCTION: Short interpregnancy interval (IPI) has been linked to adverse pregnancy outcomes. WHO recommends waiting at least 2years after a live birth and 6months after miscarriage or induced termination before conception of another pregnancy. The evidence underpinning these recommendations largely relies on data from low/middle-income countries. Furthermore, recent epidemiological investigations have suggested that these studies may overestimate the effects of IPI due to residual confounding. Future investigations of IPI effects in high-income countries drawing from large, population-based data sources are needed to inform IPI recommendations. We aim to assess the impact of IPIs on maternal and child health outcomes in high-income countries.METHODS AND ANALYSIS: This international longitudinal retrospective cohort study will include more than 18million pregnancies, making it the largest study to investigate IPI in high-income countries. Population-based data from Australia, Finland, Norway and USA will be used. Birth records in each country will be used to identify consecutive pregnancies. Exact dates of birth and clinical best estimates of gestational length will be used to estimate IPI. Administrative birth and health data sources with >99%coverage in each country will be used to identify maternal sociodemographics, pregnancy complications, details of labour and delivery, birth and child health information. We will use matched and unmatched regression models to investigate the impact of IPI on maternal and infant outcomes, and conduct meta-analysis to pool results across countries.ETHICS AND DISSEMINATION: Ethics boards at participating sites approved this research (approval was not required in Finland). Findings will be published in peer-reviewed journals and presented at international conferences, and will inform recommendations for optimal IPI in high-income countries. Findings will provide important information for women and families planning future pregnancies and for clinicians providing prenatal care and giving guidance on family planning.
View details for PubMedID 30700492
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Vasa previa and extreme prematurity: a population-based study.
Journal of perinatology : official journal of the California Perinatal Association
2019
Abstract
OBJECTIVE: To determine population-based risks of preterm birth associated with vasa previa.STUDY DESIGN: Included were 945,950 singleton, live birth cesarean deliveries with and without vasa previa (gestational ages 24-41 weeks) in California between 2007 and 2012. Odds ratios (ORs) of preterm birth were estimated using logistic regression.RESULTS: In total, 586 were complicated by vasa previa (0.06%). In total, 369 (63%) of those with vasa previa were delivered <37 weeks, compared with 91,662 (10%) of those without. Odds of extreme and very preterm birth were substantially higher for pregnancies with vasa previaeven after controlling for comorbidities known to contribute to prematurity, with ORs of 4.6 (95% confidence interval, CI: 1.7-12.5) and 16.0 (95% CI: 10.3-24.8), respectively.CONCLUSION: Based on these population-based data, most patients with vasa previa are delivered between 32 and 36 weeks gestation; however, a clinically significant portion occur before 32 weeks. These data are helpful in counseling patients with vasa previa regarding prematurity risk.
View details for PubMedID 30692614
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Variants identified in PTK7 associated with neural tube defects.
Molecular genetics & genomic medicine
2019: e584
Abstract
BACKGROUND: Variants in planar cell polarity (PCP) pathway genes have been repeatedly implicated in the pathogenesis of NTDs in both mouse models and in human cohorts. Mouse models indicate that the homogenous disruption of the Ptk7 gene, a PCP regulator, results in craniorachischisis; while embryos that are doubly heterozygous for Ptk7XST87 and Vangl2Lp mutations present with spina bifida.METHODS: In this study, we initially sequenced exons of the human PTK7 gene in 192 spina bifida patients and 190 controls from a California population. A phase II validation study was performed in 343 Chinese NTD cohort. Functional assays including immunoblotting and immunoprecipitation were used to study identified variants effect on PTK7 function.RESULTS: We identified three rare (MAF <0.001) missense heterozygous PTK7 variants (NM_001270398.1:c.581C>T, p.Arg630Ser and p.Tyr725Phe) in the spina bifida patients. In our functional analyses, p.Arg630Ser affected PTK7 mutant protein stability and increased interaction with Dvl2, while the p.Thr186Met variant decreased PTK7 interactions with Dvl2. No novel predicted-to-be-damaging variant or function-disrupted PTK7 variant was identified among the control subjects. We subsequently re-sequenced the PTK7 CDS region in 343 NTDs from China to validate the association between PTK7 and NTDs. The frequency of PTK7 rare missense variants in the Chinese NTD samples is significantly higher than in gnomAD controls.CONCLUSION: Our study suggests that rare missense variants in PTK7 contribute to the genetic risk of NTDs.
View details for PubMedID 30689296
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Women's periconceptional lowered carbohydrate intake and NTD-affected pregnancy risk in the era of prefortification with folic acid.
Birth defects research
2019
Abstract
BACKGROUND: A recent study observed women's restricted carbohydrate diet in the year before conception was associated with increased risk of neural tube defect (NTD)-affected pregnancies. That study corresponded to the era of postfortification of folic acid. Because folic acid and carbohydrate measures would derive from similar foods, investigators of that study could not determine whether the increased risk with restricted carbohydrate intake was a consequence of lower folate intake. We extend their novel observation by examining rigorous NTD data prior to folic acid fortification.METHODS: Data were derived from a population-based case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 449 NTD cases and with mothers of 458 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess macro- and micronutrient intakes based on reported intakes 3 months before conception.RESULTS: Case mothers were twice as likely to have consumed a low carbohydrate (≤5th percentile intake among controls) diet with a crude odds ratio of 2.0 (95% confidence interval, 1.2-3.4). Adjustment for race/ethnicity, education, alcohol intake, and folic acid use made very little difference on the odds ratio. Adjustment for total energy intake appeared to be the only factor to slightly attenuate the odds ratio.CONCLUSION: Our findings indicate that the association between low carbohydrate intake and NTD risk may not be wholly a function of low folic acid in the postfortification era. Such a finding offers new clues to pursue for the seemingly folate-insensitive NTDs that continue to occur.
View details for PubMedID 30681289
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The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation.
Human molecular genetics
2019
Abstract
Mutations in IRF6, TFAP2A and GRHL3 cause orofacial clefting syndromes in humans. However, Tfap2a and Grhl3 are also required for neurulation in mice. Here, we found that homeostasis of Irf6 is also required for development of the neural tube and associated structures. Over-expression of Irf6 caused exencephaly, a rostral neural tube defect, through suppression of Tfap2a and Grhl3 expression. Conversely, loss of Irf6 function caused a curly tail and coincided with a reduction of Tfap2a and Grhl3 expression in tail tissues. To test whether Irf6 function in neurulation was conserved, we sequenced samples obtained from human cases of spina bifida and anencephaly. We found two likely disease-causing variants in two samples from patients with spina bifida. Overall, these data suggest that the Tfap2a-Irf6-Grhl3 genetic pathway is shared by two embryologically distinct morphogenetic events that previously were considered independent during mammalian development. In addition, these data suggest new candidates to delineate the genetic architecture of neural tube defects and new therapeutic targets to prevent this common birth defect.
View details for PubMedID 30689861
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Maternal Lactase Polymorphism (rs4988235) Is Associated with Neural Tube Defects in Offspring in the National Birth Defects Prevention Study.
The Journal of nutrition
2019
Abstract
Background: The risk of neural tube defect (NTD)-affected pregnancies is reduced with adequate folic acid intake during early pregnancy. However, NTDs have been observed among offspring of women with adequate folic acid intake. Some of these women are possibly not absorbing enough folic acid. Because lactase deficiency can lead to poor nutrient absorption, we hypothesized that lactase-deficient women will be at increased risk of having offspring with NTDs.Objective: We examined the association between maternal rs4988235 (a lactase deficiency genetic marker) and NTDs in offspring.Methods: We conducted a case-control study using data from the National Birth Defects Prevention Study, United States, 1997-2009, restricting to non-Hispanic white (NHW) and Hispanic women. Cases were women with an offspring with an NTD (n = 378 NHW, 207 Hispanic), and controls were women with an offspring without a birth defect (n = 461 NHW, 165 Hispanic). Analyses were conducted separately by race/ethnicity, using logistic regression. Women with the CC genotype were categorized as being lactase deficient. To assess potential effect modification, analyses were stratified by lactose intake, folic acid supplementation, dietary folate, and diet quality.Results: Among NHW women, the odds of being lactase deficient were greater among cases compared with controls (OR: 1.37; 95% CI: 1.02, 1.82). Among Hispanic women, the odds of being lactase deficient were significantly lower among cases compared with controls (OR: 0.50, 95% CI: 0.33, 0.77). The association differed when stratified by lactose intake in NHW women (higher odds among women who consumed ≥12 g lactose/1000 kcal) and by dietary folate in Hispanic women (opposite direction of associations). The association did not differ when stratified by folic acid supplementation or diet quality.Conclusions: Our findings suggest that maternal lactase deficiency is associated with NTDs in offspring. However, we observed opposite directions of effect by race/ethnicity that could not be definitively explained.
View details for PubMedID 30689919
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A Genome-Wide Analysis of Clinical Chorioamnionitis among Preterm Infants.
American journal of perinatology
2019
Abstract
OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) associated with clinical chorioamnionitis among preterm infants.STUDY DESIGN: We reanalyzed a genome-wide association study (GWAS) from preterm newborns at less than 30 weeks' gestation. Cases and control definitions were determined using administrative records. There were 213 clinical chorioamnionitis cases and 707 clinically uninfected controls. We compared demographic and clinical outcomes of cases and controls. We performed a GWAS and compared the distribution of SNPs from the background genes and from the immunome genes. We used a Wilcoxon's rank-sum test to compare the SNPs normalized odds ratio and used odds ratios and p-values to determine candidate genes.RESULTS: Infants affected by clinical chorioamnionitis were more likely to have periventricular leukomalacia, high-grade retinopathy, and high-grade intraventricular hemorrhage (IVH). Although a GWAS did not identify SNPs associated with clinical chorioamnionitis at the genome-wide significance level, a direct test on the exonic variants in the human immunome revealed their significant increase of risk in clinical chorioamnionitis.CONCLUSION: Among very preterm infants, clinical chorioamnionitis was associated with periventricular leukomalacia, high-grade retinopathy, and IVH. Our analysis of variants in the human immunome indicates an association with clinical chorioamnionitis in very preterm pregnancies.
View details for PubMedID 30674050
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The contributions of genetics to premature birth.
Pediatric research
2019
View details for PubMedID 30644444
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Dominant negative GPR161 rare variants are risk factors of human spina bifida
HUMAN MOLECULAR GENETICS
2019; 28 (2): 200–208
Abstract
Spina bifida (SB) is a complex disorder of failed neural tube closure during the first month of human gestation, with a suspected etiology involving multiple gene and environmental interactions. GPR161 is a ciliary G-protein coupled receptor that regulates Sonic Hedgehog (Shh) signaling. Gpr161 null and hypomorphic mutations cause neural tube defects (NTDs) in mouse models. Herein we show that several genes involved in Shh and Wnt signaling were differentially expressed in the Gpr161 null embryos using RNA-seq analysis. To determine whether there exists an association between GPR161 and SB in humans, we performed direct Sanger sequencing on the GPR161 gene in a cohort of 384 SB patients and 190 healthy controls. We identified six rare variants of GPR161 in six SB cases, of which two of the variants were novel and did not exist in any databases. Both of these variants were predicted to be damaging by SIFT and/or PolyPhen analysis. The novel GPR161 rare variants mislocalized to the primary cilia, dysregulated Shh and Wnt signaling and inhibited cell proliferation in vitro. Our results demonstrate that GPR161 mutations cause NTDs via dysregulation of Shh and Wnt signaling in mice, and novel rare variants of GPR161 can be risk factors for SB in humans.
View details for PubMedID 30256984
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Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy.
Bioinformatics (Oxford, England)
2019; 35 (1): 95–103
Abstract
Motivation: Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.Results: We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.Availability and implementation: Datasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.Supplementary information: Supplementary data are available at Bioinformatics online.
View details for PubMedID 30561547
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Re: Herpesvirus Infection in Infants with Gastroschisis Respond
EPIDEMIOLOGY
2019; 30 (1): E2-E3
View details for DOI 10.1097/EDE.0000000000000935
View details for Web of Science ID 000452754000004
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“Following Through”: Addressing the Racial Inequality for Preterm Infants and Their Families
Pediatric Research
2019
View details for DOI 10.1038/s41390-019-0602-6
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Data-driven queries between medications and spontaneous preterm birth among 2.5 million pregnancies.
Birth defects research
2019
Abstract
Our goal was to develop an approach that can systematically identify potential associations between medication prescribed in pregnancy and spontaneous preterm birth (sPTB) by mining large administrative "claims" databases containing hundreds of medications. One such association that we illustrate emerged with antiviral medications used for herpes treatment.IBM MarketScan® databases (2007-2016) were used. A pregnancy cohort was established using International Classification of Diseases (ICD-9/10) codes. Multiple hypothesis testing and the Benjamini-Hochberg procedure that limited false discovery rate at 5% revealed, among 863 medications, five that showed odds ratios (ORs) <1. The statistically strongest was an association between antivirals and sPTB that we illustrate as a real example of our approach, specifically for treatment of genital herpes (GH). Three groups of women were identified based on diagnosis of GH and treatment during the first 36 weeks of pregnancy: (a) GH without treatment; (b) GH treated with antivirals; (c) no GH or treatment.We identified 2,538,255 deliveries. 0.98% women had a diagnosis of GH. Among them, 60.0% received antiviral treatment. Women with treated GH had OR < 1, (OR [95% CI] = 0.91 [0.85, 0.98]). In contrast, women with untreated GH had a small increased risk of sPTB (OR [95% CI] =1.22 [1.14, 1.32]).Data-driven approaches can effectively generate new hypotheses on associations between medications and sPTB. This analysis led us to examine the association with GH treatment. While unknown confounders may impact these findings, our results indicate that women with untreated GH have a modest increased risk of sPTB.
View details for DOI 10.1002/bdr2.1580
View details for PubMedID 31433567
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Preterm birth occurrence among Asian women relative to their place of birth
MOSBY-ELSEVIER. 2019: S352
View details for DOI 10.1016/j.ajog.2018.11.546
View details for Web of Science ID 000454249402006
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"Following through": addressing the racial inequality for preterm infants and their families.
Pediatric research
2019
View details for DOI 10.1038/s41390-019-0602-6
View details for PubMedID 31581171
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Short interpregnancy interval as a risk factor for preterm birth in non-Hispanic Black and White women in California.
Journal of perinatology : official journal of the California Perinatal Association
2019
Abstract
Short interpregnancy interval (IPI) is associated with adverse pregnancy outcomes, including preterm birth (PTB < 37 weeks GA). We investigated whether short IPI (< 6 months) contributes to the higher PTB frequency among non-Hispanic Blacks (NHB).Using a linked birth cohort > 1.5 million California live births, we examined frequencies of short IPI between racial/ethnic groups and estimated risks by multivariable logistic regression for spontaneous PTB. We expanded the study to births 1991-2012 and utilized a "within-mother" approach to permit methodologic inquiry about residual confounding.NHB women had higher frequency (7.6%) of short IPI than non-Hispanic White (NHW) women (4.4%). Adjusted odds ratios for PTB and short IPI were 1.64 (95% CI 1.54, 1.76) for NHW and 1.49 (1.34, 1.65) for NHB. Using within-mother analysis did not produce substantially different results.Short IPI is associated with PTB but does not explain risk disparity between NHWs and NHBs.
View details for DOI 10.1038/s41372-019-0402-1
View details for PubMedID 31209276
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Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy
BIOINFORMATICS
2019; 35 (1): 95–103
View details for DOI 10.1093/bioinformatics/bty537
View details for Web of Science ID 000459313900012
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Comparing Usual Dietary Intakes Among Subgroups of Mothers in the Year Before Pregnancy.
Public health reports (Washington, D.C. : 1974)
2018: 33354918821078
Abstract
OBJECTIVE:: The quantity and quality of dietary intake among women of reproductive age has important public health implications for nutritional status during pregnancy. We described dietary intake during the year before pregnancy among a large, diverse group of US mothers.METHODS:: We examined data from 11109 mothers who gave birth from 1997 through 2011 and participated in a population-based case-control study, the National Birth Defects Prevention Study, as controls (mothers who had babies without major birth defects). We examined whether subgroups of mothers at elevated risk of adverse pregnancy outcomes were more likely than their reference groups to have high dietary intake (>90th percentile of intake) or low dietary intake (<10th percentile of intake). We examined dietary intake of 22 nutritional factors, which were estimated from responses to a food frequency questionnaire.RESULTS:: Participants who were aged <20, were nulliparous, had
View details for PubMedID 30593261
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A machine learning approach to investigate potential risk factors for gastroschisis in California.
Birth defects research
2018
Abstract
BACKGROUND: To generate new leads about risk factors for gastroschisis, a birth defect that has been increasing in prevalence over time, we performed an untargeted data mining statistical approach.METHODS: Using data exclusively from the California Center of the National Birth Defects Prevention Study, we compared 286 cases of gastroschisis and 1,263 non-malformed, live-born controls. All infants had delivery dates between October 1997 and December 2011 and were stratified by maternal age at birth (<20 and ≥ 20years). Cases and controls were compared by maternal responses to 183 questions (219 variables) using random forest, a data mining procedure. Variables deemed important by random forest were included in logistic regression models to estimate odds ratios and 95% confidence intervals.RESULTS: Among women younger than 20, of variables deemed important, there were higher odds observed for higher consumption of chocolate, low intake of iron, acetaminophen use, and urinary tract infections during the beginning of pregnancy. After adjustment, the higher odds remained for low iron intake and a urinary tract infection in the first month of pregnancy. Among women aged 20 or older, of variables deemed important, higher odds were observed for US-born women of Hispanic ethnicity and for parental substance abuse. There were lower odds observed for obese women, women who ate any cereal the month before pregnancy, and those with higher parity.CONCLUSIONS: We did not discover many previously unreported associations, despite our novel approach to generate new hypotheses. However, our results do add evidence to some previously proposed risk factors.
View details for PubMedID 30588769
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Parental age and stillbirth: a population-based cohort of nearly 10 million California deliveries from 1991 to 2011.
Annals of epidemiology
2018
Abstract
PURPOSE: Parental age at delivery in the United States has been rising. Advanced maternal and paternal ages have been associated with adverse pregnancy outcomes including stillbirth. However, these relationships come from studies that often do not present results for both mother and father concurrently. The purpose of this study was to estimate the risk of stillbirth for maternal and paternal age in the same cohort of deliveries.METHODS: This is a population-based cohort study of all live birth and stillbirth deliveries in California from 1991 to 2011. The individual associations between maternal and paternal ages and stillbirth were estimated with hazard ratios from Cox proportional hazard models. Age was modeled continuously with restricted cubic splines to account for nonlinear relationships. Mean parental age was used as the referent group.RESULTS: J-shaped associations between maternal and paternal ages were observed in crude models where older mothers and fathers had the highest hazard ratios for stillbirth. In maternal models, after adjusting for maternal and paternal covariates, young maternal age no longer showed increased hazard ratio for stillbirth, whereas the association with older mothers remained. In adjusted paternal models, the relationship between young paternal age and stillbirth was unchanged while the hazard ratio for older fathers was slightly smaller.CONCLUSIONS: After adjusting for both parents' age, education, race/ethnicity, along with parity, older mothers and fathers were independently associated with elevated hazard ratios for stillbirth.
View details for PubMedID 30642694
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Author Correction: Enabling precision medicine in neonatology, an integrated repository for preterm birth research.
Scientific data
2018; 5 (1): 3
Abstract
The original version of the Data Descriptor contained errors in the author list and affiliations. Rita Leite's first name was misspelled as "Rite" and affiliations 4 and 5 were incorrectly swapped. In addition, members of the March of Dimes Prematurity Research Center consortium were not listed in the agreed positions within the author list. These errors have now been corrected in the HTML and PDF versions.
View details for PubMedID 30563979
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Enabling precision medicine in neonatology, an integrated repository for preterm birth research (vol 5, 180219, 2018)
SCIENTIFIC DATA
2018; 5
View details for DOI 10.1038/s41597-018-0004-3
View details for Web of Science ID 000453586800001
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Understanding health disparities.
Journal of perinatology : official journal of the California Perinatal Association
2018
Abstract
Based upon our recent insights into the determinants of preterm birth, which is the leading cause of death in children under five years of age worldwide, we describe potential analytic frameworks that provides both a common understanding and, ultimately the basis for effective, ameliorative action. Our research on preterm birth serves as an example that the framing of any human health condition is a result of complex interactions between the genome and the exposome. New discoveries of the basic biology of pregnancy, such as the complex immunological and signaling processes that dictate the health and length of gestation, have revealed a complexity in the interactions (current and ancestral) between genetic and environmental forces. Understanding of these relationships may help reduce disparities in preterm birth and guide productive research endeavors and ultimately, effective clinical and public health interventions.
View details for PubMedID 30560947
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Prenatal exposure to air pollution, maternal diabetes and preterm birth.
Environmental research
2018; 170: 160–67
Abstract
Prenatal exposure to ambient air pollution has been associated with preterm birth in several studies. Associations between air pollution and gestational or pre-existing diabetes have been hypothesized but are not well established. We examined the association between air pollution exposure in pregnancy and gestational diabetes and whether the association between air pollution and preterm birth is modified by diabetes (gestational or pre-existing) in a highly polluted area of California. Birth certificates and hospital discharge data from all singleton births from 2000 to 2006 to women living in four counties in the San Joaquin Valley of California were linked to criteria air pollution and traffic density measurements at the geocoded maternal residence. Air pollutants were dichotomized at the highest quartile and compared to the lower three quartiles. Logistic regression models were adjusted for maternal race-ethnicity, age, education, payment of birth expenses, and prenatal care. There were consistent inverse associations between exposure to air pollution during the first two trimesters and gestational diabetes (statistically significant odds ratios (OR) less than 1). When stratified by any diabetes (gestational or pre-existing), associations between air pollution exposure during pregnancy and categories of preterm birth (20-27, 28-31, 32-33, 34-36 weeks) were generally similar with few exceptions of exposures to carbon monoxide (CO) and particulate matter < 2.5 m (PM2.5). Those with diabetes and exposure higher levels of CO (in first trimester or entire pregnancy) or PM2.5 (in first trimester) had higher risk of extremely preterm birth (20-27 weeks) compared with those without diabetes. The associations between traffic-related air pollution and gestational diabetes were in the unexpected ("protective") direction. Among those with any diabetes, associations were stronger between CO and PM2.5 and extremely preterm birth.
View details for PubMedID 30579990
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Copy number variants in hypoplastic right heart syndrome
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2018; 176 (12): 2760-2767
View details for DOI 10.1002/ajmg.a.40527
View details for Web of Science ID 000454612700029
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Preterm Delivery Phenotypes in Systemic Lupus Erythematosus Pregnancies.
American journal of perinatology
2018
Abstract
OBJECTIVE: Women with systemic lupus erythematosus (SLE) are at a greater risk of preterm delivery, many of which may be medically indicated (iatrogenic). We investigated preterm delivery phenotypes in SLE and general population comparators and assessed the role of preeclampsia.STUDY DESIGN: We used population-based Swedish Register data (2001-2013) and defined maternal SLE as ≥2 SLE-coded discharge diagnoses from the Patient Register with ≥1 coded by an appropriate specialist. Women from the general population were identified using the Total Population Register. Preterm delivery was defined as <37 weeks and separated into spontaneous and iatrogenic, as well as later versus extremely preterm (32 to <37 weeks vs. <32 weeks). Maternal comorbidity was assessed, and the proportion mediated by preeclampsia was calculated examining first, subsequent, and all pregnancies.RESULTS: Preterm delivery was more common in SLE for the first (22 vs. 6%) and subsequent (15 vs. 4%) pregnancies among 781 SLE-exposed pregnancies and 11,271 non-SLE pregnancies. Of SLE-exposed first births, 27% delivered before 32 weeks, and 90% were iatrogenic (compared with 47% of non-SLE first births).CONCLUSION: Preterm delivery complicates a greater proportion of SLE pregnancies than general population pregnancies, and a considerable proportion of risk is mediated through preeclampsia.
View details for PubMedID 30477035
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Impact of post-collection freezing delay on the reliability of serum metabolomics in samples reflecting the California mid-term pregnancy biobank.
Metabolomics : Official journal of the Metabolomic Society
2018; 14 (11): 151
Abstract
Population-based biorepositories are important resources, but sample handling can affect data quality.Identify metabolites of value for clinical investigations despite extended postcollection freezing delays, using protocols representing a California mid-term pregnancy biobank.Blood collected from non-pregnant healthy female volunteers (n = 20) underwent three handling protocols after 30 min clotting at room temperature: (1) ideal-samples frozen (- 80 °C) within 2 h of collection; (2) delayed freezing-samples held at room temperature for 3 days, then 4 °C for 9 days, the median times for biobank samples, and then frozen; (3) delayed freezing with freeze-thaw-the delayed freezing protocol with a freeze-thaw cycle simulating retrieved sample sub-aliquoting. Mass spectrometry-based untargeted metabolomic analyses of primary metabolism and complex lipids and targeted profiling of oxylipins, endocannabinoids, ceramides/sphingoid-bases, and bile acids were performed. Metabolite concentrations and intraclass correlation coefficients (ICC) were compared, with the ideal protocol as the reference.Sixty-two percent of 428 identified compounds had good to excellent ICCs, a metric of concordance between measurements of samples handled with the different protocols. Sphingomyelins, phosphatidylcholines, cholesteryl esters, triacylglycerols, bile acids and fatty acid diols were the least affected by non-ideal handling, while sugars, organic acids, amino acids, monoacylglycerols, lysophospholipids, N-acylethanolamides, polyunsaturated fatty acids, and numerous oxylipins were altered by delayed freezing. Freeze-thaw effects were assay-specific with lipids being most stable.Despite extended post-collection freezing delays characteristic of some biobanks of opportunistically collected clinical samples, numerous metabolomic compounds had both stable levels and good concordance.
View details for DOI 10.1007/s11306-018-1450-9
View details for PubMedID 30830400
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Enabling precision medicine in neonatology, an integrated repository for preterm birth research.
Scientific data
2018; 5: 180219
Abstract
Preterm birth, or the delivery of an infant prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. In the last decade, the advent and continued development of molecular profiling technologies has enabled researchers to generate vast amount of 'omics' data, which together with integrative computational approaches, can help refine the current knowledge about disease mechanisms, diagnostics, and therapeutics. Here we describe the March of Dimes' Database for Preterm Birth Research (http://www.immport.org/resources/mod), a unique resource that contains a variety of 'omics' datasets related to preterm birth. The database is open publicly, and as of January 2018, links 13 molecular studies with data across tens of thousands of patients from 6 measurement modalities. The data in the repository are highly diverse and include genomic, transcriptomic, immunological, and microbiome data. Relevant datasets are augmented with additional molecular characterizations of almost 25,000 biological samples from public databases. We believe our data-sharing efforts will lead to enhanced research collaborations and coordination accelerating the overall pace of discovery in preterm birth research.
View details for PubMedID 30398470
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Risk Factors Associated With the Development of Common Ventricle Congenital Heart Disease
LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000528619402118
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Enabling precision medicine in neonatology, an integrated repository for preterm birth research
SCIENTIFIC DATA
2018; 5
View details for DOI 10.1038/sdata.2018.219
View details for Web of Science ID 000449252700001
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Maternal Height and Risk of Preeclampsia among Race/Ethnic Groups.
American journal of perinatology
2018
Abstract
OBJECTIVE: Shorter maternal height has been associated with preeclampsia risk in several populations. It has been less evident whether an independent contribution to the risk exists from maternal height consistently across different races/ethnicities. We investigated associations between maternal height and risk of preeclampsia for different races/ethnicities.STUDY DESIGN: California singleton live births from 2007 to 2011 were analyzed. Logistic regression was used to estimate adjusted odds ratios for the association between height and preeclampsia after stratification by race/ethnicity. To determine the contribution of height that is as independent of body composition as possible, we performed one analysis adjusted for body mass index (BMI) and the other for weight. Additional analyses were performed stratified by parity, and the presence of preexisting/gestational diabetes and autoimmune conditions.RESULTS: Among 2,138,012 deliveries, 3.1% preeclampsia/eclampsia cases were observed. The analysis, adjusted for prepregnancy weight, revealed an inverse relation between maternal height and risk of mild and severe preeclampsia/eclampsia. When the analysis was adjusted for BMI, an inverse relation between maternal height was observed for severe preeclampsia/eclampsia. These associations were observed for each race/ethnicity.CONCLUSION: Using a large and diverse cohort, we demonstrated that shorter height, irrespective of prepregnancy weight or BMI, is associated with an increased risk of severe preeclampsia/eclampsia across different races/ethnicities.
View details for PubMedID 30396225
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Impact of post-collection freezing delay on the reliability of serum metabolomics in samples reflecting the California mid-term pregnancy biobank
METABOLOMICS
2018; 14 (11)
View details for DOI 10.1007/s11306-018-1450-9
View details for Web of Science ID 000450525400001
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An application of data mining to identify potential risk factors for anophthalmia and microphthalmia
PAEDIATRIC AND PERINATAL EPIDEMIOLOGY
2018; 32 (6): 545–55
View details for DOI 10.1111/ppe.12509
View details for Web of Science ID 000451452900007
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Application of machine-learning to predict early spontaneous preterm birth among nulliparous non-Hispanic black and white women
ANNALS OF EPIDEMIOLOGY
2018; 28 (11): 783–89
View details for DOI 10.1016/j.annepidem.2018.08.008
View details for Web of Science ID 000450020400006
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Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study.
BMJ (Clinical research ed.)
2018; 363: k4372
Abstract
OBJECTIVE: To evaluate the impact of advanced paternal age on maternal and perinatal outcomes in the United States.DESIGN: Retrospective, population based cohort study.SETTING: US.POPULATION: 40529905 documented live births between 2007 and 2016.MAIN OUTCOME MEASURES: Primary perinatal outcomes were gestational age, birth weight, Apgar score at five minutes, admission to a neonatal intensive care unit, need for postpartum antibiotics, and seizures. Primary maternal outcomes were gestational diabetes and pre-eclampsia. Secondary outcome was the number of preventable perinatal events.RESULTS: Higher paternal age was associated with an increased risk of premature birth, low birth weight, and low Apgar score. After adjustment for maternal age, infants born to fathers aged 45 years or older had 14% higher odds of premature birth (odds ratio 1.14, 95% confidence interval 1.13 to 1.15), independent of gestational age, and 18% higher odds of seizures (1.18, 0.97 to 1.44) compared with infants of fathers aged 25 to 34 years. The odds of gestational diabetes was 34% higher (1.34, 1.29 to 1.38) in mothers with the oldest partners. 13.2% (95% confidence interval 12.5% to 13.9%) of premature births and 18.2% (17.5% to 18.9%) of gestational diabetes in births associated with older fathers were estimated to be attributable to advanced paternal age.CONCLUSIONS: Advanced paternal age is associated with negative effects on both mothers and offspring. Given the relatively low prevalence of advanced paternal age in the US, population level impacts are currently modest. Nevertheless, as advanced paternal age has doubled in the US over the past generation, further investigation is warranted of the impact on birth outcomes and public health.
View details for PubMedID 30381468
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Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study
BMJ-BRITISH MEDICAL JOURNAL
2018; 363
View details for DOI 10.1136/bmj.k4372
View details for Web of Science ID 000449564200004
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A population-based case-control study of the association between weather-related extreme heat events and orofacial clefts.
Birth defects research
2018: e1385
Abstract
BACKGROUND: Limited epidemiologic research exists on the association between weather-related extreme heat events (EHEs) and orofacial clefts (OFCs). We estimated the associations between maternal exposure to EHEs in the summer season and OFCs in offspring and investigated the potential modifying effect of body mass index on these associations.METHODS: We conducted a population-based case-control study among mothers who participated in the National Birth Defects Prevention Study for whom at least 1 day of their first two post-conception months occurred during summer. Cases were live-born infants, stillbirths, and induced terminations with OFCs; controls were live-born infants without major birth defects. We defined EHEs using the 95th and the 90th percentiles of the daily maximum universal apparent temperature distribution. We used unconditional logistic regression with Firth's penalized likelihood method to estimate adjusted odds ratios and 95% confidence intervals, controlling for maternal sociodemographic and anthropometric variables.RESULTS: We observed no association between maternal exposure to EHEs and OFCs overall, although prolonged duration of EHEs may increase the risk of OFCs in some study sites located in the Southeast climate region. Analyses by subtypes of OFCs revealed no associations with EHEs. Modifying effect by BMI was not observed.CONCLUSIONS: We did not find a significantly increased risk of OFCs associated with maternal exposure to EHEs during the relevant window of embryogenesis. Future studies should account for maternal indoor and outdoor activities and for characteristics such as hydration and use of air conditioning that could modify the effect of EHEs on pregnant women.
View details for PubMedID 30338937
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Congenital heart disease complexity and childhood cancer risk
BIRTH DEFECTS RESEARCH
2018; 110 (17): 1314–21
View details for DOI 10.1002/bdr2.1390
View details for Web of Science ID 000448368300002
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An application of data mining to identify potential risk factors for anophthalmia and microphthalmia.
Paediatric and perinatal epidemiology
2018
Abstract
BACKGROUND: We examined a large number of variables to generate new hypotheses regarding a wider range of risk factors for anophthalmia/microphthalmia using data mining.METHODS: Data were from the National Birth Defects Prevention Study, a multicentre, case-control study from 10 centres in the United States. There were 134 cases of "isolated" and 87 "nonisolated" (with other major birth defects) of anophthalmia/microphthalmia and 11052 nonmalformed controls with delivery dates October 1997-December 2011. Using random forest, a data mining procedure, we compared the two case types with controls for 201 variables. Variables considered important ranked by random forest were included in a multivariable logistic regression model to estimate odds ratios and 95% confidence intervals.RESULTS: Predictors for isolated cases included paternal race/ethnicity, maternal intake of certain nutrients and foods, and childhood health problems in relatives. Using regression, inverse associations were observed with greater maternal education and with increasing intake of folate and potatoes. Odds were slightly higher with greater paternal education, for increased intake of carbohydrates and beans, and if relatives had a childhood health problem. For nonisolated cases, predictors included paternal race/ethnicity, maternal intake of certain nutrients, and smoking in the home the month before conception. Odds were higher for Hispanic fathers and smoking in the home and NSAID use the month before conception.CONCLUSIONS: Results appear to support previously hypothesised risk factors, socio-economic status, NSAID use, and inadequate folate intake, and potentially provide new areas such as passive smoking pre-pregnancy, and paternal education and ethnicity, to explore for further understanding of anophthalmia/microphthalmia.
View details for PubMedID 30300919
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Copy number variants in hypoplastic right heart syndrome.
American journal of medical genetics. Part A
2018
Abstract
Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdeveloped and malformed structures of the right heart. Familial recurrence of HRHS indicates genetic factors contribute to its etiology. Our study investigates the presence of copy number variants (CNVs) in HRHS cases. We genotyped 42 HRHS cases identified from live births throughout California (2003-2010) using the Illumina HumanOmni2.5-8 array. We identified 14 candidate CNVs in 14 HRHS cases (33%) based on the genes included in the CNVs and their functions. Duplications overlapping part of ERBB4 were identified in two unrelated cases. ERBB4 is a neuregulin receptor with a pivotal role in cardiomyocyte differentiation and heart development. We also described a 7.5 Mb duplication at 16q11-12. Multiple genes in the duplicated region have previously been linked to heart defects and cardiac development, including RPGRIP1L, RBL2, SALL1, and MYLK3. Of the 14 validated CNVs, we identified four CNVs in close proximity to genes linked to the Wnt signaling pathway. This study expands on our previous work supporting the role of genetics in HRHS. We identified CNVs affecting crucial genes and signaling pathways involved in right heart development. ERBB4 and duplication of the 16q11-12 region are important areas for future investigation.
View details for PubMedID 30289599
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Metagenomic analysis with strain-level resolution reveals fine-scale variation in the human pregnancy microbiome
GENOME RESEARCH
2018; 28 (10): 1467–80
View details for DOI 10.1101/gr.236000.118
View details for Web of Science ID 000446043800004
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The Authors Respond.
Epidemiology (Cambridge, Mass.)
2018
View details for PubMedID 30299403
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Metagenomic analysis with strain-level resolution reveals fine-scale variation in the human pregnancy microbiome.
Genome research
2018
Abstract
Recent studies suggest that the microbiome has an impact on gestational health and outcome. However, characterization of the pregnancy-associated microbiome has largely relied on 16S rRNA gene amplicon-based surveys. Here, we describe an assembly-driven, metagenomics-based, longitudinal study of the vaginal, gut, and oral microbiomes in 292 samples from 10 subjects sampled every three weeks throughout pregnancy. Nonhuman sequences in the amount of 1.53 Gb were assembled into scaffolds, and functional genes were predicted for gene- and pathway-based analyses. Vaginal assemblies were binned into 97 draft quality genomes. Redundancy analysis (RDA) of microbial community composition at all three body sites revealed gestational age to be a significant source of variation in patterns of gene abundance. In addition, health complications were associated with variation in community functional gene composition in the mouth and gut. The diversity of Lactobacillus iners-dominated communities in the vagina, unlike most other vaginal community types, significantly increased with gestational age. The genomes of co-occurring Gardnerella vaginalis strains with predicted distinct functions were recovered in samples from two subjects. In seven subjects, gut samples contained strains of the same Lactobacillus species that dominated the vaginal community of that same subject and not other Lactobacillus species; however, these within-host strains were divergent. CRISPR spacer analysis suggested shared phage and plasmid populations across body sites and individuals. This work underscores the dynamic behavior of the microbiome during pregnancy and suggests the potential importance of understanding the sources of this behavior for fetal development and gestational outcome.
View details for PubMedID 30232199
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Stillbirth and Live Birth at Periviable Gestational Age: A Comparison of Prevalence and Risk Factors.
American journal of perinatology
2018
Abstract
OBJECTIVE: We compared the prevalence of and risk factors for stillbirth and live birth at periviable gestational age (20-25 weeks).STUDY DESIGN: This is a cohort study of 2.5 million singleton births in California from 2007 to 2011. We estimated racial-ethnic prevalence ratios and used multivariable logistic regression for risk factor comparisons.RESULTS: In this study, 42% of deliveries at 20 to 25 weeks' gestation were stillbirths, and 22% were live births who died within 24 hours. The prevalence of delivery at periviable gestation was 3.4 per 1,000 deliveries among whites, 10.9 for blacks, 3.5 for Asians, and 4.4 for Hispanics. Nonwhite race-ethnicity, lower education, uninsured status, being U.S. born, older age, obesity, smoking, pre-pregnancy hypertension, nulliparity, interpregnancy interval, and prior preterm birth or stillbirth were all associated with increased risk of both stillbirth and live birth at 20 to 25 weeks' gestation, compared with delivery of a live birth at 37 to 41 weeks.CONCLUSION: Inclusion of stillbirths and live births in studies of deliveries at periviable gestations is important.
View details for PubMedID 30208499
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Maternal ambient heat exposure during early pregnancy in summer and spring and congenital heart defects - A large US population-based, case-control study
ENVIRONMENT INTERNATIONAL
2018; 118: 211–21
Abstract
Few studies have assessed the effect of ambient heat during the fetal development period on congenital heart defects (CHDs), especially in transitional seasons. We examined and compared the associations between extreme heat and CHD phenotypes in summer and spring, assessed their geographical differences, and compared different heat indicators.We identified 5848 CHD cases and 5742 controls (without major structural defects) from the National Birth Defects Prevention Study, a US multicenter, population-based case-control study. Extreme heat events (EHEs) were defined by using the 95th (EHE95) or 90th (EHE90) percentile of daily maximum temperature and its frequency and duration during postconceptional weeks 3-8. We used a two-stage Bayesian hierarchical model to examine both regional and study-wide associations. Exposure odds ratios (ORs) were calculated using multivariate logistic regression analyses, while controlling for potential confounding factors.Overall, we observed no significant relationships between maternal EHE exposure and CHDs in most regions during summer. However, we found that 3-11 days of EHE90 during summer and spring was significantly associated with ventricular septal defects (VSDs) study-wide (ORs ranged: 2.17-3.24). EHE95 in spring was significantly associated with conotruncal defects and VSDs in the South (ORs: 1.23-1.78). Most EHE indicators in spring were significantly associated with increased septal defects (both VSDs and atrial septal defects (ASDs)) in the Northeast.While generally null results were found, long duration of unseasonable heat was associated with the increased risks for VSDs and ASDs, mainly in South and Northeast of the US. Further research to confirm our findings is needed.
View details for PubMedID 29886237
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The uncertain fate of the National Institutes of Health (NIH) pediatric research portfolio: In support of an investment strategy to improve the public health of the nation through perinatal research
PEDIATRIC RESEARCH
2018; 84 (3): 321–22
View details for DOI 10.1038/s41390-018-0036-6
View details for Web of Science ID 000451231500006
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Change in Prevalence of Orofacial Clefts in California between 1987 and 2010
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2018; 176 (9): 1910–16
View details for DOI 10.1002/ajmg.a.40384
View details for Web of Science ID 000445271900017
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Epidemiology of anophthalmia and microphthalmia: Prevalence and patterns in Texas, 1999-2009
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2018; 176 (9): 1810–18
Abstract
Anophthalmia and microphthalmia are a set of rare, yet severe, birth defects considered to be part of a spectrum of developmental ocular malformations ranging from smaller than average to completely absent eyes. Despite their clinical significance, little is known about the etiologies of these conditions. The goal of this study was to expand our understanding of the epidemiology of anophthalmia and microphthalmia. Data for this population-based assessment were obtained from the Texas Birth Defects Registry (TBDR) and Center for Health Statistics for the period 1999-2009. Descriptive analyses and estimates of birth prevalence and prevalence ratios (PR) were determined for this defect. There were 1,262 definite anophthalmia and microphthalmia patients identified in the TBDR, with an overall combined prevalence of 3.0 per 10,000 live births. More than half (55.7%) of the patients had at least one chromosome abnormality or syndrome. In addition, 92.4% of nonsyndromic patients (i.e., have no recorded chromosome abnormalities or syndromes) had at least one additional birth defect. After adjustment for multiple factors, the prevalence of nonsyndromic anophthalmia and microphthalmia was higher among mothers who had ≥2 previous fetal deaths (PR = 1.43, 95% confidence interval [CI]: 1.03-1.97) and among mothers with any reported diabetes (PR = 2.08, 95% CI: 1.49-2.90). Our results confirm that children with anophthalmia and microphthalmia frequently have genetic syndromes or are born with other major birth defects. Our findings add to the limited body of literature on anophthalmia and microphthalmia as well as help define subgroups of women who are more likely to have children with this malformation.
View details for PubMedID 30070760
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Application of machine-learning to predict early spontaneous preterm birth among nulliparous non-Hispanic black and white women.
Annals of epidemiology
2018
Abstract
PURPOSE: Spontaneous preterm birth is a leading cause of perinatal mortality in the United States, occurring disproportionately among non-Hispanic black women compared to other race-ethnicities. Clinicians lack tools to identify first-time mothers at risk for spontaneous preterm birth. This study assessed prediction of early (<32weeks) spontaneous preterm birth among non-Hispanic black and white women by applying state-of-the-art machine-learning to multilevel data from a large birth cohort.METHODS: Data from birth certificate and hospital discharge records for 336,214 singleton births to nulliparous women in California from 2007 to 2011 were used in cross-validated regressions, with multiple imputation for missing covariate data. Residential census tract information was overlaid for 281,733 births. Prediction was assessed with areas under the receiver operator characteristic curves (AUCs).RESULTS: Cross-validated AUCs were low (0.62 [min=0.60, max=0.63] for non-Hispanic blacks and 0.63 [min=0.61, max=0.65] for non-Hispanic whites). Combining racial-ethnic groups improved prediction (cross-validated AUC=0.67 [min=0.65, max=0.68]), approaching what others have achieved using biomarkers. Census tract-level information did not improve prediction.CONCLUSIONS: The resolution of administrative data was inadequate to precisely predict individual risk for early spontaneous preterm birth despite the use of advanced statistical methods.
View details for PubMedID 30236415
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Prediction of preterm birth with and without preeclampsia using mid-pregnancy immune and growth-related molecular factors and maternal characteristics
JOURNAL OF PERINATOLOGY
2018; 38 (8): 963–72
Abstract
To evaluate if mid-pregnancy immune and growth-related molecular factors predict preterm birth (PTB) with and without (±) preeclampsia.Included were 400 women with singleton deliveries in California in 2009-2010 (200 PTB and 200 term) divided into training and testing samples at a 2:1 ratio. Sixty-three markers were tested in 15-20 serum samples using multiplex technology. Linear discriminate analysis was used to create a discriminate function. Model performance was assessed using area under the receiver operating characteristic curve (AUC).Twenty-five serum biomarkers along with maternal age <34 years and poverty status identified >80% of women with PTB ± preeclampsia with best performance in women with preterm preeclampsia (AUC = 0.889, 95% confidence interval (0.822-0.959) training; 0.883 (0.804-0.963) testing).Together with maternal age and poverty status, mid-pregnancy immune and growth factors reliably identified most women who went on to have a PTB ± preeclampsia.
View details for PubMedID 29795450
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Change in Prevalence of Orofacial Clefts in California between 1987 and 2010.
American journal of medical genetics. Part A
2018
Abstract
INTRODUCTION: To extend the knowledge base about possible prevalence declines of specific orofacial cleft phenotypes, here we examine prevalence in a population base from California over a two-decade period among numerous race/ethnic groups.METHODS: This population-based study used vital statistics and birth defects registry data. Its population involved all births (~1.5 million births) in central California counties from 1987 to 2010. Orofacial clefts were defined as cleft lip with or without cleft palate (CLP, n=1766), and cleft palate (CP, n=922) only. The slope of prevalence of each cleft phenotype over the period 1987-2010 was estimated using weighted least squares regression.RESULTS: Birth prevalence of CLP was 121/100,000 live births, and 63/100,000 live births for CP. The slope for CLP decreased by 1.2 (slope: -1.2; 95% CI: -1.9, -0.5), and for CP by 0.7 (slope: -0.7; 95% CI: -1.7, 0.2) for CP. Stratification by race/ethnicity or infant sex did not demonstrate a statistical difference in slopes.CONCLUSIONS: We observed a decline in the prevalence in CLP in all ethnic groups, however did not observe the same amount of decline in CP, perhaps due to antenatal screening.
View details for PubMedID 30063089
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Women's periconceptional diet and risk of biliary atresia in offspring
BIRTH DEFECTS RESEARCH
2018; 110 (12): 994-1000
View details for DOI 10.1002/bdr2.1340
View details for Web of Science ID 000445630800004
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The uncertain fate of the National Institutes of Health (NIH) pediatric research portfolio: In support of an investment strategy to improve the public health of the nation through perinatal research.
Pediatric research
2018
View details for PubMedID 29976966
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Natural Selection Has Differentiated the Progesterone Receptor among Human Populations
AMERICAN JOURNAL OF HUMAN GENETICS
2018; 103 (1): 45–57
View details for DOI 10.1016/j.ajhg.2018.05.009
View details for Web of Science ID 000438168800004
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Residential agricultural pesticide exposures and risks of preeclampsia.
Environmental research
2018; 164: 546–55
Abstract
We investigated risks of preeclampsia phenotypes from potential residential pesticide exposures, including 543 individual chemicals and 69 physicochemical groupings that were applied in the San Joaquin Valley of California during the study period, 1998-2011. The study population was derived from birth certificate data linked with Office of Statewide Health Planning and Development maternal and infant hospital discharge data. The following numbers of women with preeclampsia phenotypes were identified: 1045 with superimposed (pre-existing hypertension with preeclampsia) preeclampsia (265 with gestational weeks 20-31 and 780 with gestational weeks 32-36); 3471 with severe preeclampsia (824 with gestational weeks 20-31 and 2647 with gestational weeks 32-36); and 2780 with mild preeclampsia (207 with gestational weeks 20-31 and 2573 with gestational weeks 32-36). The reference population for these groups was 197,461 women who did not have diabetes (gestational or pre-existing), did not have any hypertensive disorder, and who delivered at 37 weeks or later. The frequency of any exposure was lower or about the same in each preeclampsia case group (further delineated by gestational age), and month time period, relative to the frequency in reference population controls. Nearly all odds ratios were below 1.0 for these any vs no exposure comparisons. This study showed a general lack of increased risks between a range of agriculture pesticide exposures near women's residences and various preeclampsia phenotypes.
View details for PubMedID 29614386
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Herpesvirus Infection in Infants with Gastroschisis
EPIDEMIOLOGY
2018; 29 (4): 571–73
Abstract
Gastroschisis is a congenital malformation that has been shown to be more common in younger mothers and appears to be increasing in prevalence in the United States and elsewhere. Epidemiologic data suggest a potential role of infection and recent studies report an association between maternal antibodies to human herpesviruses (HHV) and development of gastroschisis.In this study, we examined newborn bloodspots from 50 children with gastroschisis and 50 healthy controls using a highly sensitive digital droplet polymerase chain reaction assay covering eight human herpesviruses [herpes simplex sirus 1/2, Epstein-Barr virus (HHV-4), cytomegalovirus (HHV-5), HHV-6A/B, HHV-7, and HHV-8], to examine the presence of herpesvirus DNA at birth, which would suggest in utero infection.One control tested positive for low-level cytomegalovirus infection. We found no evidence of an association between herpesvirus DNA in neonatal blood spots taken at birth and gastroschisis.Our results do not support direct involvement of herpesviruses in the etiology of gastroschisis. However, there are several limitations in our study, most notably the known induction of this congenital malformation early in pregnancy and our analysis of blood taken at birth. Therefore, we cannot conclude that herpesviruses play no role in the etiology of gastroschisis and further research is needed to better define this relationship.
View details for PubMedID 29634591
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Residential agricultural pesticide exposures and risks of preeclampsia
ENVIRONMENTAL RESEARCH
2018; 164: 546–55
View details for DOI 10.1016/j.envres.2018.03.020
View details for Web of Science ID 000431387100065
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Prediction of preterm birth with and without preeclampsia using mid-pregnancy immune and growth-related molecular factors and maternal characteristics (vol 38, pg 946, 2018)
JOURNAL OF PERINATOLOGY
2018; 38 (7): 946
Abstract
This Article was originally published under Nature Research's License to Publish, but has nowbeen made available under a [CC BY 4.0] license. The PDF and HTML versions of the Articlehave been modified accordingly.
View details for PubMedID 29941898
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Natural Selection Has Differentiated the Progesterone Receptor among Human Populations.
American journal of human genetics
2018
Abstract
The progesterone receptor (PGR) plays a central role in maintaining pregnancy and is significantly associated with medical conditions such as preterm birth that affects 12.6% of all the births in U.S. PGR has been evolving rapidly since the common ancestor of human and chimpanzee, and we herein investigated evolutionary dynamics of PGR during recent human migration and population differentiation. Our study revealed substantial population differentiation at the PGR locus driven by natural selection, where very recent positive selection in East Asians has substantially decreased its genetic diversity by nearly fixing evolutionarily novel alleles. On the contrary, in European populations, the PGR locus has been promoted to a highly polymorphic state likely due to balancing selection. Integrating transcriptome data across multiple tissue types together with large-scale genome-wide association data for preterm birth, our study demonstrated the consequence of the selection event in East Asians on remodeling PGR expression specifically in the ovary and determined a significant association of early spontaneous preterm birth with the evolutionarily selected variants. To reconstruct its evolutionary trajectory on the human lineage, we observed substantial differentiation between modern and archaic humans at the PGR locus, including fixation of a deleterious missense allele in the Neanderthal genome that was later introgressed in modern human populations. Taken together, our study revealed substantial evolutionary innovation in PGR even during very recent human evolution, and its different forms among human populations likely result in differential susceptibility to progesterone-associated disease conditions including preterm birth.
View details for PubMedID 29937092
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Noninvasive blood tests for fetal development predict gestational age and preterm delivery
SCIENCE
2018; 360 (6393): 1133–36
Abstract
Noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care. Ultrasound, the current gold standard, is not always affordable in low-resource settings and does not predict spontaneous preterm birth, a leading cause of infant death. In a pilot study of 31 healthy pregnant women, we found that measurement of nine cell-free RNA (cfRNA) transcripts in maternal blood predicted gestational age with comparable accuracy to ultrasound but at substantially lower cost. In a related study of 38 women (23 full-term and 15 preterm deliveries), all at elevated risk of delivering preterm, we identified seven cfRNA transcripts that accurately classified women who delivered preterm up to 2 months in advance of labor. These tests hold promise for prenatal care in both the developed and developing worlds, although they require validation in larger, blinded clinical trials.
View details for PubMedID 29880692
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Nutrient intake in women before conception and risks of anophthalmia and microphthalmia in their offspring.
Birth defects research
2018; 110 (10): 863–70
Abstract
BACKGROUND: We previously explored associations between nutrients including folate and other macro and micronutrients and risks of anophthalmia or microphthalmia in the National Birth Defects Prevention Study. In the current study, we expand those previous results with larger sample sizes and conduct analyses with an additional diet quality index using more recent data.METHODS: The National Birth Defects Prevention Study is a population-based, multicenter case-control study of over 30 major birth defects, with estimated due dates from October 1997 to December 2011. Cases were 224 infants diagnosed with anophthalmia or microphthalmia. Controls were 11,109 live-born, nonmalformed infants randomly selected by each study center. Mothers completed a standardized, computer-assisted telephone interview between 6 weeks and 24 months after delivery. Mothers responded to a shortened food frequency questionnaire, assessing their nutrient intake for the year before pregnancy, and questions about periconceptional (2 months before to 2 months after conception) vitamin supplement use. Nutrient intake quartiles were based on the intake among controls.RESULTS: Among vitamin supplement users, odds of anophthalmia/microphthalmia were decreased for women with intake levels in the highest quartile of folate (0.56, 95% confidence interval [CI] 0.32-0.98), magnesium (0.42, 95% CI 0.22-0.82), and vitamin E (0.50, 95% CI 0.29-0.89). Among women not reporting vitamin supplement use, the odds were significantly increased for beta-carotene (2.5, 95% CI 1.10-5.68) and decreased for retinol (0.37, 95% CI 0.19-0.73).CONCLUSIONS: In this expanded analysis, we observed associations for a few nutrients, specifically forms of vitamin A. However, the heterogeneity of results by form and vitamin use necessitates further inquiry.
View details for PubMedID 29504274
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Nutrient intake in women before conception and risks of anophthalmia and microphthalmia in their offspring
BIRTH DEFECTS RESEARCH
2018; 110 (10): 863–70
View details for DOI 10.1002/bdr2.1201
View details for Web of Science ID 000434062300004
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Reproductive suppression, birth defects, and periviable birth.
Evolutionary applications
2018; 11 (5): 762-767
Abstract
We argue that reproductive suppression has clinical implications beyond its contribution to the burden of spontaneous abortion. We theorize that the incidence of births before the 28th week of gestation, which contribute disproportionately to infant morbidity and mortality, varies over time in part due to reproductive suppression in the form of selection in utero. We further theorize that the prevalence of structural birth defects among survivors to birth from conception cohorts gauges selection in utero. We based these theories on literature positing that natural selection conserved mechanisms that spontaneously abort "risky" pregnancies including those otherwise likely to yield infants with structural birth defects or small-for-gestational age males. We test our theory using high-quality birth defect surveillance data. We identify 479,885 male infants exposed to strong selection defined as membership in conception cohorts ranked in the lowest quartile of odds of a birth defect among live-born females. We estimate the risk of periviable birth among these infants as a function of selective pressure as well as of mother's race/ethnicity and age. We find that male infants from exposed conception cohorts exhibited 10% lower odds of periviable birth than males from other conception cohorts. Our findings support the argument that selection in utero has implications beyond its contribution to the burden of spontaneous abortion.
View details for DOI 10.1111/eva.12585
View details for PubMedID 29875817
View details for PubMedCentralID PMC5979761
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Reproductive suppression, birth defects, and periviable birth
EVOLUTIONARY APPLICATIONS
2018; 11 (5): 762–67
View details for DOI 10.1111/eva.12585
View details for Web of Science ID 000433572400015
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Women's periconceptional diet and risk of biliary atresia in offspring.
Birth defects research
2018
Abstract
INTRODUCTION: We examined the association of biliary atresia with maternal dietary intake, using National Birth Defects Prevention Study (NBDPS) data from 152 cases and 11,112 nonmalformed controls born 1997-2011.METHODS: NBDPS is a multisite, population-based case-control study. Exposure data were from maternal telephone interviews, which included a food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were generated from logistic regression models that included nutritional factors as continuous variables and were adjusted for energy intake only or energy intake plus covariates (maternal race-ethnicity, education, age, prepregnancy body mass index, vitamin/mineral supplement intake, conception during summer). Models included a quadratic term for the nutrient if p<0.10. ORs reflect odds of having biliary atresia for nutrient values at the 75th compared to 25th percentile values of each nutrient, based on distributions among controls.RESULTS: ORs for which the 95% CI excluded 1.00 were energy-adjusted ORs for calcium (0.63), protein (0.65), riboflavin (0.71), and diet quality index (0.69), and fully adjusted ORs for calcium (0.68) and vitamin E (0.72). ORs that were fully adjusted for covariates tended to be closer to 1.0 than ORs adjusted only for energy intake. ORs for the other studied nutrients had 95% CIs that included 1.00.CONCLUSIONS: NBDPS is the first study to include detailed information on maternal dietary intake and risk of biliary atresia. Our results suggest reduced risks associated with some nutrients, which may provide etiologic clues but should be interpreted with caution given the small number of cases and novelty of the investigation.
View details for PubMedID 29762915
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Failed umbilical artery catheterization and adverse outcomes in extremely low birth weight infants.
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
2018: 1–5
Abstract
PURPOSE: To determine whether successful catheterization of the umbilical artery is associated with a reduced risk of death or neurodevelopment impairment among critically ill extremely low birth weight (ELBW) infants.STUDY DESIGN: A retrospective chart review was conducted between 2007 and 2014 at Stanford University for all ELBW infants that required intubation immediately after birth. The primary outcome was death or neurodevelopmental impairment at 18-22 months. We measured the association of successful umbilical artery catheterization with the primary outcome using multivariable logistic regression with adjustment for gestational age. Bayesian analysis was also performed due to small sample size.RESULTS: Eighty-four ELBW infants met inclusion criteria. Successful umbilical artery catheterization occurred in 88% of infants and failed catheterization in 12%. Death or neurodevelopmental impairment occurred in 41% of infants with successful catheterization, compared to 60% of infants with failed catheterization of the umbilical artery, adjusted odds ratio 0.3, 95% confidence interval 0.1-1.3, p=.11. The Bayesian analysis indicated a 92% posterior probability of reduced death or neurodevelopmental impairment with successful catheterization and a 68% posterior probability of reduced death or neurodevelopmental by absolute risk difference of 20% or more, adjusted relative risk 0.74, 95% confidence interval 0.45-1.14.CONCLUSIONS: Among critically ill ELBW infants, successful catheterization of the umbilical artery compared to failed catheterization was not statistically significantly associated with the primary outcome. However, the Bayesian analysis indicated a high likelihood of benefit associated with successful umbilical artery catheterization.
View details for PubMedID 29681181
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Genetic variation in biotransformation enzymes, air pollution exposures, and risk of spina bifida
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2018; 176 (5): 1055–90
Abstract
Spina bifida is a birth defect characterized by incomplete closure of the embryonic neural tube. Genetic factors as well as environmental factors have been observed to influence risks for spina bifida. Few studies have investigated possible gene-environment interactions that could contribute to spina bifida risk. The aim of this study is to examine the interaction between gene variants in biotransformation enzyme pathways and ambient air pollution exposures and risk of spina bifida. We evaluated the role of air pollution exposure during pregnancy and gene variants of biotransformation enzymes from bloodspots and buccal cells in a California population-based case-control (86 cases of spina bifida and 208 non-malformed controls) study. We considered race/ethnicity and folic acid vitamin use as potential effect modifiers and adjusted for those factors and smoking. We observed gene-environment interactions between each of the five pollutants and several gene variants: NO (ABCC2), NO2 (ABCC2, SLC01B1), PM10 (ABCC2, CYP1A1, CYP2B6, CYP2C19, CYP2D6, NAT2, SLC01B1, SLC01B3), PM2.5 (CYP1A1 and CYP1A2). These analyses show positive interactions between air pollution exposure during early pregnancy and gene variants associated with metabolizing enzymes. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of pollution.
View details for PubMedID 29681089
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Occurrence of Selected Structural Birth Defects Among Women With Preeclampsia and Other Hypertensive Disorders
AMERICAN JOURNAL OF EPIDEMIOLOGY
2018; 187 (4): 668–76
Abstract
To explore a potential association between preeclampsia and selected birth defects, we examined the prevalence of certain birth defects among women with hypertensive disorders including preeclampsia. We analyzed data from 2,499,536 singleton live births in California from 2007 to 2011, including maternal and infant demographics from birth certificates as well as clinical details from delivery hospitalization records. We examined defect groups that were recognizable at birth (e.g., spina bifida and cleft lip). Hypertensive disorders included preexisting hypertension, gestational hypertension, mild preeclampsia, severe preeclampsia/eclampsia, and preeclampsia superimposed on preexisting hypertension. Relative risk values with 95% confidence intervals for each birth defect were calculated by hypertensive group, as well as independent and joint associations of hypertensive and diabetic disorders. Risks of each type of birth defect were higher among offspring of women with hypertensive disorders compared with those without. The risks of birth defects among offspring of women with only a hypertensive disorder were significantly higher than that among women with neither hypertensive nor diabetic disorders (relative risks ranged from 1.37 to 2.77). Risks of birth defects were highest among those born to women with both hypertensive and diabetic disorders compared with those with neither (relative risks ranged from 1.80 to 6.22). These findings support the existence of an association between preeclampsia and certain birth defects and suggest that diabetes may be a contributing factor.
View details for PubMedID 29020134
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Maternal Height and Risk of Preeclampsia.
SAGE PUBLICATIONS INC. 2018: 207A–208A
View details for Web of Science ID 000429928200458
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Demographic Characteristics and Outcomes of Pregnancies among Homeless Women in California.
SAGE PUBLICATIONS INC. 2018: 87A
View details for Web of Science ID 000429928200091
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Neonatal Outcomes of Pregnancies Complicated by Maternal Homelessness in California.
SAGE PUBLICATIONS INC. 2018: 135A
View details for Web of Science ID 000429928200237
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Divergent Patterns of Mitochondrial and Nuclear Ancestry Are Associated with the Risk for Preterm Birth
JOURNAL OF PEDIATRICS
2018; 194: 40-+
Abstract
To examine linkages between mitochondrial genetics and preterm birth by assessing the risk for preterm birth associated with the inheritance of nuclear haplotypes that are ancestrally distinct from mitochondrial haplogroup.Genome-wide genotyping studies of cohorts of preterm and term individuals were evaluated. We determined the mitochondrial haplogroup and nuclear ancestry for individuals and developed a scoring for the degree to which mitochondrial ancestry is divergent from nuclear ancestry.Infants with higher degrees of divergent mitochondrial ancestry were at increased risk for preterm birth (0.124 for preterm vs 0.105 for term infants; P< .05). This finding was validated in 1 of 2 replication cohorts. We also observed that greater degrees of divergent ancestry correlated with earlier delivery within the primary study population, but this finding was not replicated in secondary cohorts born preterm.Individuals with divergent patterns of mitochondrial and nuclear ancestry are at increased risk for preterm birth. These findings may in part explain the higher rates of preterm birth in African Americans and in individuals with a matrilineal family history of preterm birth.
View details for PubMedID 29249523
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Mass Cytometry and Proteomic Based Prediction of the Onset of Labor.
SAGE PUBLICATIONS INC. 2018: 153A
View details for Web of Science ID 000429928200292
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A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth
SCIENTIFIC REPORTS
2018; 8: 226
Abstract
Preterm birth (PTB), or the delivery prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. Although twin studies estimate that maternal genetic contributions account for approximately 30% of the incidence of PTB, and other studies reported fetal gene polymorphism association, to date no consistent associations have been identified. In this study, we performed the largest reported genome-wide association study analysis on 1,349 cases of PTB and 12,595 ancestry-matched controls from the focusing on genomic fetal signals. We tested over 2 million single nucleotide polymorphisms (SNPs) for associations with PTB across five subpopulations: African (AFR), the Americas (AMR), European, South Asian, and East Asian. We identified only two intergenic loci associated with PTB at a genome-wide level of significance: rs17591250 (P = 4.55E-09) on chromosome 1 in the AFR population and rs1979081 (P = 3.72E-08) on chromosome 8 in the AMR group. We have queried several existing replication cohorts and found no support of these associations. We conclude that the fetal genetic contribution to PTB is unlikely due to single common genetic variant, but could be explained by interactions of multiple common variants, or of rare variants affected by environmental influences, all not detectable using a GWAS alone.
View details for PubMedID 29317701
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Residential Agricultural Pesticide Exposures and Risks of Spontaneous Preterm Birth
EPIDEMIOLOGY
2018; 29 (1): 8–21
Abstract
Pesticides exposures are aspects of the human exposome that have not been sufficiently studied for their contribution to risk for preterm birth. We investigated risks of spontaneous preterm birth from potential residential exposures to 543 individual chemicals and 69 physicochemical groupings that were applied in the San Joaquin Valley of California during the study period, 1998-2011.The study population was derived from birth certificate data linked with Office of Statewide Health Planning and Development maternal and infant hospital discharge data. After exclusions, the analytic study base included 197,461 term control births and 27,913 preterm case births. Preterm cases were more narrowly defined as 20-23 weeks (n = 515), 24-27 weeks (n = 1,792), 28-31 weeks (n = 3,098), or 32-36 weeks (n = 22,508).The frequency of any (versus none) pesticide exposure was uniformly lower in each preterm case group relative to the frequency in term controls, irrespective of gestational month of exposure. All odds ratios were below 1.0 for these any versus no exposure comparisons. The majority of odds ratios were below 1.0, many of them statistically precise, for preterm birth and exposures to specific chemical groups or chemicals.This study showed a general lack of increased risk of preterm birth associated with a range of agriculture pesticide exposures near women's residences.
View details for DOI 10.1097/EDE.0000000000000758
View details for Web of Science ID 000417683700009
View details for PubMedID 28926371
View details for PubMedCentralID PMC5718919
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Antioxidant Consumption is Associated with Decreased Odds of Congenital Limb Deficiencies
PAEDIATRIC AND PERINATAL EPIDEMIOLOGY
2018; 32 (1): 90–99
Abstract
Approximately 1 in 2000 infants is born with a limb deficiency in the US. Research has shown that women's periconceptional diet and use of vitamin supplements can affect risk of birth defects. We investigated whether maternal consumption of nutritional antioxidants was associated with occurrence of transverse limb deficiency (TLD) and longitudinal limb deficiencies (LLD).We analysed case-control data from mothers and their singleton infants with TLD (n = 566), LLD (n = 339), or no malformation (controls; n = 9384) in the National Birth Defects Prevention Study (1997-2009). Using a modified food frequency, we estimated usual pre-pregnancy antioxidant consumption by total fruit and vegetable consumption (in grams) grouped into tertiles, and cumulative antioxidant score (ranging from 1 to 10) based on consumption of three antioxidants: beta-carotene, lycopene, and lutein. We estimated odds ratios (OR) adjusted for maternal age, race/ethnicity, education, smoking, alcohol use, body mass index, and total energy.Compared to women in the lowest tertile of fruit and vegetable consumption, women in the highest tertile were less likely to have infants with TLD (OR 0.74, 95% CI 0.57, 0.96) or LLD (OR 0.82, 95% CI 0.59, 1.13). Compared to the lowest antioxidant consumption score of 1, those with the highest score of 10 had ORs of 0.68 (95% CI 0.48, 0.95) for TLD and 0.77 (95% CI 0.50, 1.17) for LLD.Dietary intake of antioxidants was associated with reduced odds of limb deficiencies. These findings add further evidence for women's periconceptional diet reducing occurrence of some birth defects.
View details for PubMedID 28869773
View details for PubMedCentralID PMC5771883
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Congenital heart disease complexity and childhood cancer risk.
Birth defects research
2018; 110 (17): 1314–21
Abstract
Childhood cancer is increased in those with birth defects, including those with congenital heart disease (CHD). Lymphoma risk is increased in children with CHD. This study analyzes the effect of CHD and CHD severity on childhood cancer risk.We analyzed cancer risk in a population-based cohort of children with and without CHD born between 1988 and 2004 by linking data from the California Birth Defects Monitoring Program with data from the California Cancer Registry. We compared cancer risk in children with and without CHD, excluding children with chromosomal anomalies.Of >3 million children in the birth cohort, 65,585 had birth defects (2%), 25,981 with CHD. Cancer occurred in 4,781 (0.15%) children, 43 (0.17%) with CHD. Cancer risk in CHD was increased (hazard ratio [HR]) 2.63, 95% CI: 1.95, 3.55). Leukemia was the most common cancer in those without CHD (1,722/4,738, 36%), central nervous system tumors were second (1,073/4,738, 23%), and lymphoma third (410/4,738, 9%). Among children with CHD, lymphoma and leukemia occurred with the same frequency (12/43, 28% for each). HR for lymphoma was 8.37 (CI: 4.71, 14.86) with CHD versus without. HR for leukemia was 2.05 (CI: 1.16, 3.61) with CHD versus without. CHD complexity was higher in lymphoma (3, interquartile range [IQR]: 2-3) than those with leukemia (1, IQR, 1-2; p < .02).Cancer risk is increased in children with CHD. Lymphoma risk is increased in CHD and is correlated with more complex CHD. These results suggest a shared developmental origin for CHD and lymphoma may be present.
View details for PubMedID 30328285
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First Trimester Plasma Glucose Values in Women without Diabetes are Associated with Risk for Congenital Heart Disease in Offspring.
The Journal of pediatrics
2018; 195: 275–78
Abstract
In a retrospective study of 19 171 mother-child dyads, elevated random plasma glucose values during early pregnancy were directly correlated with increased risk for congenital heart disease in offspring. Plasma glucose levels proximal to the period of cardiac development may represent a modifiable risk factor for congenital heart disease in expectant mothers without diabetes.
View details for PubMedID 29254757
View details for PubMedCentralID PMC5869072
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Copy number variants in Ebstein anomaly
PLOS ONE
2017; 12 (12): e0188168
Abstract
Ebstein anomaly (EA) is a rare congenital defect characterized by apical displacement of the septal tricuspid leaflets and atrialization of the right ventricle. The etiology of EA is unclear; however, recurrence in families and the association of EA with genetic syndromes and copy number variants (CNVs) suggest a genetic component.We performed a population-based study to search for recurrent and novel CNVs in a previously unreported set of EA cases.We genotyped 60 EA cases identified from all live births (2,891,076) from selected California counties (1991-2010) using the Illumina HumanOmni2.5-8 array. We identified 38 candidate CNVs in 28 (46%) cases and prioritized and validated 11 CNVs based on the genes included.Five CNVs (41%) overlapped or were close to genes involved in early myocardial development, including NODAL, PDLIM5, SIX1, ASF1A and FGF12. We also replicated a previous association of EA with CNVs at 1p34.1 and AKAP12. Finally, we identified four CNVs overlapping or in close proximity to the transcription factors HES3, TRIM71, CUX1 and EIF4EBP2.This study supports the relationship of genetic factors to EA and demonstrates that defects in cardiomyocytes and myocardium differentiation may play a role. Abnormal differentiation of cardiomyocytes and how genetic factors contribute should be examined for their association with EA.
View details for PubMedID 29216221
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Simultaneously Monitoring Immune Response and Microbial Infections during Pregnancy through Plasma cfRNA Sequencing
CLINICAL CHEMISTRY
2017; 63 (11): 1695–1704
Abstract
Plasma cell-free RNA (cfRNA) encompasses a broad spectrum of RNA species that can be derived from both human cells and microbes. Because cfRNA is fragmented and of low concentration, it has been challenging to profile its transcriptome using standard RNA-seq methods.We assessed several recently developed RNA-seq methods on cfRNA samples. We then analyzed the dynamic changes of both the human transcriptome and the microbiome of plasma during pregnancy from 60 women.cfRNA reflects a well-orchestrated immune modulation during pregnancy: an up-regulation of antiinflammatory genes and an increased abundance of antimicrobial genes. We observed that the plasma microbiome remained relatively stable during pregnancy. The bacteria Ureaplasma shows an increased prevalence and increased abundance at postpartum, which is likely to be associated with postpartum infection. We demonstrated that cfRNA-seq can be used to monitor viral infections. We detected a number of human pathogens in our patients, including an undiagnosed patient with a high load of human parvovirus B19 virus (B19V), which is known to be a potential cause of complications in pregnancy.Plasma cfRNA-seq demonstrates the potential to simultaneously monitor immune response and microbial infections during pregnancy.
View details for PubMedID 28904056
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Population-based case-control study of the association between weather-related extreme heat events and neural tube defects
BIRTH DEFECTS RESEARCH
2017; 109 (18): 1482–93
Abstract
Elevated body core temperature has been shown to have teratogenic effects in animal studies. Our study evaluated the association between weather-related extreme heat events (EHEs) in the summer season and neural tube defects (NTDs), and further investigated whether pregnant women with a high pregestational body mass index (BMI) have a greater risk of having a child with NTDs associated with exposure to EHE than women with a normal BMI.We conducted a population-based case-control study among mothers of infants with NTDs and mothers of infants without major birth defects, who participated in the National Birth Defects Prevention Study and had at least 1 day of the third or fourth week postconception during summer months. EHEs were defined using the 95th and the 90th percentiles of the daily maximum universal apparent temperature. Adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression models with Firth's penalized likelihood method while controlling for other known risk factors.Overall, we did not observe a significant association between EHEs and NTDs. At the climate region level, consistently elevated but not statistically significant estimates were observed for at least 2 consecutive days with daily universal apparent maximum temperature above the 95th percentile of the UATmax distribution for the season, year, and weather monitoring station in New York (Northeast), North Carolina and Georgia (Southeast), and Iowa (Upper Midwest). No effect modification by BMI was observed.EHEs occurring during the relevant developmental window of embryogenesis do not appear to appreciably affect the risk of NTDs. Future studies should refine exposure assessment, and more completely account for maternal activities that may modify the effects of weather exposure. Birth Defects Research 109:1482-1493, 2017.© 2017 Wiley Periodicals, Inc.
View details for PubMedID 28766872
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Nulliparous teenagers and preterm birth in California
JOURNAL OF PERINATAL MEDICINE
2017; 45 (8): 959–67
Abstract
Young maternal age is one of the numerous risk factors for delivery before 37 weeks of gestation, yet the mechanisms are unclear. The purpose of the current study was to investigate the association between teenagers and the risk of preterm birth (PTB) in a large and recent cohort study.We conducted a population-based retrospective cohort study using 2007-2011 California birth certificate records linked with hospital discharge indices and United States census data for nulliparous 13-20 year olds who gave birth to singletons. Maternal age was examined categorically at 1 year intervals. PTB was defined as delivery at <37 weeks of gestation with further distinction between <32 and 32-36 weeks, and between spontaneous and medically indicated deliveries. Adjusted multivariable logistic regression was used to estimate odds ratios (OR) for PTB.The prevalence of PTB was highest among the youngest (13 year olds, 14.5%) and lowest among the oldest (20 year olds, 6.7%). After adjusting for maternal and paternal race/ethnicity, paternal age, initiation of prenatal care, source of payment, pre-pregnancy body-mass-index (BMI), height, smoking, and poverty; young mothers of ages 13, 14, 15, and 16 years had increased odds for spontaneous PTB at <32 weeks [OR (CI): 3.76 (1.83-7.75), 1.65 (1.10-2.48), 1.55 (1.24-1.93), 1.19 (1.00-1.42), respectively] compared to 20 year olds. All teenagers, excluding 19 year olds, had elevated odds of spontaneous PTB at 32-36 weeks.Nulliparous teenagers were at increased risk for spontaneous PTB, especially those 16 years or younger. Medically indicated PTB was not associated with young age.
View details for DOI 10.1515/jpm-2016-0313
View details for Web of Science ID 000415085900008
View details for PubMedID 28343179
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Preterm Birth Phenotypes in Women with Autoimmune Diseases
WILEY. 2017
View details for Web of Science ID 000411824102207
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Preterm Delivery Phenotypes in SLE Pregnancies
WILEY. 2017
View details for Web of Science ID 000411824102208
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Maternal Exposure to Nitrogen Dioxide, Intake of Methyl Nutrients, and Congenital Heart Defects in Offspring
AMERICAN JOURNAL OF EPIDEMIOLOGY
2017; 186 (6): 719–29
Abstract
Nutrients that regulate methylation processes may modify susceptibility to the effects of air pollutants. Data from the National Birth Defects Prevention Study (United States, 1997-2006) were used to estimate associations between maternal exposure to nitrogen dioxide (NO2), dietary intake of methyl nutrients, and the odds of congenital heart defects in offspring. NO2 concentrations, a marker of traffic-related air pollution, averaged across postconception weeks 2-8, were assigned to 6,160 nondiabetic mothers of cases and controls using inverse distance-squared weighting of air monitors within 50 km of maternal residences. Intakes of choline, folate, methionine, and vitamins B6 and B12 were assessed using a food frequency questionnaire. Hierarchical regression models, which accounted for similarities across defects, were constructed, and relative excess risks due to interaction were calculated. Relative to women with the lowest NO2 exposure and high methionine intake, women with the highest NO2 exposure and lowest methionine intake had the greatest odds of offspring with a perimembranous ventricular septal defect (odds ratio = 3.23, 95% confidence interval: 1.74, 6.01; relative excess risk due to interaction = 2.15, 95% confidence interval: 0.39, 3.92). Considerable departure from additivity was not observed for other defects. These results provide modest evidence of interaction between nutrition and NO2 exposure during pregnancy.
View details for DOI 10.1093/aje/kwx139
View details for Web of Science ID 000410728500012
View details for PubMedID 28520847
View details for PubMedCentralID PMC5610640
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Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2017; 114 (36): 9623–28
Abstract
Blood circulates throughout the human body and contains molecules drawn from virtually every tissue, including the microbes and viruses which colonize the body. Through massive shotgun sequencing of circulating cell-free DNA from the blood, we identified hundreds of new bacteria and viruses which represent previously unidentified members of the human microbiome. Analyzing cumulative sequence data from 1,351 blood samples collected from 188 patients enabled us to assemble 7,190 contiguous regions (contigs) larger than 1 kbp, of which 3,761 are novel with little or no sequence homology in any existing databases. The vast majority of these novel contigs possess coding sequences, and we have validated their existence both by finding their presence in independent experiments and by performing direct PCR amplification. When their nearest neighbors are located in the tree of life, many of the organisms represent entirely novel taxa, showing that microbial diversity within the human body is substantially broader than previously appreciated.
View details for PubMedID 28830999
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An immune clock of human pregnancy
SCIENCE IMMUNOLOGY
2017; 2 (15)
View details for DOI 10.1126/sciimmunol.aan2946
View details for Web of Science ID 000434327200004
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A Multivariate Dynamic Spatial Factor Model for Speciated Pollutants and Adverse Birth Outcomes
INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH
2017; 14 (9)
Abstract
Evidence suggests that exposure to elevated concentrations of air pollution during pregnancy is associated with increased risks of birth defects and other adverse birth outcomes. While current regulations put limits on total PM2.5 concentrations, there are many speciated pollutants within this size class that likely have distinct effects on perinatal health. However, due to correlations between these speciated pollutants, it can be difficult to decipher their effects in a model for birth outcomes. To combat this difficulty, we develop a multivariate spatio-temporal Bayesian model for speciated particulate matter using dynamic spatial factors. These spatial factors can then be interpolated to the pregnant women's homes to be used to model birth defects. The birth defect model allows the impact of pollutants to vary across different weeks of the pregnancy in order to identify susceptible periods. The proposed methodology is illustrated using pollutant monitoring data from the Environmental Protection Agency and birth records from the National Birth Defect Prevention Study.
View details for PubMedID 28891988
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Social disadvantage and the black-white disparity in spontaneous preterm delivery among California births
PLOS ONE
2017; 12 (8): e0182862
Abstract
We examined the contribution of social disadvantage to the black-white disparity in preterm birth. Analyses included linked vital and hospital discharge records from 127,358 black and 615,721 white singleton California births from 2007-11. Odds ratios (OR) were estimated by 4 logistic regression models for 2 outcomes: early (<32 wks) and moderate (32-36 wks) spontaneous preterm birth (ePTB, mPTB), stratified by 2 race-ethnicity groups (blacks and whites). We then conducted a potential impact analysis. The OR for less than high school education (vs. college degree) was 1.8 (95% confidence interval 1.6, 2.1) for ePTB among whites but smaller for the other 3 outcome groups (ORs 1.3-1.4). For all 4 groups, higher census tract poverty was associated with increased odds (ORs 1.03-1.05 per 9% change in poverty). Associations were less noteworthy for the other variables (payer, and tract percent black and Gini index of income inequality). Setting 3 factors (education, poverty, payer) to 'favorable' values was associated with lower predicted probability of ePTB (25% lower among blacks, 31% among whites) but a 9% higher disparity, compared to probabilities based on observed values; for mPTB, respective percentages were 28% and 13% lower probability, and 17% lower disparity. Results suggest that social determinants contribute to preterm delivery and its disparities, and that future studies should focus on ePTB and more specific factors related to social circumstances.
View details for PubMedID 28800643
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Interpregnancy Interval and Adverse Pregnancy Outcomes: An Analysis of Successive Pregnancies and Interpregnancy Interval and Pregnancy Outcomes: Causal or Not?
OBSTETRICS AND GYNECOLOGY
2017; 130 (2): 463
View details for PubMedID 28742651
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Cohort Variation in Selection During Pregnancy and Risk of Selected Birth Defects Among Males.
Epidemiology
2017; 28 (4): 580-586
Abstract
The literature theorizes, but does not test, that variation over time in selective loss in utero affects the observed count of live-born birth defects cases. We test the hypothesis that the risk of birth defects among live-born males varies inversely with the strength of selection against males in utero.We identified a subset of six birth defect phenotypes among males from the California Birth Defects Monitoring Program, an active surveillance system for over 490,000 male singletons born in eight California counties from 1986 to 2004. We assigned each birth defect case infant to a monthly conception cohort at risk of selection in utero. We used the monthly sex ratio at birth (M:F), derived from each conception cohort, as the indicator of selection against males. We analyzed the odds ratio of birth defects with both individual-level logistic regression and aggregate time-series methods.Consistent with selection in utero, male infants from conception cohorts with low outlying sex ratios (i.e., stronger selectivity) exhibit fewer than expected birth defects (adjusted odds ratio [OR] = 0.86; 95% confidence interval [CI] = 0.76, 0.98). Aggregate time-series tests also yield similar findings (OR = 0.81; 95% CI = 0.71, 0.90).Our findings among males indicate that variation in the strength of selectivity in utero accounts for a portion of observed cohort differences in morbidity due to birth defects. These findings suggest that "revealed prevalence" of morbidity across birth cohorts varies, at least in part, from selective loss in utero. See video abstract at, http://links.lww.com/EDE/B209.
View details for DOI 10.1097/EDE.0000000000000661
View details for PubMedID 28346269
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Maternal prepregnancy body mass index and risk of bronchopulmonary dysplasia.
Pediatric research
2017
Abstract
BackgroundWe examined the relationship between women's prepregnancy BMI and development of bronchopulmonary dysplasia (BPD) in their preterm offspring, hypothesizing that obesity-associated inflammation may increase risk.MethodsWe studied infants born in California between 2007 and 2011, using linked data from California Perinatal Quality Care Collaborative neonatal intensive care units, hospital discharge, and vital statistics. We included infants with birthweight <1,500 g or gestational age at birth of 22-29 weeks. BPD was defined as continuous supplemental oxygen use at 36 weeks' postmenstrual age.ResultsAmong 12,621 infants, 4,078 (32%) had BPD. After adjustment for maternal race/ethnicity, age, education, payer source, and infant sex, BMI status underweight I (BMI <16.9, odds ratio (OR) 1.7, 95% confidence interval (CI) 1.3-2.1) and obesity III (BMI ⩾40.0, OR 1.3, 95% CI 1.0-1.6) were associated with an increased risk of BPD. When considering maternal BMI as a continuous variable, a nonlinear association with BPD was observed for male infants and infants delivered at 25-29 weeks of gestational age, but not for other subgroups.ConclusionBoth high and low maternal BMI were associated with increased BPD risk. These findings support the notion that BPD is a multi-factorial disease that may sometimes have its origins in utero and be influenced by maternal inflammation.Pediatric Research advance online publication, 31 May 2017; doi:10.1038/pr.2017.90.
View details for DOI 10.1038/pr.2017.90
View details for PubMedID 28399116
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The association of maternal lymphatic markers and critical congenital heart defects in the fetus-A population based case-control study
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2017; 173 (5): 1231-1236
Abstract
The objective ot this study was to investigate whether lymphatic markers measured in women during the second trimester are associated with critical congenital heart defects (CCHDs) in offspring. This is a retrospective cohort study of pregnant women who participated in the California Prenatal Screening Program. CCHD data in the offspring was captured by linking birth certificate data with hospital patient discharge records. Second trimester samples were assayed for vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) AA/BB, and PDGF AB. Logistic models were used to evaluate the association between lymphatic biomarkers and CCHD. Models were adjusted for other serum biomarkers and maternal characteristics. Results are presented in odds ratios (OR) with 95% confidence intervals (CI). We identified 93 cases with CCHDs and 194 controls without CCHDs. The crude and adjusted OR for log (ln) VEGF was 1.07 (95%CI 0.94-1.22) and 1.08 (95%CI 0.94-1.24), respectively; for ln PDGF AB/BB was 0.93 (95%CI 0.6-1.35) and 0.58 (95%CI 0.32-1.05), respectively. There was a significant association between ln PDFG AA and CCHDs (crude OR 1.83 (95%CI 1.05-3.2); adjusted OR 2.41 (95%CI 1.06-5.44)). Levels of circulating PDGF AA were highest in cases with hypoplastic left heart syndrome (HLHS) (mean 8.78 +/- 1.54 pg/ml). In this study, increased mid-pregnancy maternal serum levels of PDGF AA were associated with CCHDs in offspring. The highest PDGF AA levels were found in mothers of fetuses with HLHS. These findings may be useful in screening for CCHDs and offer insight into their association with nuchal translucency.
View details for DOI 10.1002/ajmg.a.38152
View details for Web of Science ID 000399691500015
View details for PubMedID 28323386
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journal of maternal-fetal & neonatal medicine
2017: 1-7
Abstract
Approximately 10% of US couples are inter-racial/ethnic. Substantial variation in preterm birth (PTB) rates is seen when stratified by race/ethnicity, although most studies focused solely on maternal racial/ethnic demographics. Our aims were to analyze the contribution of paternal in addition to maternal race/ethnicity, and to evaluate risk of spontaneous PTB for previously understudied inter-racial/ethnic couples.California singleton live births from 2007 to 2010 were included. Race/ethnicity was determined based on self-report, obtained from birth certificates and defined as African American (AA), Hispanic, Asian, and White. Logistic regression was used to estimate odds ratios of spontaneous PTB at 20-23, 24-31, 32-36 and <37 weeks of gestation, with White-White couples as reference. Results were stratified by previous PTB, pre-gestational and gestational diabetes and hypertension. To investigate the paternal contribution to the risk for any given maternal race/ethnicity we assessed the rates of PTB among inter-racial/ethnic couples compared to the respective same-race couple. Odds ratios were adjusted for maternal age, parity, BMI, prenatal care, payor status, education and smoking.Among 1,664,939 live births, 13% (n = 216,417) were born to inter-racial/ethnic couples. Compared to White-White couples, risk for spontaneous PTB was increased across all inter-racial/ethnic couples with a non-White mother, except when the father was Asian. Patterns of association were similar after stratification by previous PTB, hypertension and diabetes. Paternal race/ethnicity was also a significant risk factor for PTB.Increased risks for spontaneous PTB were seen in most inter-racial/ethnic couple groupings. In addition to maternal race/ethnicity, paternal race/ethnicity was a significant risk factor in many inter-racial/ethnic couplings. Identifying such different risk profiles based on both maternal and paternal race/ethnicity may offer new lines of research inquiry for the underlying etiologies of PTB.
View details for DOI 10.1080/14767058.2017.1293029
View details for PubMedID 28399669
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Air pollution, neighborhood acculturation factors, and neural tube defects among Hispanic women in California
BIRTH DEFECTS RESEARCH
2017; 109 (6): 403-422
Abstract
Neural tube defects (NTDs) are one of the most common types of birth defects. Environmental pollutants and acculturation have been associated with NTDs independently. The potential effect modification of acculturation in the relationship between ambient air pollution and risks of NTDs is not well understood.We investigated whether associations between traffic-related air pollutant exposure in early gestation and NTDs, and more specifically spina bifida, were modified by individual and neighborhood acculturation factors among 139 cases and 466 controls born in the San Joaquin Valley of California, 1997 to 2006. Five criteria pollutant exposures in tertiles, two outcomes, and seven neighborhood acculturation factors from the U.S. Census at the block group level were included for a total of 280 investigated associations. Estimates were adjusted for maternal education and multivitamin use in the first 2 months of pregnancy. Additional analyses were stratified by nativity.Increased odds of NTDs were observed for individuals who had high exposures to carbon monoxide, nitrogen oxide, or nitrogen dioxide and lived in neighborhoods that were more acculturated. Conversely, there were increased odds of NTDs for those who had high prenatal exposure to PM10 and lived in neighborhoods that were less acculturated. The results of spina bifida alone were generally stronger in magnitude. When stratified by individual nativity (U.S.- vs. foreign-born), carbon monoxide, nitrogen oxide, and nitrogen dioxide were more strongly associated with NTDs among U.S.-born Hispanic mothers.Neighborhood acculturation factors were modifiers of the relationship between air pollution and NTDs in California, though not in a consistent direction for all pollutants. Birth Defects Research 109:403-422, 2017. © 2017 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23602
View details for Web of Science ID 000398804400001
View details for PubMedID 28398703
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Fetal de novo mutations and preterm birth.
PLoS genetics
2017; 13 (4)
Abstract
Preterm birth (PTB) affects ~12% of pregnancies in the US. Despite its high mortality and morbidity, the molecular etiology underlying PTB has been unclear. Numerous studies have been devoted to identifying genetic factors in maternal and fetal genomes, but so far few genomic loci have been associated with PTB. By analyzing whole-genome sequencing data from 816 trio families, for the first time, we observed the role of fetal de novo mutations in PTB. We observed a significant increase in de novo mutation burden in PTB fetal genomes. Our genomic analyses further revealed that affected genes by PTB de novo mutations were dosage sensitive, intolerant to genomic deletions, and their mouse orthologs were likely developmentally essential. These genes were significantly involved in early fetal brain development, which was further supported by our analysis of copy number variants identified from an independent PTB cohort. Our study indicates a new mechanism in PTB occurrence independently contributed from fetal genomes, and thus opens a new avenue for future PTB research.
View details for DOI 10.1371/journal.pgen.1006689
View details for PubMedID 28388617
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The Complex Relationship of Obesity and Spontaneous Preterm Birth.
SAGE PUBLICATIONS INC. 2017: 189A
View details for Web of Science ID 000399043900436
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Acute Fatty Liver of Pregnancy and Risk of Preterm Birth.
SAGE PUBLICATIONS INC. 2017: 246A–247A
View details for Web of Science ID 000399043900621
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What factors are related to recurrent preterm birth among underweight women?
journal of maternal-fetal & neonatal medicine
2017: 1-19
Abstract
Our objective was to identify factors associated with recurrent preterm birth among underweight women.Maternally linked hospital and birth certificate records of deliveries in California between 2007 and 2010 were used. Consecutive singleton pregnancies of women with underweight body mass index (BMI <18.5 kg/m(2)) in the first pregnancy were analyzed. Pregnancies were categorized based on outcome of the first and second birth as: term-term; term-preterm; preterm-term and preterm-preterm.We analyzed 4971 women with underweight BMI in the first pregnancy. Of these, 670 had at least one preterm birth. Among these 670, 86 (21.8%) women experienced a recurrent preterm birth. Odds for first term - second preterm birth were decreased for increases in maternal age (aOR: 0.90, 95%CI: 0.95-0.99) whereas inter-pregnancy interval <6 months was related to both first term - second preterm birth (aOR:1.66, 95%CI: 1.21-2.28) and first preterm birth - second term birth (aOR: 1.43, 95%CI: 1.04-1.96). Factors associated with recurrent preterm birth were: negative or no change in pre-pregnancy weight between pregnancies (aOR: 1.67, 95%CI: 1.07-2.60), inter-pregnancy interval <6 months (aOR: 2.14, 95%CI: 1.29-3.56), and maternal age in the first pregnancy (aOR: 0.93, 95%CI: 0.90-0.97).Recurrent preterm birth among underweight women was associated with younger age, short inter-pregnancy interval, and negative or no weight change between pregnancies.
View details for DOI 10.1080/14767058.2017.1292243
View details for PubMedID 28166677
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An Electronic Health Record Investigation of Lenticulostriate Vasculopathy Features.
American journal of perinatology
2017; 34 (3): 253-258
Abstract
Objective Lenticulostriate vasculopathy (LSV) is characterized by linear hyperechogenicities in the basal ganglia found on the head ultrasounds of infants. We reviewed electronic health records of infants with and without LSV to investigate whether physician dictations indicated symptoms which could reflect subtle basal ganglia injury. Study Design In a case-control study, we analyzed data from 46 infants with LSV and 127 controls. Infants were stratified between term and preterm birth. Odds ratios (ORs) and 95% confidence intervals were calculated for tone abnormalities, apnea, feeding difficulties, seizures, and movement abnormalities in the presence of LSV. Results Both term and preterm infants with LSV showed elevated risks for tone abnormalities (OR: 3.6 and 2.9, respectively). Term infants with LSV showed elevated risks for hypotonia (OR: 4.3), apnea (OR: 2.9), and feeding difficulties (OR: 4.1). Preterm infants with LSV showed elevated risks for truncal hypotonia (OR: 3.9) and hyperreflexia (OR: 3.9). Conclusion Our findings provide some evidence that LSV is associated with an increased risk of early signs of abnormal development, possibly relating to signs of subtle basal ganglia injury. Historically LSV has been considered incidental. The associations identified here suggest that LSV findings are worthy of further study.
View details for DOI 10.1055/s-0036-1585417
View details for PubMedID 27471823
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Maternal underweight and obesity and risk of orofacial clefts in a large international consortium of population-based studies
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
2017; 46 (1): 190–99
Abstract
Evidence on association of maternal pre-pregnancy weight with risk of orofacial clefts is inconsistent.Six large case-control studies of orofacial clefts from Northern Europe and the USA were included in analyses pooling individual-level data. Cases included 4943 mothers of children with orofacial clefts (cleft lip only: 1135, cleft palate with cleft lip: 2081, cleft palate only: 1727) and controls included 10 592 mothers of unaffected children. Association of orofacial cleft risk with pre-pregnancy maternal weight classified by level of body mass index (BMI, kg/m 2 ) was evaluated using logistic regression adjusting for multiple covariates.Cleft palate, both alone and with cleft lip (CP+/-CL), was associated with maternal class II+ pre-pregnancy obesity (≥ 35)compared with normal weight [adjusted odds ratio (aOR) = 1.36; 95% confidence interval (CI) = 1.16, 1.58]. CP+/-CL was marginally associated with maternal underweight (aOR = 1.16; 95% CI = 0.98, 1.36). Cleft lip alone was not associated with BMI.In this largest population-based study to date, we found an increased risk of cleft palate, with or without cleft lip, in class II+ obese mothers compared with normal-weight mothers; underweight mothers may also have an increased risk, but this requires further study. These results also suggest that extremes of weight may have a specific effect on palatal development.
View details for PubMedID 27215617
View details for PubMedCentralID PMC5837498
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Acylcarnitine Profiles Reflect Metabolic Vulnerability for Necrotizing Enterocolitis in Newborns Born Premature.
journal of pediatrics
2017; 181: 80-85 e1
Abstract
To evaluate the association between newborn acylcarnitine profiles and the subsequent development of necrotizing enterocolitis (NEC) with the use of routinely collected newborn screening data in infants born preterm.A retrospective cohort study was conducted with the use of discharge records for infants born preterm admitted to neonatal intensive care units in California from 2005 to 2009 who had linked state newborn screening results. A model-development cohort of 94 110 preterm births from 2005 to 2008 was used to develop a risk-stratification model that was then applied to a validation cohort of 22 992 births from 2009.Fourteen acylcarnitine levels and acylcarnitine ratios were associated with increased risk of developing NEC. Each log unit increase in C5 and free carnitine /(C16 + 18:1) was associated with a 78% and a 76% increased risk for developing NEC, respectively (OR 1.78, 95% CI 1.53-2.02, and OR 1.76, 95% CI 1.51-2.06). Six acylcarnitine levels, along with birth weight and total parenteral nutrition, identified 89.8% of newborns with NEC in the model-development cohort (area under the curve 0.898, 95% CI 0.889-0.907) and 90.8% of the newborns with NEC in the validation cohort (area under the curve 0.908, 95% CI 0.901-0.930).Abnormal fatty acid metabolism was associated with prematurity and the development of NEC. Metabolic profiling through newborn screening may serve as an objective biologic surrogate of risk for the development of disease and thus facilitate disease-prevention strategies.
View details for DOI 10.1016/j.jpeds.2016.10.019
View details for PubMedID 27836286
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The Relationship of Nosocomial Infection Reduction to Changes in Neonatal Intensive Care Unit Rates of Bronchopulmonary Dysplasia
JOURNAL OF PEDIATRICS
2017; 180: 105-?
Abstract
To examine whether recent reductions in rates of nosocomial infection have contributed to changes in rates of bronchopulmonary dysplasia (BPD) in a population-based cohort.This was a retrospective, population-based cohort study that used the California Perinatal Quality Care Collaborative database from 2006 to 2013. Eligible infants included those less than 30 weeks' gestational age and less than 1500 g who survived to 3 days of life. Primary variables of interest were rates of nosocomial infections and BPD. Adjusted rates of nosocomial infections and BPD from a baseline period (2006-2010) were compared with a later period (2011-2013). The correlation of changes in rates across periods for both variables was assessed by hospital of care.A total of 22 967 infants from 129 hospitals were included in the study. From the first to second time period, the incidence of nosocomial infections declined from 24.7% to 15% and BPD declined from 35% to 30%. Adjusted hospital rates of BPD and nosocomial infections were correlated positively with a calculated 8% reduction of BPD rates attributable to reductions in nosocomial infections.Successful interventions to reduce rates of nosocomial infections may have a positive impact on other comorbidities such as BPD. The prevention of nosocomial infections should be viewed as a significant component in avoiding long-term neonatal morbidities.
View details for DOI 10.1016/j.jpeds.2016.09.030
View details for Web of Science ID 000390028100022
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Maternal Stressors and Social Support and Risks of Delivering Babies With Gastroschisis or Hypospadias.
American journal of epidemiology
2017; 185 (12): 1240–46
Abstract
We examined the association of maternal stressful life events and social support with risks of gastroschisis and hypospadias, using data from the National Birth Defects Prevention Study, a population-based case-control study of US births taking place in 2006-2011. We examined maternal self-reports of 7 life events and 3 sources of social support during the periconceptional period among mothers of 593 gastroschisis cases, 1,142 male hypospadias cases, and 4,399 nonmalformed controls. Responses to the questions on stressful life events were summed to form an index (higher is worse), as were responses to questions on social support (higher is better). We used logistic regression to estimate adjusted odds ratios and 95% confidence intervals. The adjusted odds ratios for gastroschisis for a 4-point increase in the stress index were 3.5 (95% confidence interval (CI): 2.6, 4.8) among nonteenage mothers (age ≥20 years) and 1.0 (95% CI: 0.5, 1.7) among teenage mothers (age <20 years). The odds ratio for hypospadias (among all mothers) was 0.8 (95% CI: 0.7, 1.1). Adjusted odds ratios for a social support score of 3 (versus 0) in the 3 respective groups were 0.6 (95% CI: 0.4, 1.0), 1.0 (95% CI: 0.5, 2.3), and 0.6 (95% CI: 0.4, 0.9). Given the lack of prior research on these outcomes and stress, results should be interpreted with caution.
View details for PubMedID 28505275
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Maternal Smoking, Alcohol, and Caffeine Exposures and Risk of Hypospadias.
Birth defects research
2017; 109 (14): 1127–33
Abstract
We examined the association of hypospadias risk with maternal smoking and consumption of alcohol and caffeine.We analyzed data from mothers of 2437 moderate/severe cases and 5472 nonmalformed controls born from 1997 to 2011 who participated in the National Birth Defects Prevention Study (NBDPS). Exposures were assessed by maternal telephone interviews. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for mother's age, parity, race-ethnicity, education, vitamin/mineral supplement intake, obesity, and study center.Active smoking during the first month of pregnancy was associated with reduced risk, with smaller ORs for increasing quantity smoked; the OR for smoking >1/2 pack/day was 0.7 (95% CI, 0.5-0.9). Among nonsmokers, the OR for any secondhand smoke exposure was 0.8 (95% CI, 0.7-0.9). ORs for alcohol and caffeine consumption were near one and CIs included 1.0. In an analysis of joint exposures to smoking and alcohol and caffeine consumption, the only OR for which the 95% CI excluded 1.0 was for women who smoked, drank, and had low caffeine consumption (OR, 0.6; 95% CI, 0.4-0.8).Maternal exposure to cigarette smoke was associated with reduced risk, and women who smoked, drank, and had low caffeine intake were at lowest risk. We do not interpret these results to suggest that these exposures have overall benefit to a pregnant woman or developing fetus. They may, however, offer clues to help us understand mechanisms that lead to hypospadias. Birth Defects Research 109:1127-1133, 2017. © 2017 Wiley Periodicals, Inc.
View details for PubMedID 28635116
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DNA Methylome Profiling on the Infinium HumanMethylation450 Array from Limiting Quantities of Genomic DNA from a Single, Small Archived Bloodspot.
Genetic testing and molecular biomarkers
2017; 21 (8): 516–19
Abstract
Archived newborn bloodspots are valuable sample collections for genetic and epigenetic disease research. However, they have often been stored for long periods of time, under less than ideal circumstances, and nucleic acid yields can be low, particularly when samples become limiting. We wished to determine whether the quantity and quality of genomic DNA (gDNA) isolated from a single, surgical bloodspot punch (2 mm dia.) was adequate for accurate and reliable DNA methylome profiling on the Illumina HumanMethylation450 array.A total of 25-750 ng of archived bloodspot or Jurkat cell gDNA were bisulfite converted and analyzed on the array without any additional DNA amplification steps. Methylation profiles were assessed for call rate, call confidence (detection p-value), and reproducibility.Using 25 ng gDNA from either Jurkat cells or dried bloodspots, array-wide call rates (∼99.9%) and detection p-values (99.9% with p < 5 × 10-6) were excellent. There was good agreement between methylation profiles generated from 25 ng gDNA and those generated from 750 ng (ρ > 0.98), although a fraction of CpG sites (2-8% depending on experiment) exhibited quantitative differences. Genome-wide methylation levels were strikingly reproducible from 25 ng DNA in both replicate and interindividual samples (ρ > 0.98).Twenty-five nanograms of gDNA, isolated from a single, surgical punch (2 mm dia.) of an archived newborn bloodspot, generate a genome-wide methylation profile on the Illumina HumanMethylation450 array that is robust, reproducible, and suitable for differential methylation studies.
View details for PubMedID 28609193
View details for PubMedCentralID PMC5568181
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Selected birth defects among males following the United States terrorist attacks of 11 September 2001.
Birth defects research
2017; 109 (16): 1277–83
Abstract
The terrorist attacks of 11 September 2001 (hereafter referred to as 9/11) preceded an increase in male fetal deaths and reduced male live births among exposed gestational cohorts across several geographic locations in the United States, including California. We analyze whether the extreme stressor of 9/11 may have selected against frail males in utero by testing if the prevalence of male births with selected defects in California fell among cohorts exposed to the stressor during gestation.We used data from the California Birth Defects Monitoring Program from July 1985 to January 2004 (223 conception cohorts). We included six birth defects that as a group of phenotypes disproportionately affect males. We applied time-series methods and defined as "exposed to 9/11" the cohorts conceived in February, March, April, May, June, July, and August 2001.Three of the seven monthly conception cohorts exposed to 9/11 in utero show lower than expected odds of live born males with the studied defects: February 2001 (odds ratio [OR] = 0.39; 95% confidence interval [CI], 0.21-0.71), May 2001 (OR = 0.36; 95% CI, 0.16-0.81), and August 2001 (OR = 0.51; 95% CI, 0.28-0.93).The population-wide stressor of 9/11 precedes a reduction in the risk of live born males with selected birth defects. Our analysis contributes to the understanding of adaptation to stress among pregnant women exposed to large and unexpected ambient stressors. Results further support the notion that the prevalence of live born defects may reflect temporal variation in cohort selection in utero against frail males. Birth Defects Research 109:1277-1283, 2017. © 2017 Wiley Periodicals, Inc.
View details for PubMedID 28722355
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Risk of recurrent preterm birth among women according to change in partner.
Journal of perinatal medicine
2017; 45 (1): 63-70
Abstract
There is well-established literature indicating change in partner as a risk for preeclampsia, yet the research on the risk of preterm birth after a change in partners has been sparse and inconsistent. Using a population of California live born singletons, we aimed to determine the risk of preterm birth after a change in partner between the first and second pregnancies. The risk of preterm and early term delivery in the second pregnancy was calculated for mothers who did or did not change partners between births with the referent group as women who delivered both pregnancies at term and did not change partners. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. Relative to women who delivered at 39 weeks or later in the second pregnancy and did not change partners, preterm birth risks were somewhat lower for women who changed partners between the first and second pregnancies compared to those women who did not change partners. For example, 10.6% of women who did not change partners and delivered their second pregnancy before 34 weeks also delivered their first pregnancy before 34 weeks, while 8.5% of women who changed partners delivered before 34 weeks. Findings suggest partner change may alter the risk of preterm birth.
View details for DOI 10.1515/jpm-2016-0207
View details for PubMedID 27718495
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An Investigation of Connections between Birth Defects and Cancers Arising in Adolescence and Very Young Adulthood.
The Journal of pediatrics
2017; 185: 237–40
Abstract
This study investigated the relationship between birth defects and cancer in adolescents and very young adults using California's population-based registries. Although overall cancer risk was elevated among individuals with chromosomal birth defects, this was not observed in those with nonchromosomal birth defects, as was demonstrated previously in younger children.
View details for PubMedID 28336146
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Replication and refinement of a vaginal microbial signature of preterm birth in two racially distinct cohorts of US women.
Proceedings of the National Academy of Sciences of the United States of America
2017
Abstract
Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. Previous studies have suggested that the maternal vaginal microbiota contributes to the pathophysiology of PTB, but conflicting results in recent years have raised doubts. We conducted a study of PTB compared with term birth in two cohorts of pregnant women: one predominantly Caucasian (n = 39) at low risk for PTB, the second predominantly African American and at high-risk (n = 96). We profiled the taxonomic composition of 2,179 vaginal swabs collected prospectively and weekly during gestation using 16S rRNA gene sequencing. Previously proposed associations between PTB and lower Lactobacillus and higher Gardnerella abundances replicated in the low-risk cohort, but not in the high-risk cohort. High-resolution bioinformatics enabled taxonomic assignment to the species and subspecies levels, revealing that Lactobacillus crispatus was associated with low risk of PTB in both cohorts, while Lactobacillus iners was not, and that a subspecies clade of Gardnerella vaginalis explained the genus association with PTB. Patterns of cooccurrence between L. crispatus and Gardnerella were highly exclusive, while Gardnerella and L. iners often coexisted at high frequencies. We argue that the vaginal microbiota is better represented by the quantitative frequencies of these key taxa than by classifying communities into five community state types. Our findings extend and corroborate the association between the vaginal microbiota and PTB, demonstrate the benefits of high-resolution statistical bioinformatics in clinical microbiome studies, and suggest that previous conflicting results may reflect the different risk profile of women of black race.
View details for PubMedID 28847941
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Vasa previa and extreme prematurity
MOSBY-ELSEVIER. 2017: S419
View details for Web of Science ID 000414256403036
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A Proteomic Clock of Human Pregnancy.
American journal of obstetrics and gynecology
2017
Abstract
Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome.The recent availability of a highly-multiplexed platform affording the simultaneous measurement of 1,310 plasma proteins opens the door for a more explorative approach. The major aim of this study was to examine whether analysis of plasma collected during gestation of term pregnancy would allow identifying a set of proteins that tightly track gestational age. Establishing precisely-timed plasma proteomic changes during term pregnancy is a critical step in identifying deviations from regular patterns due to fetal and maternal maladaptations. A second aim was to gain insight into functional attributes of identified proteins, and link such attributes to relevant immunological changes.Pregnant women participated in this longitudinal study. In two subsequent subsets of 21 (training cohort) and 10 (validation cohort) women, specific blood specimens were collected during the first (7-14 wks), second (15-20 wks), and third (24-32 wks) trimesters, and 6 wks post-partum for analysis with a highly-multiplexed aptamer-based platform. An elastic net algorithm was applied to infer a proteomic model predicting gestational age. A bootstrapping procedure and piece-wise regression analysis was used to extract the minimum number of proteins required for predicting gestational age without compromising predictive power. Gene ontology analysis was applied to infer enrichment of molecular functions among proteins included in the proteomic model. Changes in abundance of proteins with such functions were linked to immune features predictive of gestational age at the time of sampling in pregnancies delivering at term.An independently validated model consisting of 74 proteins strongly predicted gestational age (p = 3.8x10-14, R = 0.97). The model could be reduced to eight proteins without losing its predictive power (p = 1.7x10-3, R = 0.91). The three top ranked proteins were glypican 3, chorionic somatomammotropin hormone, and granulins. Proteins activating the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway were enriched in the proteomic model, chorionic somatomammotropin hormone being the top ranked protein. Abundance of chorionic somatomammotropin hormone strongly correlated with STAT5 signaling activity in CD4 T cells, the endogenous cell-signaling event most predictive of gestational age.Results indicate that precisely timed changes in the plasma proteome during term pregnancy mirror a "proteomic clock". Importantly, the combined use of several plasma proteins was required for accurate prediction. The exciting promise of such a "clock" is that deviations from its regular chronological profile may assist in the early diagnoses of pregnancy-relate pathologies and point to underlying pathophysiology. Functional analysis of the proteomic model generated the novel hypothesis that somatomammotropin hormone may critically regulate T-cell function during pregnancy.
View details for PubMedID 29277631
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Risky Business: Meeting the Structural Needs of Transdisciplinary Science.
The Journal of pediatrics
2017; 191: 255–58
View details for PubMedID 29173314
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The twin preterm birth problem: do preterm birth subtypes matter?
MOSBY-ELSEVIER. 2017: S199
View details for Web of Science ID 000414256401282
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An immune clock of human pregnancy.
Science immunology
2017; 2 (15)
Abstract
The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies.
View details for PubMedID 28864494
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Risk of recurrent preterm birth among women according to change in partner
JOURNAL OF PERINATAL MEDICINE
2017; 45 (1): 63-70
Abstract
There is well-established literature indicating change in partner as a risk for preeclampsia, yet the research on the risk of preterm birth after a change in partners has been sparse and inconsistent. Using a population of California live born singletons, we aimed to determine the risk of preterm birth after a change in partner between the first and second pregnancies. The risk of preterm and early term delivery in the second pregnancy was calculated for mothers who did or did not change partners between births with the referent group as women who delivered both pregnancies at term and did not change partners. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. Relative to women who delivered at 39 weeks or later in the second pregnancy and did not change partners, preterm birth risks were somewhat lower for women who changed partners between the first and second pregnancies compared to those women who did not change partners. For example, 10.6% of women who did not change partners and delivered their second pregnancy before 34 weeks also delivered their first pregnancy before 34 weeks, while 8.5% of women who changed partners delivered before 34 weeks. Findings suggest partner change may alter the risk of preterm birth.
View details for DOI 10.1515/jpm-2016-0207
View details for Web of Science ID 000393201100009
View details for PubMedCentralID PMC5380385
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Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways
HUMAN GENETICS
2016; 135 (12): 1355-1364
Abstract
Classic heterotaxy consists of congenital heart defects with abnormally positioned thoracic and abdominal organs. We aimed to uncover novel, genomic copy-number variants (CNVs) in classic heterotaxy cases. A microarray containing 2.5 million single-nucleotide polymorphisms (SNPs) was used to genotype 69 infants (cases) with classic heterotaxy identified from California live births from 1998 to 2009. CNVs were identified using the PennCNV software. We identified 56 rare CNVs encompassing genes in the NODAL (NIPBL, TBX6), BMP (PPP4C), and WNT (FZD3) signaling pathways, not previously linked to classic heterotaxy. We also identified a CNV involving FGF12, a gene previously noted in a classic heterotaxy case. CNVs involving RBFOX1 and near MIR302F were detected in multiple cases. Our findings illustrate the importance of body patterning pathways for cardiac development and left/right axes determination. FGF12, RBFOX1, and MIR302F could be important in human heterotaxy, because they were noted in multiple cases. Further investigation into genes involved in the NODAL, BMP, and WNT body patterning pathways and into the dosage effects of FGF12, RBFOX1, and MIR302F is warranted.
View details for DOI 10.1007/s00439-016-1727-x
View details for Web of Science ID 000385345900004
View details for PubMedID 27637763
View details for PubMedCentralID PMC5065782
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Folic acid fortification and prevalences of neural tube defects, orofacial clefts, and gastroschisis in California, 1989 to 2010.
Birth defects research. Part A, Clinical and molecular teratology
2016; 106 (12): 1032-1041
Abstract
We examined whether prevalences of neural tube defects (NTDs), orofacial clefts, and gastroschisis changed more rapidly after than before folic acid fortification in California.This population-based study used vital statistics and birth defects registry data. The study population included all live births and stillbirths delivered in central California counties from 1989 to 2010. Cases included deliveries with NTDs, orofacial clefts, and gastroschisis. Weighted least squares regression was used to estimate slopes during prefortification (before 1997) and postfortification (after 1998), respectively. The difference of the two slopes with the 95% confidence interval (CI) was calculated.For all NTDs combined, slopes indicated that NTD prevalence was decreasing by 8.7 (slope: -8.7; 95% CI, -13.5--3.9) cases per 100,000 deliveries per year before fortification and by 1.7 (slope: -1.7; 95% CI, -3.7-0.3) after fortification; thus the decline had slowed by 7.0 (95% CI, 2.7-11.3) cases per 100,000 deliveries per year. For orofacial clefts, slopes for cleft lip with/without palate as well as for cleft palate alone indicated that the postfortification slope was lower than the prefortification slope suggesting a more accelerated decrease in the postfortification time period. For gastroschisis, the slope after fortification was lower compared with prefortification, indicating a less accelerated prevalence increase in the postfortification time period. Stratification by race/ethnicity did not substantially alter results.We observed a slower decline in prevalence of NTDs, an emergence of a decline in orofacial clefts, and a slower increase in gastroschisis, during the postfortification period in central California, relative to the prefortification period. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1032-1041, 2016. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23514
View details for PubMedID 27191125
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Women's prepregnancy underweight as a risk factor for preterm birth: a retrospective study.
bjog-an international journal of obstetrics and gynaecology
2016; 123 (12): 2001-2007
Abstract
To investigate the distribution of known factors for preterm birth (PTB) by severity of maternal underweight; to investigate the risk-adjusted relation between severity of underweight and PTB, and to assess whether the relation differed by gestational age.Retrospective cohort study.State of California, USA.Maternally linked hospital and birth certificate records of 950 356 California deliveries in 2007-2010 were analysed. Singleton live births of women whose prepregnancy body mass index (BMI) was underweight (<18.5 kg/m(2) ) or normal (18.50-24.99 kg/m(2) ) were analysed. Underweight BMI was further categorised as: severe (<16.00), moderate (16.00-16.99) or mild (17.00-18.49). PTB was grouped as 22-27, 28-31, 32-36 or <37 weeks (compared with 37-41 weeks). Adjusted multivariable Poisson regression modeling was used to estimate relative risk for PTB.Risk of PTB.About 72 686 (7.6%) women were underweight. Increasing severity of underweight was associated with increasing percent PTB: 7.8% (n = 4421) in mild, 9.0% (n = 1001) in moderate and 10.2% (475) in severe underweight. The adjusted relative risk of PTB also significantly increased: adjusted relative risk (aRR) = 1.22 (95% CI 1.19-1.26) in mild, aRR = 1.41 (95% CI 1.32-1.50) in moderate and aRR = 1.61 (95% CI 1.47-1.76) in severe underweight. These findings were similar in spontaneous PTB, medically indicated PTB, and the gestational age groupings.Increasing severity of maternal prepregnancy underweight BMI was associated with increasing risk-adjusted PTB at <37 weeks. This increasing risk was of similar magnitude in spontaneous and medically indicated births and in preterm delivery at 28-31 and at 32-36 weeks of gestation.Increasing severity of maternal underweight BMI was associated with increasing risk of preterm birth.
View details for DOI 10.1111/1471-0528.14027
View details for PubMedID 27172996
View details for PubMedCentralID PMC5069076
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Paternal and Joint Parental Occupational Pesticide Exposure and Spina Bifida in the National Birth Defects Prevention Study, 1997 to 2002
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2016; 106 (11): 963-971
Abstract
Because of persistent concerns over the association between pesticides and spina bifida, we examined the role of paternal and combined parental occupational pesticide exposures in spina bifida in offspring using data from a large population-based study of birth defects.Occupational information from fathers of 291 spina bifida cases and 2745 unaffected live born control infants with estimated dates of delivery from 1997 to 2002 were collected by means of maternal report. Two expert industrial hygienists estimated exposure intensity and frequency to insecticides, herbicides, and fungicides. Multivariable logistic regression models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for exposure to any pesticide and to any class of pesticide (yes/no; and by median), and exposure to combinations of pesticides (yes/no) and risk of spina bifida. Adjusted odds ratios were also estimated by parent exposed to pesticides (neither, mother only, father only, both parents).Joint parental occupational pesticide exposure was positively associated with spina bifida (aOR, 1.5; 95% CI, 0.9-2.4) when compared with infants with neither maternal nor paternal exposures; a similar association was not observed when only one parent was exposed. There was a suggested positive association between combined paternal insecticide and fungicide exposures and spina bifida (aOR, 1.5; 95% CI, 0.8-2.8), however, nearly all other aORs were close to unity.Overall, there was little evidence paternal occupational pesticide exposure was associated with spina bifida. However, the small numbers make it difficult to precisely evaluate the role of pesticide classes, individually and in combination. Birth Defects Research (Part A) 106:963-971, 2016. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23551
View details for Web of Science ID 000392817500013
View details for PubMedID 27891778
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Sequence variation in folate pathway genes and risks of human cleft lip with or without cleft palate.
American journal of medical genetics. Part A
2016; 170 (11): 2777-2787
Abstract
In an effort to comprehensively interrogate genetic variation in the folate pathway for risk of cleft lip with or without cleft palate (CLP), we evaluated 504 common and rare variants in 35 folate-related genes in a panel of 330 infants with CLP and 367 non-malformed controls. Odds ratios (OR) with 95% confidence intervals were computed for common genotypes. A Case-Control Difference metric was calculated for rare variants to highlight differentially occurring alleles. Interactions between variants and a maternal folate intake variable were also evaluated. In gene-only results, significant odds ratios were observed for multiple variants in the BHMT/BHMT2/DMGDH gene cluster, particularly in Hispanic infants. Also in this cluster, rare variant analysis highlighted a substantial case-control difference in BHMT rs60340837 (synonymous Y284Y). In Hispanics, the ALDH1L1 I812V variant (rs4646750) was the most significant risk allele: OR = 3.8 (95%CI = 1.6-9.2) when heterozygous. In non-Hispanic white infants, we observed significant risk for AHCYL2 rs1095423 (homozygous OR = 3.0, 95%CI 1.1-7.8) and the 68 bp CBS insertion (c.844ins68; heterozygous OR = 2.4, 95%CI = 1.1-5.3). Rare variant analysis in this group revealed case-control differences in MTRR and several other methionine cycle genes, a process implicated previously in clefting risk. In women with low folate intake specifically, increased risks were observed for CBS rs2851391 (OR = 3.6, 95%CI = 1.3-9.6) and the R259P nonsynonymous variant of TCN2 (rs1801198; OR = 2.8, 95%CI = 1.2-6.3). This comprehensive study provides further direction on candidate loci to help disentangle the folate-related developmental phenomena in human clefting risk. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37874
View details for PubMedID 27604992
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Gene variants as risk factors for gastroschisis.
American journal of medical genetics. Part A
2016; 170 (11): 2788-2802
Abstract
In a population-based case-control study in California of 228 infants, we investigated 75 genetic variants in 20 genes and risk of gastroschisis with regard to maternal age, race/ethnicity, vitamin use, and smoking exposure. We hypothesized that genes related to vascular compromise may interact with environmental factors to affect the risk of gastroschisis. Haplotypes were constructed for 75 gene variants using the HaploView program. Risk for gastroschisis associated with each gene variant was calculated for both the homozygotes and the heterozygotes, with the homozygous wildtypes as the referent. Risks were estimated as odds ratios (ORs) with 95% confidence intervals (CIs) by logistic regression. We found 11 gene variants with increased risk and four variants with decreased risk of gastroschisis for heterozygous (ORh ) or homozygous variants (ORv ) genotypes. These included NOS3 (rs1036145) ORh = 0.4 (95% CI: 0.2-0.7); NOS3 (rs10277237) ORv = 2.7 (95% CI: 1.3-6.0); ADD1 (rs12503220) ORh = 2.9 (95% CI: 1.6-5.4), GNB3 (rs5443) ORh = 0.2 (95% CI: 0.1-0.5), ORv = 0.4 (95% CI: 0.2-0.9); ICAM1 (rs281428) ORv = 6.9 (95% CI: 2.1-22.9), ICAM1 (rs3093030) ORv = 2.6 (95% CI: 1.2-5.6); ICAM4 (rs281438) ORv = 4.9 (95% CI: 1.4-16.6), ICAM5 (rs281417) ORh = 2.1 (95% CI: 1.1-4.1), ORv = 4.8 (95% CI: 1.7-13.6); ICAM5 (rs281440) ORh = 23.7 (95% CI: 5.5-102.5), ORv = 20.6 (95% CI: 3.4-124.3); ICAM5 (rs2075741) ORv = 2.2 (95% CI: 1.1-4.4); NAT1 ORv = 0.3 (95% CI: 0.1-0.9). There were additional associations between several gene variants and gastroschisis among women aged 20-24 and among mothers with and without vitamin use. NOS3, ADD1, ICAM1, ICAM4, and ICAM5 warrant further investigation in additional populations and with the interaction of additional environmental exposures. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37883
View details for PubMedID 27616475
View details for PubMedCentralID PMC5096035
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Genetic variation of FOXE1 and risk for orofacial clefts in a California population.
American journal of medical genetics. Part A
2016; 170 (11): 2770-2776
Abstract
We investigated whether orofacial clefts are associated with polymorphic variation within and around FOXE1. This California population-based case control study focused on white Hispanic and white nonHispanic infants among which there were 262 infants with cleft lip with or without cleft palate (CL/P), 103 with cleft palate only (CPO), and 382 unaffected controls. These cases and controls were genotyped for 13 SNPs across 220 Kb at the FOXE1 Locus. We observed associations with multiple FOXE1 SNPs for CL/P and for CPO, especially for the Hispanic study population. Increased risks were associated with the more common allele for all SNPs tested. Our results implicate FOXE1 as an important locus whose polymorphic variation increases risks for all types of isolated clefts, and opens a new biological pathway to investigate in efforts to understand genetic factors underlying human clefting. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37871
View details for PubMedID 27604706
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Interpregnancy interval after live birth or pregnancy termination and estimated risk of preterm birth: a retrospective cohort study.
bjog-an international journal of obstetrics and gynaecology
2016; 123 (12): 2009-2017
Abstract
We assessed whether interpregnancy interval (IPI) length after live birth and after pregnancy termination was associated with preterm birth (PTB).Multiyear birth cohort.Fetal death, birth and infant death certificates in California merged with Office of Statewide Health Planning and Development.One million California live births (2007-10) after live birth and after pregnancy termination.Logistic regression was used to estimate odds ratios (ORs) of PTB of 20-36 weeks of gestation and its subcategories for IPIs after a live birth and after a pregnancy termination. We used conditional logistic regression (two IPIs/mother) to investigate associations within mothers.PTB relative to gestations of ≥ 37 weeks.Analyses included 971 211 women with IPI after live birth, and 138 405 women with IPI after pregnancy termination with 30.6% and 74.6% having intervals of <18 months, respectively. IPIs of <6 months or 6-11 months after live birth showed increased odds of PTB adjusted ORs for PTB of 1.71 (95% CI 1.65-1.78) and 1.20 (95% CI 1.16-1.24), respectively compared with intervals of 18-23 months. An IPI >36 months (versus 18-23 months) was associated with increased odds for PTB. Short IPI after pregnancy termination showed a decreased OR of 0.87 (95% CI 0.81-0.94). The within-mother analysis showed the association of increased odds of PTB for short IPI, but not for long IPI.Women with IPI <1 or >3 years after a live birth were at increased odds of PTB-an important group for intervention to reduce PTB. Short IPI after pregnancy termination was associated with reduced odds for PTB and needs to be further explored.Short and long IPI after live birth, but not after pregnancy termination, showed increased odds for PTB.
View details for DOI 10.1111/1471-0528.14165
View details for PubMedID 27405702
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Mapping the Fetomaternal Peripheral Immune System at Term Pregnancy.
Journal of immunology
2016
Abstract
Preterm labor and infections are the leading causes of neonatal deaths worldwide. During pregnancy, immunological cross talk between the mother and her fetus is critical for the maintenance of pregnancy and the delivery of an immunocompetent neonate. A precise understanding of healthy fetomaternal immunity is the important first step to identifying dysregulated immune mechanisms driving adverse maternal or neonatal outcomes. This study combined single-cell mass cytometry of paired peripheral and umbilical cord blood samples from mothers and their neonates with a graphical approach developed for the visualization of high-dimensional data to provide a high-resolution reference map of the cellular composition and functional organization of the healthy fetal and maternal immune systems at birth. The approach enabled mapping of known phenotypical and functional characteristics of fetal immunity (including the functional hyperresponsiveness of CD4(+) and CD8(+) T cells and the global blunting of innate immune responses). It also allowed discovery of new properties that distinguish the fetal and maternal immune systems. For example, examination of paired samples revealed differences in endogenous signaling tone that are unique to a mother and her offspring, including increased ERK1/2, MAPK-activated protein kinase 2, rpS6, and CREB phosphorylation in fetal Tbet(+)CD4(+) T cells, CD8(+) T cells, B cells, and CD56(lo)CD16(+) NK cells and decreased ERK1/2, MAPK-activated protein kinase 2, and STAT1 phosphorylation in fetal intermediate and nonclassical monocytes. This highly interactive functional map of healthy fetomaternal immunity builds the core reference for a growing data repository that will allow inferring deviations from normal associated with adverse maternal and neonatal outcomes.
View details for PubMedID 27793998
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The Relationship of Nosocomial Infection Reduction to Changes in Neonatal Intensive Care Unit Rates of Bronchopulmonary Dysplasia.
journal of pediatrics
2016
Abstract
To examine whether recent reductions in rates of nosocomial infection have contributed to changes in rates of bronchopulmonary dysplasia (BPD) in a population-based cohort.This was a retrospective, population-based cohort study that used the California Perinatal Quality Care Collaborative database from 2006 to 2013. Eligible infants included those less than 30 weeks' gestational age and less than 1500 g who survived to 3 days of life. Primary variables of interest were rates of nosocomial infections and BPD. Adjusted rates of nosocomial infections and BPD from a baseline period (2006-2010) were compared with a later period (2011-2013). The correlation of changes in rates across periods for both variables was assessed by hospital of care.A total of 22 967 infants from 129 hospitals were included in the study. From the first to second time period, the incidence of nosocomial infections declined from 24.7% to 15% and BPD declined from 35% to 30%. Adjusted hospital rates of BPD and nosocomial infections were correlated positively with a calculated 8% reduction of BPD rates attributable to reductions in nosocomial infections.Successful interventions to reduce rates of nosocomial infections may have a positive impact on other comorbidities such as BPD. The prevention of nosocomial infections should be viewed as a significant component in avoiding long-term neonatal morbidities.
View details for DOI 10.1016/j.jpeds.2016.09.030
View details for PubMedID 27742123
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Inflammatory biomarkers and spontaneous preterm birth among obese women.
journal of maternal-fetal & neonatal medicine
2016; 29 (20): 3317-3322
Abstract
To identify associations between second-trimester serum inflammatory biomarkers and preterm birth among obese women.In this nested case-control study, we compared 65 serum inflammatory biomarkers in obese women whose pregnancies resulted in early spontaneous preterm birth (<32 weeks gestation, n = 34) to obese women whose pregnancies resulted in term birth (n = 34). These women were selected from a larger population-based California cohort. Random forest and classification and regression tree techniques were employed to identify biomarkers of importance, and adjusted odds ratios (aORs) and 95% confidence intervals (CI) were estimated using logistic regression.Random forest and classification and regression tree techniques found that soluble vascular endothelial growth factor receptor-3 (sVEGFR3), soluble interleukin-2 receptor alpha-chain (sIL-2RA) and soluble tumor necrosis factor receptor-1 (sTNFR1) were related to preterm birth. Using multivariable logistic regression to compare preterm cases and term controls, decreased serum levels of sVEGFR3 and increased serum levels of sIL-2RA and sTNFR1 were associated with increased risk of preterm birth among obese women, aOR = 3.2 (95% CI: 1.0-9.9), aOR = 2.8 (95% CI: 0.9-9.0), and aOR = 4.1 (95% CI: 1.2-14.1), respectively.In this pilot study, we identified three serum biomarkers indicative of inflammation to be associated with spontaneous preterm birth among obese women: sVEGFR3, sIL-2RA and sTNFR1.
View details for DOI 10.3109/14767058.2015.1124083
View details for PubMedID 26700828
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Cross-Country Individual Participant Analysis of 4.1 Million Singleton Births in 5 Countries with Very High Human Development Index Confirms Known Associations but Provides No Biologic Explanation for 2/3 of All Preterm Births
PLOS ONE
2016; 11 (9)
Abstract
Preterm birth is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. Understanding of risk factors remains poor, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high income countries. We hypothesized that understanding the basis for these wide variations could lead to interventions that reduce preterm birth incidence in countries with high rates. We thus sought to assess the contributions of known risk factors for both spontaneous and provider-initiated preterm birth in selected high income countries, estimating also the potential impact of successful interventions due to advances in research, policy and public health, or clinical practice.We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries with very high human development index (Czech Republic, New Zealand, Slovenia, Sweden) and one comparator U.S. state (California) to determine the specific contribution (adjusting for confounding effects) of 21 factors. Both individual and population-attributable preterm birth risks were determined, as were contributors to cross-country differences. We also assessed the ability to predict preterm birth given various sets of known risk factors.Previous preterm birth and preeclampsia were the strongest individual risk factors of preterm birth in all datasets, with odds ratios of 4.6-6.0 and 2.8-5.7, respectively, for individual women having those characteristics. In contrast, on a population basis, nulliparity and male sex were the two risk factors with the highest impact on preterm birth rates, accounting for 25-50% and 11-16% of excess population attributable risk, respectively (p<0.001). The importance of nulliparity and male sex on population attributable risk was driven by high prevalence despite low odds ratios for individual women. More than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biologic explanation, and 63% of difference between countries cannot be explained with known factors; thus, research is necessary to elucidate the underlying mechanisms of preterm birth and, hence, therapeutic intervention. Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries. Known risk factors had an area under the curve of less than 0.7 in ROC analysis of preterm birth prediction within countries. These data suggest that other influences, as yet unidentified, are involved in preterm birth. Further research into biological mechanisms is warranted.We have quantified the causes of variation in preterm birth rates among countries with very high human development index. The paucity of explicit and currently identified factors amenable to intervention illustrates the limited impact of changes possible through current clinical practice and policy interventions. Our research highlights the urgent need for research into underlying biological causes of preterm birth, which alone are likely to lead to innovative and efficacious interventions.
View details for DOI 10.1371/journal.pone.0162506
View details for Web of Science ID 000383681000035
View details for PubMedID 27622562
View details for PubMedCentralID PMC5021369
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Body Mass Index Change between Pregnancies and Risk of Spontaneous Preterm Birth.
American journal of perinatology
2016; 33 (10): 1017-1022
Abstract
Objective Studies have reported an increased risk of spontaneous preterm birth associated with elevated prepregnancy body mass index (BMI) among nulliparous but not multiparous women. We examined whether changes in BMI and weight between pregnancies contributed to risk of preterm birth among obese (BMI > 29 kg/m(2)) women. Study Design This study utilized maternally linked California birth records of sequential singleton births between 2007 and 2010. Preterm birth was defined as 20 to 31 or 32 to 36 weeks of gestation. BMI was examined as category change and by tertile of weight change. Primary analyses included women without diabetes or hypertensive disorders; these women were compared with those without prior preterm birth, women with preterm deliveries preceded by spontaneous preterm labor, and women without any exclusions (i.e., diabetes or hypertensive disorders). Results Analyses showed that obesity was not associated with increased risk of spontaneous preterm birth among multiparous women. Women whose BMI increased had a decreased risk of spontaneous preterm birth at 32 to 36 weeks. Change in BMI or weight between pregnancies did not substantively alter results. Conclusion Among multiparous women, obesity was associated with reduced risk of spontaneous preterm delivery. This observed association is complex and may be influenced by maternal age, gestational age, placental insufficiency, and altered immune response.
View details for DOI 10.1055/s-0036-1572533
View details for PubMedID 27128743
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Joint effects of genetic variants and residential proximity to pesticide applications on hypospadias risk.
Birth defects research. Part A, Clinical and molecular teratology
2016; 106 (8): 653-658
Abstract
We examined risks associated with joint exposure of gene variants and pesticides.Analyses included 189 cases and 390 male controls born from 1991 to 2003 in California's San Joaquin Valley. We used logistic regression to examine risks associated with joint exposures of gene variants and pesticides that our previous work identified as associated with hypospadias. Genetic variables were based on variants in DGKK, genes involved in sex steroid synthesis/metabolism, and genes involved in genital tubercle development. Pesticide exposure was based on residential proximity to commercial agricultural pesticide applications.Odds ratios (ORs) were highest among babies with joint exposures, who had two- to fourfold increased risks; for example, the OR was 3.7 (95% confidence interval [CI], 0.8-16.5) among subjects with the risk-associated DGKK haplotype and pesticide exposure; OR, 1.5 (95% CI, 0.7-3.1) among subjects with the haplotype and no pesticide exposure; and OR, 0.9 (95% CI, 0.5-1.6) among subjects without the haplotype but with pesticide exposure, relative to subjects with neither. However, results did not provide statistical evidence that these risks were significantly greater than expected on an additive scale, relative to risks associated with one exposure at a time.We observed elevated risks associated with joint exposures to selected pesticides and genetic variants but no statistical evidence for interaction. Birth Defects Research (Part A) 106:653-658, 2016. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23508
View details for PubMedID 27098078
View details for PubMedCentralID PMC4983249
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Gastroschisis and maternal intake of phytoestrogens
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2016; 170 (8): 2078-2082
Abstract
The prevalence of gastroschisis has increased significantly in the past few decades. The strongest risks have been observed for women <25 years old or of low body mass index, and maternal diet also been proposed to be associated with risk. The objective of this study was to evaluate whether the risk of gastroschisis is associated with maternal dietary intake of phytoestrogens. The analysis includes data on mothers of 409 gastroschisis cases and 3,007 controls who delivered their infants from 2005 to 2010 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. Detailed information was obtained from maternal telephone interviews that included a validated food frequency questionnaire. We conducted logistic regression analyses that included each phytoestrogen in its continuous form (to test for linearity) and quadratic form (to test for non-linearity), adjusted for maternal energy intake, age, BMI, race-ethnicity, and smoking in 1st trimester. Logistic regression analysis indicated that biochanin A, formonoetin, and coumestrol had a significant non-linear association with gastroschisis (P-value <0.05 for quadratic term). Lower intakes were associated with increased risk, with somewhat stronger but relatively modest associations at the lower end of the distribution; for example, the ORs for the 10th versus 50th percentiles ranged from 1.1 to 1.2. Associations were not significant for the other phytoestrogens. This study provides some evidence for association with certain phytoestrogens, after adjusting for covariates. The implications of our findings for clinical practice are uncertain pending other studies examining this association. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37659
View details for Web of Science ID 000379948400016
View details for PubMedID 27232448
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Recurrence of Preterm Birth and Early Term Birth.
Obstetrics and gynecology
2016; 128 (2): 364-372
Abstract
To examine recurrent preterm birth and early term birth in women's initial and immediately subsequent pregnancies.This retrospective cohort study included 163,889 women who delivered their first and second liveborn singleton neonates between 20 and 44 weeks of gestation in California from 2005 through 2011. Data from hospital discharge records and birth certificates were used for analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression models adjusted for risk factors.Shorter gestational duration in the first pregnancy increased the risk of subsequent preterm birth (both early, before 32 weeks of gestation, and later, from 32 to 36 weeks of gestation) as well as early term birth (37-38 weeks of gestation). Compared with women with a prior term birth, women with a prior early preterm birth (before 32 weeks of gestation) were at the highest risk for a subsequent early preterm birth (58/935 [6.2%] compared with 367/118,505 [0.3%], adjusted OR 23.3, 95% CI 17.2-31.7). Women with a prior early term birth had more than a twofold increased risk for subsequent preterm birth (before 32 weeks of gestation: 171/36,017 [0.5%], adjusted OR 2.0, 95% CI 1.6-2.3; from 32 to 36 weeks of gestation: 2,086/36,017 [6.8%], adjusted OR 3.0, 95% CI 2.9-3.2) or early term birth (13,582/36,017 [37.7%], adjusted OR 2.2, 95% CI 2.2-2.3).Both preterm birth and early term birth are associated with these outcomes in a subsequent pregnancy. Increased clinical attention and research efforts may benefit from a focus on women with a prior early term birth as well as those with prior preterm birth.
View details for DOI 10.1097/AOG.0000000000001506
View details for PubMedID 27400000
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Obituary: Dr. Ed Lammer
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2016; 106 (7): 515-516
View details for DOI 10.1002/bdra.23524
View details for Web of Science ID 000382840300001
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Preterm Birth as a Calendar Event or Immunologic Anomaly
JAMA PEDIATRICS
2016; 170 (6): 525–26
View details for PubMedID 27089062
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The genetic predisposition to bronchopulmonary dysplasia
CURRENT OPINION IN PEDIATRICS
2016; 28 (3): 318-323
Abstract
Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in premature infants. Twin studies have shown strong heritability underlying this disease; however, the genetic architecture of BPD remains unclear.A number of studies employed different approaches to characterize the genetic aberrations associated with BPD, including candidate gene studies, genome-wide association studies, exome sequencing, integrative omics analysis, and pathway analysis. Candidate gene studies identified a number of genes potentially involved with the development of BPD, but the etiological contribution from each gene is not substantial. Copy number variation studies and three independent genome-wide association studies did not identify genetic variations significantly and consistently associated with BPD. A recent exome-sequencing study pointed to rare variants implicated in the disease. In this review, we summarize these studies' methodology and findings, and suggest future research directions to better understand the genetic underpinnings of this potentially life-long lung disease.Genetic factors play a significant role in the development of BPD. Recent studies suggested that rare variants in genes participating in lung development pathways could contribute to BPD susceptibility.
View details for DOI 10.1097/MOP.0000000000000344
View details for Web of Science ID 000376387000010
View details for PubMedID 26963946
View details for PubMedCentralID PMC4853271
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A Multi-Omics Analysis of Human Nucleus-Coded Mitochondrial Genes with Mouse Extraembryonic Tissue/Placenta Phenotypes: Implications in Mitochondria-Mediated Maternal and Fetal Complications.
SAGE PUBLICATIONS INC. 2016: 320A
View details for Web of Science ID 000372879200871
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Elevated body mass index and decreased diet quality among women and risk of birth defects in their offspring.
Birth defects research. Part A, Clinical and molecular teratology
2016; 106 (3): 164-171
Abstract
We examined whether risks of 32 birth defects were higher than expected in the presence of overweight or obese body mass index (BMI) and low diet quality, based on estimating individual and joint effects of these factors and calculating relative excess risk due to interaction.Analyses included mothers of 20,250 cases with birth defects and 8617 population-based controls without birth defects born from 1997 to 2009 and interviewed for the National Birth Defects Prevention Study. We used logistic regression to generate adjusted odds ratios (AORs) reflecting the combined effects of BMI and diet quality. We focused analyses on 16 birth defects (n = 11,868 cases, 8617 controls) for which initial results suggested an association with BMI or diet quality.Relative to the reference group (normal weight women with not low diet quality, i.e., >lowest quartile), AORs for low diet quality among normal weight women tended to be >1, and AORs for overweight and obese women tended to be stronger among women who had low diet quality than not low diet quality. For 9/16 birth defects, AORs for obese women who had low diet quality-the group we hypothesized to have highest risk-were higher than other stratum-specific AORs. Most relative excess risk due to interactions were positive but small (<0.5), with confidence intervals that included zero.These findings provide evidence for the hypothesis of highest birth defect risks among offspring to women who are obese and have low diet quality but insufficient evidence for an interaction of these factors in their contribution to risk. Birth Defects Research (Part A) 106:164-171, 2016. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23471
View details for PubMedID 26663631
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Elevated body mass index and decreased diet quality among women and risk of birth defects in their offspring
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2016; 106 (3): 164-171
Abstract
We examined whether risks of 32 birth defects were higher than expected in the presence of overweight or obese body mass index (BMI) and low diet quality, based on estimating individual and joint effects of these factors and calculating relative excess risk due to interaction.Analyses included mothers of 20,250 cases with birth defects and 8617 population-based controls without birth defects born from 1997 to 2009 and interviewed for the National Birth Defects Prevention Study. We used logistic regression to generate adjusted odds ratios (AORs) reflecting the combined effects of BMI and diet quality. We focused analyses on 16 birth defects (n = 11,868 cases, 8617 controls) for which initial results suggested an association with BMI or diet quality.Relative to the reference group (normal weight women with not low diet quality, i.e., >lowest quartile), AORs for low diet quality among normal weight women tended to be >1, and AORs for overweight and obese women tended to be stronger among women who had low diet quality than not low diet quality. For 9/16 birth defects, AORs for obese women who had low diet quality-the group we hypothesized to have highest risk-were higher than other stratum-specific AORs. Most relative excess risk due to interactions were positive but small (<0.5), with confidence intervals that included zero.These findings provide evidence for the hypothesis of highest birth defect risks among offspring to women who are obese and have low diet quality but insufficient evidence for an interaction of these factors in their contribution to risk. Birth Defects Research (Part A) 106:164-171, 2016. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23471
View details for Web of Science ID 000372908700002
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Failed endotracheal intubation and adverse outcomes among extremely low birth weight infants.
Journal of perinatology
2016; 36 (2): 112-115
Abstract
To quantify the importance of successful endotracheal intubation on the first attempt among extremely low birth weight (ELBW) infants who require resuscitation after delivery.A retrospective chart review was conducted for all ELBW infants ⩽1000 g born between January 2007 and May 2014 at a level IV neonatal intensive care unit. Infants were included if intubation was attempted during the first 5 min of life or if intubation was attempted during the first 10 min of life with heart rate <100. The primary outcome was death or neurodevelopmental impairment. The association between successful intubation on the first attempt and the primary outcome was assessed using multivariable logistic regression with adjustment for birth weight, gestational age, gender and antenatal steroids.The study sample included 88 ELBW infants. Forty percent were intubated on the first attempt and 60% required multiple intubation attempts. Death or neurodevelopmental impairment occurred in 29% of infants intubated on the first attempt, compared with 53% of infants that required multiple attempts, adjusted odds ratio 0.4 (95% confidence interval 0.1 to 1.0), P<0.05.Successful intubation on the first attempt is associated with improved neurodevelopmental outcomes among ELBW infants. This study confirms the importance of rapid establishment of a stable airway in ELBW infants requiring resuscitation after birth and has implications for personnel selection and role assignment in the delivery room.Journal of Perinatology advance online publication, 5 November 2015; doi:10.1038/jp.2015.158.
View details for DOI 10.1038/jp.2015.158
View details for PubMedID 26540244
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Risk of recurrent preterm birth among women according to change in paternity
MOSBY-ELSEVIER. 2016: S324
View details for DOI 10.1016/j.ajog.2015.10.651
View details for Web of Science ID 000367092800600
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Remembering Edward J. Lammer, MD.
American journal of medical genetics. Part A
2016; 170 (11): 2767–68
View details for PubMedID 27481654
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Lower rate of selected congenital heart defects with better maternal diet quality: a population-based study.
Archives of disease in childhood. Fetal and neonatal edition
2016; 101 (1): 43-49
Abstract
To evaluate whether better diet quality in mothers is associated with lower risk for major non-syndromic congenital heart defects in their children.Multicentre population-based case-control study, the National Birth Defects Prevention Study.Ten sites in the USA.Mothers of babies with major non-syndromic congenital heart defects (n=9885) and mothers with unaffected babies (n=9468) with estimated date of delivery from 1997 to 2009.Adjusted ORs for specific major congenital heart defects by quartiles of maternal diet quality in the year before pregnancy, assessed by the Diet Quality Index for pregnancy (DQI-P) and the Mediterranean Diet Score. Quartile 1 (Q1) reflecting the worst diet quality and Q4 the best diet quality.Better diet quality was associated with reduced risk for some conotruncal and atrial septal heart defects. For DQI-P, estimated risks reductions (Q4 vs Q1) for conotruncal defects were 37% for tetralogy of Fallot (OR 0.63, 95% CI 0.49 to 0.80) and 24% overall (OR 0.76, 95% CI 0.64 to 0.91); and for septal defects, 23% for atrial septal defects (OR 0.77, 95% CI 0.63 to 0.94) and 14% overall (OR 0.86, 95% CI 0.75 to 1.00). Risk reductions were weaker or minimal for most other major congenital heart defects.Better diet quality is associated with a reduced occurrence of some conotruncal and septal heart defects. This finding suggests that a reduction in certain cardiac malformations may be an additional benefit of improved maternal diet quality, reinforcing current preconception care recommendations.
View details for DOI 10.1136/archdischild-2014-308013
View details for PubMedID 26304461
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Residential agricultural pesticide exposures and risks of selected birth defects among offspring in the San Joaquin Valley of California.
Birth defects research. Part A, Clinical and molecular teratology
2016; 106 (1): 27-35
Abstract
We examined associations of birth defects with residential proximity to commercial agricultural pesticide applications in California. Subjects included 367 cases representing five types of birth defects and 785 nonmalformed controls born 1997 to 2006.Associations with any versus no exposure to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for covariates. Overall, 46% of cases and 38% of controls were classified as exposed to pesticides within a 500 m radius of mother's address during a 3-month periconceptional window.We estimated odds ratios (ORs) for 85 groups and 95 chemicals with five or more exposed cases and control mothers. Ninety-five percent confidence intervals (CI) excluded 1.0 for 11 ORs for groups and 22 ORs for chemicals, ranging from 1.9 to 3.1 for groups and 1.8 to 4.9 for chemicals except for two that were <1 (noted below).For groups, these ORs were for anotia/microtia (n = 95 cases) and dichlorophenoxy acids/esters and neonicotinoids; anorectal atresia/stenosis (n = 77) and alcohol/ethers and organophosphates (these ORs were < 1.0); transverse limb deficiencies (n = 59) and dichlorophenoxy acids/esters, petroleum derivatives, and triazines; and craniosynostosis (n = 79) and alcohol/ethers, avermectins, neonicotinoids, and organophosphates. For chemicals, ORs were: anotia/microtia and five pesticides from the groups dichlorophenoxy acids/esters, copper-containing compounds, neonicotinoids, organophosphates, and triazines; transverse limb deficiency and six pesticides - oxyfluorfen and pesticides from the groups copper-containing compounds, 2,6-dinitroanilines, neonicotinoids, petroleum derivatives and polyalkyloxy compounds; craniosynostosis and 10 pesticides - oxyfluorfen and pesticides from the groups alcohol/ethers, avermectins, n-methyl-carbamates, neonicotinoids, ogranophosphates (two chemicals), polyalkyloxy compounds (two chemicals), and pyrethroids; and congenital diaphragmatic hernia (n = 62) and a copper-containing compound.
View details for DOI 10.1002/bdra.23459
View details for PubMedID 26689858
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Temporal and geographic patterns of home births in California 1991-2010
MOSBY-ELSEVIER. 2016: S395
View details for DOI 10.1016/j.ajog.2015.10.801
View details for Web of Science ID 000367092800744
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Preterm birth rates by gestational age and demographic factors in twins compared to singletons in California 2007-2010
MOSBY-ELSEVIER. 2016: S374–S375
View details for DOI 10.1016/j.ajog.2015.10.760
View details for Web of Science ID 000367092800706
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Teenage pregnancy, body mass index, and preterm birth
MOSBY-ELSEVIER. 2016: S394–S395
View details for DOI 10.1016/j.ajog.2015.10.800
View details for Web of Science ID 000367092800743
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Association between gestational duration in first pregnancies and birth timing in second pregnancies
MOSBY-ELSEVIER. 2016: S442
View details for DOI 10.1016/j.ajog.2015.10.898
View details for Web of Science ID 000367092800837
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Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring
JAMA PEDIATRICS
2015; 169 (12): 1112-1116
Abstract
There is a well-described association between maternal diabetes mellitus and risk of congenital heart disease (CHD) in offspring. Although the clinical diagnoses of type 2 diabetes or gestational diabetes are strong risk factors for CHD, subclinical abnormalities of glucose and insulin metabolism are common within the general population and could also confer risk for CHD. We hypothesize that continuous measures of blood analytes related to maternal diabetes are related to odds of cardiac malformations.To explore the potential association of 2 different CHD phenotypes in offspring with maternal midpregnancy measures of glucose and insulin.Case-control study from a population-based cohort of 277 pregnant women in southern and central California carrying infants with tetralogy of Fallot (TOF) (n = 55), dextrotransposition of the great arteries (dTGA) (n = 42), or healthy infants without CHD (n = 180). Serum samples were collected from 2003 through 2007. The analysis was conducted from March through June 2015.Blood analytes related to maternal glucose metabolism were measured from random nonfasting second-trimester blood samples. We measured serum insulin levels by a validated radioimmunoassay, and we measured glucose levels. Multivariable logistic regression models estimated the association between these levels and case status.Serum glucose values were elevated in the maternal samples for offspring with TOF (median, 97.0 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) relative to controls (median, 91.5 mg/dL) (P = .01, Wilcoxon rank sum test), a phenomenon not observed in the maternal samples for offspring with dTGA (median, 90.0 mg/dL) relative to controls (P = .18, Wilcoxon rank sum test). Serum insulin levels were significantly different between controls (median, 18.8 μIU/mL [to convert to picomoles per liter, multiply by 6.945]) and maternal samples for offspring with dTGA (median, 13.1 μIU/mL; P = .048, Wilcoxon rank sum test) but not with TOF (median, 14.3 μIU/mL; P = .35, Wilcoxon rank sum test). Relative to maternal blood glucose levels of infants without cardiac malformations, we observed that maternal blood glucose levels in models including insulin were strongly associated with odds of TOF (adjusted odds ratio = 7.54; 95% CI, 2.30-24.69) but not with dTGA (adjusted odds ratio = 1.16; 95% CI, 0.28-4.79).These results represent a direct correlation of glucose as a continuous variable to odds of specific cardiac malformations. The association between serum glucose and odds of TOF indicates the need for additional epidemiological and mechanistic investigations into the risk conferred by insulin signaling and glucose metabolism during early pregnancy.
View details for DOI 10.1001/jamapediatrics.2015.2831
View details for Web of Science ID 000366334600014
View details for PubMedID 26457543
View details for PubMedCentralID PMC4996656
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Reply to Keelan and Payne: Microbiota-related pathways for preterm birth
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2015; 112 (47): E6415
View details for PubMedID 26515091
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Effects of race/ethnicity and BMI on the association between height and risk for spontaneous preterm birth
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
2015; 213 (5)
View details for DOI 10.1016/j.ajog.2015.07.005
View details for Web of Science ID 000365763400027
View details for PubMedID 26187451
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Air Pollution, Neighbourhood Socioeconomic Factors, and Neural Tube Defects in the San Joaquin Valley of California
PAEDIATRIC AND PERINATAL EPIDEMIOLOGY
2015; 29 (6): 536-545
Abstract
Environmental pollutants and neighbourhood socioeconomic factors have been associated with neural tube defects, but the potential impact of interaction between ambient air pollution and neighbourhood socioeconomic factors on the risks of neural tube defects is not well understood.We used data from the California Center of the National Birth Defects Study and the Children's Health and Air Pollution Study to investigate whether associations between air pollutant exposure in early gestation and neural tube defects were modified by neighbourhood socioeconomic factors in the San Joaquin Valley of California, 1997-2006. There were 5 pollutant exposures, 3 outcomes, and 9 neighbourhood socioeconomic factors included for a total of 135 investigated associations. Estimates were adjusted for maternal race-ethnicity, education, and multivitamin use.We present below odds ratios (ORs) that exclude 1 and a chi-square test of homogeneity P-value of <0.05. We observed increased odds of spina bifida comparing the highest to lowest quartile of particulate matter <10 μm (PM10 ) among those living in a neighbourhood with: (i) median household income of less than $30 000 per year [OR 5.1, 95% confidence interval (CI) 1.7, 15.3]; (ii) more than 20% living below the federal poverty level (OR 2.6, 95% CI 1.1, 6.0); and (iii) more than 30% with less than or equal to a high school education (OR 3.2, 95% CI 1.4, 7.4). The ORs were not statistically significant among those higher socioeconomic status (SES) neighbourhoods.Our results demonstrate effect modification by neighbourhood socioeconomic factors in the association of particulate matter and neural tube defects in California.
View details for DOI 10.1111/ppe.12244
View details for Web of Science ID 000362723900009
View details for PubMedID 26443985
View details for PubMedCentralID PMC4646169
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Role of infant sex in the association between air pollution and preterm birth
ANNALS OF EPIDEMIOLOGY
2015; 25 (11): 874-876
View details for DOI 10.1016/j.annepidem.2015.08.005
View details for PubMedID 26475983
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Effects of race/ethnicity and BMI on the association between height and risk for spontaneous preterm birth.
American journal of obstetrics and gynecology
2015; 213 (5): 700 e1-9
Abstract
Short height and obesity have each been associated with increased risk for preterm birth (PTB). However, the effect of short height on PTB risk, across different race/ethnicities and body mass index (BMI) categories, has not been studied. Our objective was to determine the influence of maternal height on the risk for PTB within race/ethnic groups, BMI groups, or adjusted for weight.All California singleton live births from 2007 through 2010 were included from birth certificate data (vital statistics) linked to hospital discharge data. Prepregnancy BMI (kg/m(2)) was categorized as underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), or obese (≥30.0). Maternal race/ethnicity was categorized as: non-Hispanic white, non-Hispanic black, Hispanic, and Asian. Maternal height was classified into 5 categories (shortest, short, middle, tall, tallest) based on racial/ethnic-specific height distributions, with the middle category serving as reference. Poisson regression models were used to estimate relative risks for the association between maternal height and risk of spontaneous PTB (<37 weeks and <32 weeks). Models were stratified on race/ethnicity and BMI. Generalized additive regression models were used to detect nonlinearity of the association. Covariates considered were: maternal age, weight, parity, prenatal care, education, medical payment, previous PTB, gestational and pregestational diabetes, pregestational hypertension, preeclampsia/eclampsia, and smoking.Among 1,655,385 California singleton live births, 5.2% were spontaneous PTB <37 weeks. Short stature (first height category) was associated with increased risk for PTB for non-Hispanic whites and Hispanics across all BMI categories. Among obese women, tall stature (fifth category) was associated with reduced risk for spontaneous PTB for non-Hispanic whites, Asians, and Hispanics. The same pattern of association was seen for height and risk for spontaneous PTB <32 weeks. In the generalized additive regression model plots, short stature was associated with increased risk for spontaneous PTB of <32 and <37 weeks of gestation among whites and Asians. However, this association was not observed for blacks and Hispanics.Maternal shorter height is associated with a modest increased risk for spontaneous PTB regardless of BMI. Our results suggest that PTB risk assessment should consider race/ethnicity-specific height with respect to the norm in addition to BMI assessment.
View details for DOI 10.1016/j.ajog.2015.07.005
View details for PubMedID 26187451
View details for PubMedCentralID PMC4631690
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Prepregnancy Obesity and Risks of Stillbirth
PLOS ONE
2015; 10 (10)
Abstract
We examined the association of maternal obesity with risk of stillbirth, focusing on whether the pattern of results varied by gestational age or maternal race-ethnicity or parity.Analyses included 4,012 stillbirths and 1,121,234 liveborn infants delivered in California from 2007-2010. We excluded stillbirths due to congenital anomalies, women with hypertensive disorders or diabetes, and plural births, to focus on fetuses and women without these known contributing conditions. We used Poisson regression to estimate relative risks (RR) and 95% confidence intervals (CI). Separate models were run for stillbirths delivered at 20-23, 24-27, 28-31, 32-36, 37-41 weeks, relative to liveborn deliveries at 37-41 weeks.For stillbirth at 20-23 weeks, RRs were elevated for all race-ethnicity and parity groups. The RR for a 20-unit change in BMI (which reflects the approximate BMI difference between a normal weight and an Obese III woman) was 3.5 (95% CI 2.2, 5.6) for nulliparous white women and ranged from 1.8 to 5.0 for other sub-groups. At 24-27 weeks, the association was significant (p<0.05) only for multiparous non-Hispanic whites; at 28-31 weeks, for multiparous whites and nulliparous whites and blacks; at 32-36 weeks, for multiparous whites and nulliparous blacks; and at 37-41 weeks, for all groups except nulliparous blacks. The pattern of results was similar when restricted to stillbirths due to unknown causes and somewhat stronger when restricted to stillbirths attributable to obstetric causes.Increased risks were observed across all gestational ages, and some evidence of heterogeneity of the associations was observed by race-ethnicity and parity.
View details for DOI 10.1371/journal.pone.0138549
View details for PubMedID 26466315
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Maternal characteristics and mid-pregnancy serum biomarkers as risk factors for subtypes of preterm birth.
BJOG : an international journal of obstetrics and gynaecology
2015; 122 (11): 1484-1493
Abstract
To examine the relationship between maternal characteristics, serum biomarkers and preterm birth (PTB) by spontaneous and medically indicated subtypes.Population-based cohort.California, United States of America.From a total population of 1 004 039 live singleton births in 2009 and 2010, 841 665 pregnancies with linked birth certificate and hospital discharge records were included.Characteristics were compared for term and preterm deliveries by PTB subtype using logistic regression and odds ratios adjusted for maternal characteristics and obstetric factors present in final stepwise models and 95% confidence intervals. First-trimester and second-trimester serum marker levels were analysed in a subset of 125 202 pregnancies with available first-trimester and second-trimester serum biomarker results.PTB by subtype.In fully adjusted models, ten characteristics and three serum biomarkers were associated with increased risk in each PTB subtype (Black race/ethnicity, pre-existing hypertension with and without pre-eclampsia, gestational hypertension with pre-eclampsia, pre-existing diabetes, anaemia, previous PTB, one or two or more previous caesarean section(s), interpregnancy interval ≥ 60 months, low first-trimester pregnancy-associated plasma protein A, high second-trimester α-fetoprotein, and high second-trimester dimeric inhibin A). These risks occurred in 51.6-86.2% of all pregnancies ending in PTB depending on subtype. The highest risk observed was for medically indicated PTB <32 weeks in women with pre-existing hypertension and pre-eclampsia (adjusted odds ratio 89.7, 95% CI 27.3-111.2).Our findings suggest a shared aetiology across PTB subtypes. These commonalities point to targets for further study and exploration of risk reduction strategies.Findings suggest a shared aetiology across preterm birth subtypes. Patterns may inform risk reduction efforts.
View details for DOI 10.1111/1471-0528.13495
View details for PubMedID 26111589
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Periconceptional changes in weight and risk of delivering offspring with conotruncal heart defects.
Birth defects research. Part A, Clinical and molecular teratology
2015; 103 (10): 843-846
Abstract
Maternal nutritional status has been recognized as a contributor to conotruncal heart defects, but there is limited understanding of the specific nutrition-related factors involved. In this California case-control study of 296 conotruncal cases and 695 nonmalformed controls we explored whether weight loss during early pregnancy was associated with an increased risk of d-transposition of the great arteries (dTGA) and tetralogy of Fallot (TOF) conotruncal defects.During telephone interviews women were asked whether they were dieting to lose weight or using weight loss remedies during 2 months before or 2 months after conception, and how much weight they gained or lost in the first 2 months of pregnancy or during the year before pregnancy.Odds ratios for dieting to lose weight and use of weight loss remedies for dTGA and TOF were not substantially elevated and all had confidence intervals that included 1.0. Mothers who had a loss of >5 lbs in the first 2 months of pregnancy as well as mothers who lost and gained >5 lbs in the first 2 months of pregnancy also did not show a significant increased risk of delivering case infants when compared with women with no weight change in the year before pregnancy.Given current recommendations about limited weight gain for obese pregnant women, these data indicate that dieting may not substantially increase a fetus' risk of having a conotruncal defect.
View details for DOI 10.1002/bdra.23381
View details for PubMedID 26033835
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Maternal Asthma, Preterm Birth, and Risk of Bronchopulmonary Dysplasia.
journal of pediatrics
2015; 167 (4): 875-880 e1
Abstract
To study the relationship between maternal asthma and the development of bronchopulmonary dysplasia (BPD).Using a large population-based California cohort, we investigated associations between maternal asthma and preterm birth subtype, as well as maternal asthma and BPD. We used data from 2007-2010 maternal delivery discharge records of 2 009 511 pregnancies and International Classification of Diseases, Ninth Revision codes. Preterm birth was defined as <37 weeks gestational age (GA), with subgroups of <28 weeks, 28-32 weeks, and 33-37 weeks GA, as well as preterm subtype, defined as spontaneous, medically indicated, or unknown. Linkage between the 2 California-wide datasets yielded 21 944 singleton preterm infants linked to their mother's records, allowing estimation of the risk of BPD in mothers with asthma and those without asthma.Maternal asthma was associated with increased odds (OR, 1.42; 95% CI, 1.38-1.46) of preterm birth at <37 weeks GA, with the greatest risk for 28-32 GA (aOR, 1.60; 95% CI, 1.47-1.74). Among 21 944 preterm infants, we did not observe an elevated risk for BPD in infants born to mothers with asthma (aOR, 1.03; 95% CI, 0.9-1.2). Stratification by maternal treatment with antenatal steroids revealed increased odds of BPD in infants whose mothers had asthma but did not receive antenatal steroids (aOR, 1.54; 95% CI, 1.15-2.06), but not in infants whose mothers had asthma and were treated with antenatal steroids (aOR, 0.85; 95% CI, 0.67-1.07).Asthma in mothers who did not receive antenatal steroid treatment is associated with an increased risk of BPD in their preterm infants.
View details for DOI 10.1016/j.jpeds.2015.06.048
View details for PubMedID 26254835
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Maternal Asthma, Preterm Birth, and Risk of Bronchopulmonary Dysplasia.
journal of pediatrics
2015; 167 (4): 875-880 e1
Abstract
To study the relationship between maternal asthma and the development of bronchopulmonary dysplasia (BPD).Using a large population-based California cohort, we investigated associations between maternal asthma and preterm birth subtype, as well as maternal asthma and BPD. We used data from 2007-2010 maternal delivery discharge records of 2 009 511 pregnancies and International Classification of Diseases, Ninth Revision codes. Preterm birth was defined as <37 weeks gestational age (GA), with subgroups of <28 weeks, 28-32 weeks, and 33-37 weeks GA, as well as preterm subtype, defined as spontaneous, medically indicated, or unknown. Linkage between the 2 California-wide datasets yielded 21 944 singleton preterm infants linked to their mother's records, allowing estimation of the risk of BPD in mothers with asthma and those without asthma.Maternal asthma was associated with increased odds (OR, 1.42; 95% CI, 1.38-1.46) of preterm birth at <37 weeks GA, with the greatest risk for 28-32 GA (aOR, 1.60; 95% CI, 1.47-1.74). Among 21 944 preterm infants, we did not observe an elevated risk for BPD in infants born to mothers with asthma (aOR, 1.03; 95% CI, 0.9-1.2). Stratification by maternal treatment with antenatal steroids revealed increased odds of BPD in infants whose mothers had asthma but did not receive antenatal steroids (aOR, 1.54; 95% CI, 1.15-2.06), but not in infants whose mothers had asthma and were treated with antenatal steroids (aOR, 0.85; 95% CI, 0.67-1.07).Asthma in mothers who did not receive antenatal steroid treatment is associated with an increased risk of BPD in their preterm infants.
View details for DOI 10.1016/j.jpeds.2015.06.048
View details for PubMedID 26254835
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Heightened risk of preterm birth and growth restriction after a first-born son
ANNALS OF EPIDEMIOLOGY
2015; 25 (10): 743-747
Abstract
In Scandinavia, delivery of a first-born son elevates the risk of preterm delivery and intrauterine growth restriction of the next-born infant. External validity of these results remains unclear. We test this hypothesis for preterm delivery and growth restriction using the linked California birth cohort file. We examined the hypothesis separately by race and/or ethnicity.We retrieved data on 2,852,976 births to 1,426,488 mothers with at least two live births. Our within-mother tests applied Cox proportional hazards (preterm delivery, defined as less than 37 weeks gestation) and linear regression models (birth weight for gestational age percentiles).For non-Hispanic whites, Hispanics, Asians, and American Indian and/or Alaska Natives, analyses indicate heightened risk of preterm delivery and growth restriction after a first-born male. The race-specific hazard ratios for preterm delivery range from 1.07 to 1.18. Regression coefficients for birth weight for gestational age percentile range from -0.73 to -1.49. The 95% confidence intervals for all these estimates do not contain the null. By contrast, we could not reject the null for non-Hispanic black mothers.Whereas California findings generally support those from Scandinavia, the null results among non-Hispanic black mothers suggest that we do not detect adverse outcomes after a first-born male in all racial and/or ethnic groups.
View details for DOI 10.1016/j.annepidem.2015.07.002
View details for PubMedID 26265442
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Serological Targeted Analysis of an ITIH4 Peptide Isoform: A Preterm Birth Biomarker and Its Associated SNP Implications
JOURNAL OF GENETICS AND GENOMICS
2015; 42 (9): 507-510
View details for DOI 10.1016/j.jgg.2015.06.001
View details for PubMedID 26408095
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Temporal and spatial variation of the human microbiota during pregnancy
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2015; 112 (35): 11060-11065
Abstract
Despite the critical role of the human microbiota in health, our understanding of microbiota compositional dynamics during and after pregnancy is incomplete. We conducted a case-control study of 49 pregnant women, 15 of whom delivered preterm. From 40 of these women, we analyzed bacterial taxonomic composition of 3,767 specimens collected prospectively and weekly during gestation and monthly after delivery from the vagina, distal gut, saliva, and tooth/gum. Linear mixed-effects modeling, medoid-based clustering, and Markov chain modeling were used to analyze community temporal trends, community structure, and vaginal community state transitions. Microbiota community taxonomic composition and diversity remained remarkably stable at all four body sites during pregnancy (P > 0.05 for trends over time). Prevalence of a Lactobacillus-poor vaginal community state type (CST 4) was inversely correlated with gestational age at delivery (P = 0.0039). Risk for preterm birth was more pronounced for subjects with CST 4 accompanied by elevated Gardnerella or Ureaplasma abundances. This finding was validated with a set of 246 vaginal specimens from nine women (four of whom delivered preterm). Most women experienced a postdelivery disturbance in the vaginal community characterized by a decrease in Lactobacillus species and an increase in diverse anaerobes such as Peptoniphilus, Prevotella, and Anaerococcus species. This disturbance was unrelated to gestational age at delivery and persisted for up to 1 y. These findings have important implications for predicting premature labor, a major global health problem, and for understanding the potential impact of a persistent, altered postpartum microbiota on maternal health, including outcomes of pregnancies following short interpregnancy intervals.
View details for DOI 10.1073/pnas.1502875112
View details for Web of Science ID 000360383200068
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Determinants of chronic lung disease severity in the first year of life; A population based study.
Pediatric pulmonology
2015; 50 (9): 878-888
Abstract
First, create a clinical severity score for patients with chronic lung disease of infancy (CLDi) following neonatal intensive care unit (NICU) stay. Second, using California wide population-based data, identify factors associated with clinical severity of CLDi at 4-9 months corrected gestational age (CGA).Pediatric pulmonologists ranked and weighted eight factors reflecting clinical severity of CLDi. Utilizing these data we scored and assigned these to 4-9 month old CGA moderate/severe bronchopulmonary dysplasia (BPD) infants, born<30 weeks gestational age (GA), within the California High Risk Infant Follow up (HRIF) program. Infants were studied relative to factors from the California Perinatal Quality Care Collaborative (CPQCC).We received survey responses from 43/88 pediatric pulmonologists from 28/53 North American training centers who are experts in CLDi. Strong agreement between ranking (72-100%) of respiratory system parameters and weighting (out of 100 points weighting was within 20 points) was observed with severity of CLDi. Data from 940 CLDi premature infants <30 weeks GA were obtained. Infants with severe CLDi scores at 4-9 months CGA (relative to a zero score) showed positive associations with being male, odds ratio[OR] = 2.45[confidence interval (CI) 1.26-4.77]), >30 ventilator days, OR = 3.82 (1.30-11.2), postnatal steroids OR = 3.94 (1.94-7.84), and a surprising inverse association with retinopathy of prematurity stage 3-4, OR = 0.24 (0.09-0.67) CONCLUSIONS: The CLDi clinical severity score allowed for standardized assessment of pulmonary morbidity, and evaluation of risk factors in the NICU for CLDi following NICU discharge. These observations point to risk factors associated with CLDi outcomes at 4-9 months CGA. Pediatr Pulmonol. 2015; 50:878-888. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/ppul.23148
View details for PubMedID 25651820
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Determinants of chronic lung disease severity in the first year of life; A population based study
PEDIATRIC PULMONOLOGY
2015; 50 (9): 878-888
Abstract
First, create a clinical severity score for patients with chronic lung disease of infancy (CLDi) following neonatal intensive care unit (NICU) stay. Second, using California wide population-based data, identify factors associated with clinical severity of CLDi at 4-9 months corrected gestational age (CGA).Pediatric pulmonologists ranked and weighted eight factors reflecting clinical severity of CLDi. Utilizing these data we scored and assigned these to 4-9 month old CGA moderate/severe bronchopulmonary dysplasia (BPD) infants, born<30 weeks gestational age (GA), within the California High Risk Infant Follow up (HRIF) program. Infants were studied relative to factors from the California Perinatal Quality Care Collaborative (CPQCC).We received survey responses from 43/88 pediatric pulmonologists from 28/53 North American training centers who are experts in CLDi. Strong agreement between ranking (72-100%) of respiratory system parameters and weighting (out of 100 points weighting was within 20 points) was observed with severity of CLDi. Data from 940 CLDi premature infants <30 weeks GA were obtained. Infants with severe CLDi scores at 4-9 months CGA (relative to a zero score) showed positive associations with being male, odds ratio[OR] = 2.45[confidence interval (CI) 1.26-4.77]), >30 ventilator days, OR = 3.82 (1.30-11.2), postnatal steroids OR = 3.94 (1.94-7.84), and a surprising inverse association with retinopathy of prematurity stage 3-4, OR = 0.24 (0.09-0.67) CONCLUSIONS: The CLDi clinical severity score allowed for standardized assessment of pulmonary morbidity, and evaluation of risk factors in the NICU for CLDi following NICU discharge. These observations point to risk factors associated with CLDi outcomes at 4-9 months CGA. Pediatr Pulmonol. 2015; 50:878-888. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/ppul.23148
View details for Web of Science ID 000360091000007
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Exome Sequencing of Neonatal Blood Spots and the Identification of Genes Implicated in Bronchopulmonary Dysplasia.
American journal of respiratory and critical care medicine
2015; 192 (5): 589-596
Abstract
Bronchopulmonary dysplasia (BPD), a prevalent severe lung disease of premature infants, has a strong genetic component. Large-scale genome-wide association studies for common variants have not revealed its genetic basis.Given the historical high mortality rate of extremely preterm infants who now survive and develop BPD, we hypothesized that risk loci underlying this disease are under severe purifying selection during evolution; thus, rare variants likely explain greater risk of the disease.We performed exome sequencing on 50 BPD-affected and unaffected twin pairs using DNA isolated from neonatal blood spots and identified genes affected by extremely rare nonsynonymous mutations. Functional genomic approaches were then used to systematically compare these affected genes.We identified 258 genes with rare nonsynonymous mutations in patients with BPD. These genes were highly enriched for processes involved in pulmonary structure and function including collagen fibril organization, morphogenesis of embryonic epithelium, and regulation of Wnt signaling pathway; displayed significantly elevated expression in fetal and adult lungs; and were substantially up-regulated in a murine model of BPD. Analyses of mouse mutants revealed their phenotypic enrichment for embryonic development and the cyanosis phenotype, a clinical manifestation of BPD.Our study supports the role of rare variants in BPD, in contrast with the role of common variants targeted by genome-wide association studies. Overall, our study is the first to sequence BPD exomes from newborn blood spot samples and identify with high confidence genes implicated in BPD, thereby providing important insights into its biology and molecular etiology.
View details for DOI 10.1164/rccm.201501-0168OC
View details for PubMedID 26030808
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Heme oxygenase-1 promoter polymorphisms and risk of spina bifida.
Birth defects research. Part A, Clinical and molecular teratology
2015; 103 (9): 741-746
Abstract
Spina bifida is the most common form of neural tube defects (NTDs). Etiologies of NTDs are multifactorial, and oxidative stress is believed to play a key role in NTD development. Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, has multiple protective properties including mediating antioxidant processes, making it an ideal candidate for study. The inducible HO isoform (HO-1) has two functional genetic polymorphisms: (GT)n dinucleotide repeats and A(-413)T SNP (rs2071746), both of which can affect its promoter activity. However, no study has investigated a possible association between HO-1 genetic polymorphisms and risk of NTDs.This case-control study included 152 spina bifida cases (all myelomeningoceles) and 148 nonmalformed controls obtained from the California Birth Defects Monitoring Program reflecting births during 1990 to 1999. Genetic polymorphisms were determined by polymerase chain reaction and amplified fragment length polymorphisms/restriction fragment length polymorphisms using genomic DNA extracted from archived newborn blood spots. Genotype and haplotype frequencies of two HO-1 promoter polymorphisms between cases and controls were compared.For (GT)n dinucleotide repeat lengths and the A(-413)T SNP, no significant differences in allele frequencies or genotypes were found. Linkage disequilibrium was observed between the HO-1 polymorphisms (D': 0.833); however, haplotype analyses did not show increased risk of spina bifida overall or by race/ethnicity.Although, an association was not found between HO-1 polymorphisms and risk of spina bifida, we speculate that the combined effect of low HO-1 expression and exposures to known environmental oxidative stressors (low folate status or diabetes), may overwhelm antioxidant defenses and increase risk of NTDs and warrants further study. Birth Defects Research (Part A), 2014. © 2014 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23343
View details for PubMedID 26173399
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Implementing Mass Cytometry at the Bedside to Study the Immunological Basis of Human Diseases: Distinctive Immune Features in Patients with a History of Term or Preterm Birth
CYTOMETRY PART A
2015; 87A (9): 817-829
Abstract
Single-cell technologies have immense potential to shed light on molecular and biological processes that drive human diseases. Mass cytometry (or Cytometry by Time Of Flight mass spectrometry, CyTOF) has already been employed in clinical studies to comprehensively survey patients' circulating immune system. As interest in the "bedside" application of mass cytometry is growing, the delineation of relevant methodological issues is called for. This report uses a newly generated dataset to discuss important methodological considerations when mass cytometry is implemented in a clinical study. Specifically, the use of whole blood samples versus peripheral blood mononuclear cells (PBMCs), design of mass-tagged antibody panels, technical and analytical implications of sample barcoding, and application of traditional and unsupervised approaches to analyze high-dimensional mass cytometry datasets are discussed. A mass cytometry assay was implemented in a cross-sectional study of 19 women with a history of term or preterm birth to determine whether immune traits in peripheral blood differentiate the two groups in the absence of pregnancy. Twenty-seven phenotypic and 11 intracellular markers were simultaneously analyzed in whole blood samples stimulated with lipopolysaccharide (LPS at 0, 0.1, 1, 10, and 100 ng mL(-1) ) to examine dose-dependent signaling responses within the toll-like receptor 4 (TLR4) pathway. Complementary analyses, grounded in traditional or unsupervised gating strategies of immune cell subsets, indicated that the prpS6 and pMAPKAPK2 responses in classical monocytes are accentuated in women with a history of preterm birth (FDR<1%). The results suggest that women predisposed to preterm birth may be prone to mount an exacerbated TLR4 response during the course of pregnancy. This important hypothesis-generating finding points to the power of single-cell mass cytometry to detect biologically important differences in a relatively small patient cohort. © 2015 International Society for Advancement of Cytometry.
View details for DOI 10.1002/cyto.a.22720
View details for Web of Science ID 000360590500009
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Implementing Mass Cytometry at the Bedside to Study the Immunological Basis of Human Diseases: Distinctive Immune Features in Patients with a History of Term or Preterm Birth.
Cytometry. Part A : the journal of the International Society for Analytical Cytology
2015; 87 (9): 817-829
Abstract
Single-cell technologies have immense potential to shed light on molecular and biological processes that drive human diseases. Mass cytometry (or Cytometry by Time Of Flight mass spectrometry, CyTOF) has already been employed in clinical studies to comprehensively survey patients' circulating immune system. As interest in the "bedside" application of mass cytometry is growing, the delineation of relevant methodological issues is called for. This report uses a newly generated dataset to discuss important methodological considerations when mass cytometry is implemented in a clinical study. Specifically, the use of whole blood samples versus peripheral blood mononuclear cells (PBMCs), design of mass-tagged antibody panels, technical and analytical implications of sample barcoding, and application of traditional and unsupervised approaches to analyze high-dimensional mass cytometry datasets are discussed. A mass cytometry assay was implemented in a cross-sectional study of 19 women with a history of term or preterm birth to determine whether immune traits in peripheral blood differentiate the two groups in the absence of pregnancy. Twenty-seven phenotypic and 11 intracellular markers were simultaneously analyzed in whole blood samples stimulated with lipopolysaccharide (LPS at 0, 0.1, 1, 10, and 100 ng mL(-1) ) to examine dose-dependent signaling responses within the toll-like receptor 4 (TLR4) pathway. Complementary analyses, grounded in traditional or unsupervised gating strategies of immune cell subsets, indicated that the prpS6 and pMAPKAPK2 responses in classical monocytes are accentuated in women with a history of preterm birth (FDR<1%). The results suggest that women predisposed to preterm birth may be prone to mount an exacerbated TLR4 response during the course of pregnancy. This important hypothesis-generating finding points to the power of single-cell mass cytometry to detect biologically important differences in a relatively small patient cohort. © 2015 International Society for Advancement of Cytometry.
View details for DOI 10.1002/cyto.a.22720
View details for PubMedID 26190063
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Temporal and spatial variation of the human microbiota during pregnancy.
Proceedings of the National Academy of Sciences of the United States of America
2015
Abstract
Despite the critical role of the human microbiota in health, our understanding of microbiota compositional dynamics during and after pregnancy is incomplete. We conducted a case-control study of 49 pregnant women, 15 of whom delivered preterm. From 40 of these women, we analyzed bacterial taxonomic composition of 3,767 specimens collected prospectively and weekly during gestation and monthly after delivery from the vagina, distal gut, saliva, and tooth/gum. Linear mixed-effects modeling, medoid-based clustering, and Markov chain modeling were used to analyze community temporal trends, community structure, and vaginal community state transitions. Microbiota community taxonomic composition and diversity remained remarkably stable at all four body sites during pregnancy (P > 0.05 for trends over time). Prevalence of a Lactobacillus-poor vaginal community state type (CST 4) was inversely correlated with gestational age at delivery (P = 0.0039). Risk for preterm birth was more pronounced for subjects with CST 4 accompanied by elevated Gardnerella or Ureaplasma abundances. This finding was validated with a set of 246 vaginal specimens from nine women (four of whom delivered preterm). Most women experienced a postdelivery disturbance in the vaginal community characterized by a decrease in Lactobacillus species and an increase in diverse anaerobes such as Peptoniphilus, Prevotella, and Anaerococcus species. This disturbance was unrelated to gestational age at delivery and persisted for up to 1 y. These findings have important implications for predicting premature labor, a major global health problem, and for understanding the potential impact of a persistent, altered postpartum microbiota on maternal health, including outcomes of pregnancies following short interpregnancy intervals.
View details for DOI 10.1073/pnas.1502875112
View details for PubMedID 26283357
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Maternal serum markers, characteristics and morbidly adherent placenta in women with previa
JOURNAL OF PERINATOLOGY
2015; 35 (8): 570-574
Abstract
To examine associations with morbidly adherent placenta (MAP) among women with placenta previa.Women with MAP (cases) and previa alone (controls) were identified from a cohort of 236 714 singleton pregnancies with both first and second trimester prenatal screening, and live birth and hospital discharge records; pregnancies with aneuploidies and neural tube or abdominal wall defects were excluded. Logistic binomial regression was used to compare cases with controls.In all, 37 cases with MAP and 699 controls with previa alone were included. Risk for MAP was increased among multiparous women with pregnancy-associated plasma protein-A (PAPP-A) ⩾95th percentile (⩾2.63 multiple of the median (MoM); adjusted OR (aOR) 8.7, 95% confidence interval (CI) 2.8 to 27.4), maternal-serum alpha fetoprotein (MS-AFP) ⩾95th percentile (⩾1.79 MoM; aOR 2.8, 95% CI 1.0 to 8.0), and 1 and ⩾2 prior cesarean deliveries (CDs; aORs 4.4, 95% CI 1.5 to 13.6 and 18.4, 95% CI 5.9 to 57.5, respectively).Elevated PAPP-A, elevated MS-AFP and prior CDs are associated with MAP among women with previa.
View details for DOI 10.1038/jp.2015.40
View details for Web of Science ID 000358684100008
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The national birth defects prevention study: A review of the methods
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2015; 103 (8): 656-669
Abstract
The National Birth Defects Prevention Study (NBDPS) is a large population-based multicenter case-control study of major birth defects in the United States.Data collection took place from 1998 through 2013 on pregnancies ending between October 1997 and December 2011. Cases could be live born, stillborn, or induced terminations, and were identified from birth defects surveillance programs in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Controls were live born infants without major birth defects identified from the same geographical regions and time periods as cases by means of either vital records or birth hospitals. Computer-assisted telephone interviews were completed with women between 6 weeks and 24 months after the estimated date of delivery. After completion of interviews, families received buccal cell collection kits for the mother, father, and infant (if living).There were 47,832 eligible cases and 18,272 eligible controls. Among these, 32,187 (67%) and 11,814 (65%), respectively, provided interview information about their pregnancies. Buccal cell collection kits with a cytobrush for at least one family member were returned by 19,065 case and 6,211 control families (65% and 59% of those who were sent a kit). More than 500 projects have been proposed by the collaborators and over 200 manuscripts published using data from the NBDPS through December 2014.The NBDPS has made substantial contributions to the field of birth defects epidemiology through its rigorous design, including case classification, detailed questionnaire and specimen collection, large study population, and collaborative activities across Centers. Birth Defects Research (Part A) 103:656-669, 2015. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23384
View details for Web of Science ID 000359740800003
View details for PubMedID 26033852
View details for PubMedCentralID PMC4558899
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Detecting gene-environment interactions in human birth defects: Study designs and statistical methods
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2015; 103 (8): 692-702
Abstract
The National Birth Defects Prevention Study (NBDPS) contains a wealth of information on affected and unaffected family triads, and thus provides numerous opportunities to study gene-environment interactions (G×E) in the etiology of birth defect outcomes. Depending on the research objective, several analytic options exist to estimate G×E effects that use varying combinations of individuals drawn from available triads.In this study, we discuss important considerations in the collection of genetic data and environmental exposures.We will also present several population- and family-based approaches that can be applied to data from the NBDPS including case-control, case-only, family-based trio, and maternal versus fetal effects. For each, we describe the data requirements, applicable statistical methods, advantages, and disadvantages.A range of approaches can be used to evaluate potentially important G×E effects in the NBDPS. Investigators should be aware of the limitations inherent to each approach when choosing a study design and interpreting results. Birth Defects Research (Part A) 103:692-702, 2015. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23382
View details for Web of Science ID 000359740800006
View details for PubMedID 26010994
View details for PubMedCentralID PMC4537677
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Developments in our understanding of the genetic basis of birth defects
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2015; 103 (8): 680-691
Abstract
Birth defects are a major cause of morbidity and mortality worldwide. There has been much progress in understanding the genetic basis of familial and syndromic forms of birth defects. However, the etiology of nonsydromic birth defects is not well-understood. Although there is still much work to be done, we have many of the tools needed to accomplish the task. Advances in next-generation sequencing have introduced a sea of possibilities, from disease-gene discovery to clinical screening and diagnosis. These advances have been fruitful in identifying a host of candidate disease genes, spanning the spectrum of birth defects. With the advent of CRISPR-Cas9 gene editing, researchers now have a precise tool for characterizing this genetic variation in model systems. Work in model organisms has also illustrated the importance of epigenetics in human development and birth defects etiology. Here we review past and current knowledge in birth defects genetics. We describe genotyping and sequencing methods for the detection and analysis of rare and common variants. We remark on the utility of model organisms and explore epigenetics in the context of structural malformation. We conclude by highlighting approaches that may provide insight into the complex genetics of birth defects. Birth Defects Research (Part A) 103:680-691, 2015. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23385
View details for Web of Science ID 000359740800005
View details for PubMedID 26033863
View details for PubMedCentralID PMC4537658
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Maternal Factors Associated with the Occurrence of Gastroschisis
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2015; 167A (7): 1534-1541
Abstract
We sought to identify age group specific maternal risk factors for gastroschisis. Maternal characteristics and prenatal factors were compared for 1,279 live born infants with gastroschisis and 3,069,678 without. Data were obtained using the California database containing linked hospital discharge, birth certificate and death records from 1 year prior to the birth to 1 year after the birth. Backwards-stepwise logistic regression models were used with maternal factors where initial inclusion was determined by a threshold of p < 0.10 on initial crude analyses. Due to the strong association of gastroschisis with young maternal age, models were stratified by age groups and odds ratios were calculated. These final models identified maternal infection as the only risk factor common to all age groups and a protective effect of obesity and gestational hypertension. In addition, age specific risk factors were identified. Although gestation at the time of infection was not available, a sexually transmitted disease complicating pregnancy was associated with increased risk in the less than 20 years of age grouping whereas viral infection was associated with increased risk only in the 20-24 and more than 24 years of age groupings. Urinary tract infection remained in the final logistic model for women less than 20 years. Short interpregnancy interval was not found to be a risk factor for any age group. Our findings support the need to explore maternal infection by type and gestational timing. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37016
View details for Web of Science ID 000356676200063
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Maternal factors associated with the occurrence of gastroschisis.
American journal of medical genetics. Part A
2015; 167 (7): 1534-1541
Abstract
We sought to identify age group specific maternal risk factors for gastroschisis. Maternal characteristics and prenatal factors were compared for 1,279 live born infants with gastroschisis and 3,069,678 without. Data were obtained using the California database containing linked hospital discharge, birth certificate and death records from 1 year prior to the birth to 1 year after the birth. Backwards-stepwise logistic regression models were used with maternal factors where initial inclusion was determined by a threshold of p < 0.10 on initial crude analyses. Due to the strong association of gastroschisis with young maternal age, models were stratified by age groups and odds ratios were calculated. These final models identified maternal infection as the only risk factor common to all age groups and a protective effect of obesity and gestational hypertension. In addition, age specific risk factors were identified. Although gestation at the time of infection was not available, a sexually transmitted disease complicating pregnancy was associated with increased risk in the less than 20 years of age grouping whereas viral infection was associated with increased risk only in the 20-24 and more than 24 years of age groupings. Urinary tract infection remained in the final logistic model for women less than 20 years. Short interpregnancy interval was not found to be a risk factor for any age group. Our findings support the need to explore maternal infection by type and gestational timing. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37016
View details for PubMedID 25913847
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Case 1: Lactic Acidosis and Respiratory Distress in a 10-Day-Old Infant.
NeoReviews
2015; 16 (7): e431-e433
View details for PubMedID 26236172
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Early-onset severe preeclampsia by first trimester pregnancy-associated plasma protein A and total human chorionic gonadotropin.
American journal of perinatology
2015; 32 (7): 703-712
Abstract
This study aims to evaluate the relationship between early-onset severe preeclampsia and first trimester serum levels of pregnancy-associated plasma protein A (PAPP-A) and total human chorionic gonadotropin (hCG).The association between early-onset severe preeclampsia and abnormal levels of first trimester PAPP-A and total hCG in maternal serum were measured in a sample of singleton pregnancies without chromosomal defects that had integrated prenatal serum screening in 2009 and 2010 (n = 129,488). Logistic binomial regression was used to estimate the relative risk (RR) of early-onset severe preeclampsia in pregnancies with abnormal levels of first trimester PAPP-A or total hCG as compared with controls.Regardless of parity, women with low first trimester PAPP-A or high total hCG were at increased risk for early-onset severe preeclampsia. Women with low PAPP-A (multiple of the median [MoM] ≤ the 10th percentile in nulliparous or ≤ the 5th percentile in multiparous) or high total hCG (MoM ≥ the 90th percentile in nulliparous or ≥ the 95th percentile in multiparous) were at more than a threefold increased risk for early-onset severe preeclampsia (RR, 4.2; 95% confidence interval [CI], 3.0-5.9 and RR, 3.3; 95% CI, 2.1-5.2, respectively).Routinely collected first trimester measurements of PAPP-A and total hCG provide unique risk information for early-onset severe preeclampsia.
View details for DOI 10.1055/s-0034-1396697
View details for PubMedID 25519199
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Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation.
American journal of medical genetics. Part A
2015; 167 (6): 1231-1242
Abstract
Right-sided and left-sided obstructive heart defects (OHDs) are subtypes of congenital heart defects, in which the heart valves, arteries, or veins are abnormally narrow or blocked. Previous studies have suggested that the development of OHDs involved a complex interplay between genetic variants and maternal factors. Using the data from 569 OHD case families and 1,644 control families enrolled in the National Birth Defects Prevention Study (NBDPS) between 1997 and 2008, we conducted an analysis to investigate the genetic effects of 877 single nucleotide polymorphisms (SNPs) in 60 candidate genes for association with the risk of OHDs, and their interactions with maternal use of folic acid supplements, and pre-pregnancy obesity. Applying log-linear models based on the hybrid design, we identified a SNP in methylenetetrahydrofolate reductase (MTHFR) gene (C677T polymorphism) with a main genetic effect on the occurrence of OHDs. In addition, multiple SNPs in betaine-homocysteine methyltransferase (BHMT and BHMT2) were also identified to be associated with the occurrence of OHDs through significant main infant genetic effects and interaction effects with maternal use of folic acid supplements. We also identified multiple SNPs in glutamate-cysteine ligase, catalytic subunit (GCLC) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) that were associated with elevated risk of OHDs among obese women. Our findings suggested that the risk of OHDs was closely related to a combined effect of variations in genes in the folate, homocysteine, or glutathione/transsulfuration pathways, maternal use of folic acid supplements and pre-pregnancy obesity.
View details for DOI 10.1002/ajmg.a.36867
View details for PubMedID 25846410
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Early-Onset Severe Preeclampsia by First Trimester Pregnancy-Associated Plasma Protein A and Total Human Chorionic Gonadotropin
AMERICAN JOURNAL OF PERINATOLOGY
2015; 32 (7): 703-711
Abstract
This study aims to evaluate the relationship between early-onset severe preeclampsia and first trimester serum levels of pregnancy-associated plasma protein A (PAPP-A) and total human chorionic gonadotropin (hCG).The association between early-onset severe preeclampsia and abnormal levels of first trimester PAPP-A and total hCG in maternal serum were measured in a sample of singleton pregnancies without chromosomal defects that had integrated prenatal serum screening in 2009 and 2010 (n = 129,488). Logistic binomial regression was used to estimate the relative risk (RR) of early-onset severe preeclampsia in pregnancies with abnormal levels of first trimester PAPP-A or total hCG as compared with controls.Regardless of parity, women with low first trimester PAPP-A or high total hCG were at increased risk for early-onset severe preeclampsia. Women with low PAPP-A (multiple of the median [MoM] ≤ the 10th percentile in nulliparous or ≤ the 5th percentile in multiparous) or high total hCG (MoM ≥ the 90th percentile in nulliparous or ≥ the 95th percentile in multiparous) were at more than a threefold increased risk for early-onset severe preeclampsia (RR, 4.2; 95% confidence interval [CI], 3.0-5.9 and RR, 3.3; 95% CI, 2.1-5.2, respectively).Routinely collected first trimester measurements of PAPP-A and total hCG provide unique risk information for early-onset severe preeclampsia.
View details for DOI 10.1055/s-0034-1396697
View details for Web of Science ID 000355418600014
View details for PubMedID 25519199
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Spatial and temporal patterns in preterm birth in the United States
PEDIATRIC RESEARCH
2015; 77 (6): 836-844
Abstract
Despite years of research, the etiologies of preterm birth remain unclear. In order to help generate new research hypotheses, this study explored spatial and temporal patterns of preterm birth in a large, total-population dataset.Data on 145 million US births in 3,000 counties from the Natality Files of the National Center for Health Statistics for 1971-2011 were examined. State trends in early (<34 wk) and late (34-36 wk) preterm birth rates were compared. K-means cluster analyses were conducted to identify gestational age distribution patterns for all US counties over time.A weak association was observed between state trends in <34 wk birth rates and the initial absolute <34 wk birth rate. Significant associations were observed between trends in <34 wk and 34-36 wk birth rates and between white and African American <34 wk births. Periodicity was observed in county-level trends in <34 wk birth rates. Cluster analyses identified periods of significant heterogeneity and homogeneity in gestational age distributional trends for US counties.The observed geographic and temporal patterns suggest periodicity and complex, shared influences among preterm birth rates in the United States. These patterns could provide insight into promising hypotheses for further research.
View details for DOI 10.1038/pr.2015.55
View details for PubMedID 25760546
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Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2015; 167A (6): 1231-1242
Abstract
Right-sided and left-sided obstructive heart defects (OHDs) are subtypes of congenital heart defects, in which the heart valves, arteries, or veins are abnormally narrow or blocked. Previous studies have suggested that the development of OHDs involved a complex interplay between genetic variants and maternal factors. Using the data from 569 OHD case families and 1,644 control families enrolled in the National Birth Defects Prevention Study (NBDPS) between 1997 and 2008, we conducted an analysis to investigate the genetic effects of 877 single nucleotide polymorphisms (SNPs) in 60 candidate genes for association with the risk of OHDs, and their interactions with maternal use of folic acid supplements, and pre-pregnancy obesity. Applying log-linear models based on the hybrid design, we identified a SNP in methylenetetrahydrofolate reductase (MTHFR) gene (C677T polymorphism) with a main genetic effect on the occurrence of OHDs. In addition, multiple SNPs in betaine-homocysteine methyltransferase (BHMT and BHMT2) were also identified to be associated with the occurrence of OHDs through significant main infant genetic effects and interaction effects with maternal use of folic acid supplements. We also identified multiple SNPs in glutamate-cysteine ligase, catalytic subunit (GCLC) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) that were associated with elevated risk of OHDs among obese women. Our findings suggested that the risk of OHDs was closely related to a combined effect of variations in genes in the folate, homocysteine, or glutathione/transsulfuration pathways, maternal use of folic acid supplements and pre-pregnancy obesity.
View details for DOI 10.1002/ajmg.a.36867
View details for Web of Science ID 000355276700009
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Spatial analysis of gastroschisis in the national birth defects prevention study
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2015; 103 (6): 544-553
Abstract
Gastroschisis is a birth defect where loops of bowel are protruding from the abdominal wall at birth. Previous research has suggested that gastroschisis cases can occur in clusters. The objective of this study was to identify if there were areas of elevated gastroschisis risk using data from the National Birth Defects Prevention Study (NBDPS), 1997 through 2007.We obtained data on cases (n = 371) through population-based birth defects surveillance systems in Arkansas, California, and Utah; controls (n = 2359) were selected from the same geographic areas as cases. Mothers were interviewed on demographic information and exposures during pregnancy, including residential history. We used first trimester maternal addresses and generalized additive models to create a continuous map surface of odds ratios (OR) by smoothing over latitude and longitude. Permutation tests were used to assess whether location of maternal residence was important and identify locations with statistically significant ORs.In Arkansas, adjusted ORs in the southwest corner were 2.0 and the global deviance was not statistically significant (p-value: 0.57). Adjusted ORs for California indicated areas of increased risk with ORs 1.3 (p-value: 0.34). In Utah, the adjusted ORs were elevated (OR: 2.4) in the south-eastern corner of the study area (p-value: 0.34).The results of this study, while not statistically significant, suggest there were spatial variations in gastroschisis births. We cannot rule out that these variations were due to edge effects or residual confounding. Birth Defects Research (Part A) 103:544-553, 2015. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23375
View details for Web of Science ID 000356674800010
View details for PubMedID 25850424
View details for PubMedCentralID PMC4478213
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Genetic Polymorphisms in ESR1 and ESR2 Genes, and Risk of Hypospadias in a Multiethnic Study Population
JOURNAL OF UROLOGY
2015; 193 (5): 1625-1631
Abstract
Estrogenic endocrine disruptors acting via estrogen receptors α (ESR1) and β (ESR2) have been implicated in the etiology of hypospadias, a common congenital malformation of the male external genitalia. We determined the association of single nucleotide polymorphisms in ESR1 and ESR2 genes with hypospadias in a racially/ethnically diverse study population of California births.We investigated the relationship between hypospadias and 108 ESR1 and 36 ESR2 single nucleotide polymorphisms in 647 cases and 877 population based nonmalformed controls among infants born in selected California counties from 1990 to 2003. Subgroup analyses were performed by race/ethnicity (nonHispanic white and Hispanic subjects) and by hypospadias severity (mild to moderate and severe).Odds ratios for 33 of the 108 ESR1 single nucleotide polymorphisms had p values less than 0.05 (p = 0.05 to 0.007) for risk of hypospadias. However, none of the 36 ESR2 single nucleotide polymorphisms was significantly associated. In stratified analyses the association results were consistent by disease severity but different sets of single nucleotide polymorphisms were significantly associated with hypospadias in nonHispanic white and Hispanic subjects. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and identified 6 haplotype blocks in ESR1 gene that had haplotypes significantly associated with an increased risk of hypospadias (OR 1.3 to 1.8, p = 0.04 to 0.00001). Similar to single nucleotide polymorphism analysis, different ESR1 haplotypes were associated with risk of hypospadias in nonHispanic white and Hispanic subjects. No significant haplotype association was observed for ESR2.The data provide evidence that ESR1 single nucleotide polymorphisms and haplotypes influence the risk of hypospadias in white and Hispanic subjects, and warrant further examination in other study populations.
View details for DOI 10.1016/j.juro.2014.11.087
View details for Web of Science ID 000353113200073
View details for PubMedID 25463985
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Craniosynostosis and Risk Factors Related to Thyroid Dysfunction
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2015; 167A (4): 701-707
View details for DOI 10.1002/ajmg.a.36953
View details for Web of Science ID 000352019000007
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Craniosynostosis and risk factors related to thyroid dysfunction.
American journal of medical genetics. Part A
2015; 167A (4): 701-707
Abstract
Thyroid disease is a common problem among women of reproductive age but often goes undiagnosed. Maternal thyroid disease has been associated with increased risk of craniosynostosis. We hypothesized that known risk factors for thyroid disease would be associated with risk of craniosynostosis among women not diagnosed with thyroid disease. Analyses included mothers of 1,067 cases and 8,494 population-based controls who were interviewed for the National Birth Defects Prevention Study. We used multivariable logistic regression to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI). After excluding women with diagnosed thyroid disease, younger maternal age (AOR 0.7, 95% CI 0.6-0.9, for <25 years versus 25-29), black or other race-ethnicity (AOR 0.3, 95% CI 0.2-0.4 and AOR 0.6, 95% CI 0.4-0.8, respectively, relative to non-Hispanic whites), fertility medications or procedures (AOR 1.5, 95% CI 1.2-2.0), and alcohol consumption (AOR 0.8, 95% CI 0.7-0.9) were associated with risk of craniosynostosis, based on confidence intervals that excluded 1.0. These associations with craniosynostosis are consistent with the direction of their association with thyroid dysfunction (i.e., younger age, black race-ethnicity and alcohol consumption are associated with reduced risk and fertility problems are associated with increased risk of thyroid disease). This study thus provides support for the hypothesis that risk factors associated with thyroid dysfunction are also associated with risk of craniosynostosis. Improved understanding of the potential association between maternal thyroid function and craniosynostosis among offspring is important given that craniosynostosis carries significant morbidity and that thyroid disease is under-diagnosed and potentially modifiable. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.36953
View details for PubMedID 25655789
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Risk of critical congenital heart defects by nuchal translucency norms
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
2015; 212 (4)
Abstract
The purpose of this study was to compare the performance of first-trimester nuchal translucency (NT) cutoff of ≥3.5 mm with NT percentiles that were calculated for crown-rump length to identify fetuses with critical congenital heart defects (CCHDs).This was a population-level study of singleton pregnancies in California with NT measurements performed between 11 and 14 weeks of gestation. Eligible cases were those that resulted in live births from 2009-2010 and had information about the presence or absence of CCHDs available in the hospital discharge records through age 1 year (n = 76,089). Logistic binomial regression methods were used to compare the rate of CCHDs by an NT percentile for crown-rump length and millimeter cutpoints.Compared with fetuses with an NT measurement of <90th percentile, fetuses with an NT of ≥99th percentile were >5 times as likely to have a CCHD (1.3% vs 0.2%; relative risk, 5.66; 95% confidence interval, 3.19-10.04) and fetuses with an NT measurement ≥3.5 mm were >12 times as likely to have a CCHD (2.8% vs 0.2%; relative risk, 12.28; 95% confidence interval, 5.11-29.51). NT ≥99th percentile had a sensitivity of 5.8% and a specificity of 98.9% for the detection of CCHDs compared with 2.6% and 99.8% for NT ≥3.5 mm.Results show that NT measurements of ≥99th percentile and ≥3.5 mm are not equivalent and that substantial risk for CCHD extends to the less restrictive ≥99th percentile cutpoint. Data suggest that the use of this cutpoint compared with the current standard could double the number of CCHDs that are identified based on NT risk.
View details for DOI 10.1016/j.ajog.2014.10.1102
View details for Web of Science ID 000352147100029
View details for PubMedID 25448520
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Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis
EUROPEAN JOURNAL OF HUMAN GENETICS
2015; 23 (3): 337-341
Abstract
We used exome sequencing to study a non-consanguineous family with two children who had anterior segment dysgenesis, sclerocornea, microphthalmia, hypotonia and developmental delays. Sanger sequencing verified two Peroxidasin (PXDN) mutations in both sibs--a maternally inherited, nonsense mutation, c.1021C>T predicting p.(Arg341*), and a paternally inherited, 23-basepair deletion causing a frameshift and premature protein truncation, c.2375_2397del23, predicting p.(Leu792Hisfs*67). We re-examined exome data from 20 other patients with structural eye defects and identified two additional PXDN mutations in a sporadic male with bilateral microphthalmia, cataracts and anterior segment dysgenesis--a maternally inherited, frameshift mutation, c.1192delT, predicting p.(Tyr398Thrfs*40) and a paternally inherited, missense substitution that was predicted to be deleterious, c.947 A>C, predicting p.(Gln316Pro). Mutations in PXDN were previously reported in three families with congenital cataracts, microcornea, sclerocornea and developmental glaucoma. The gene is expressed in corneal epithelium and is secreted into the extracellular matrix. Defective peroxidasin has been shown to impair sulfilimine bond formation in collagen IV, a constituent of the basement membrane, implying that the eye defects result because of loss of basement membrane integrity in the developing eye. Our finding of a broader phenotype than previously appreciated for PXDN mutations is typical for exome-sequencing studies, which have proven to be highly effective for mutation detection in patients with atypical presentations. We conclude that PXDN sequencing should be considered in microphthalmia with anterior segment dysgenesis.
View details for DOI 10.1038/ejhg.2014.119
View details for Web of Science ID 000349670900010
View details for PubMedCentralID PMC4326713
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Factors Associated With Recurrent Preterm Birth Among Underweight Women
SAGE PUBLICATIONS INC. 2015: 150A
View details for Web of Science ID 000351407201160
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Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis.
European journal of human genetics
2015; 23 (3): 337-341
Abstract
We used exome sequencing to study a non-consanguineous family with two children who had anterior segment dysgenesis, sclerocornea, microphthalmia, hypotonia and developmental delays. Sanger sequencing verified two Peroxidasin (PXDN) mutations in both sibs--a maternally inherited, nonsense mutation, c.1021C>T predicting p.(Arg341*), and a paternally inherited, 23-basepair deletion causing a frameshift and premature protein truncation, c.2375_2397del23, predicting p.(Leu792Hisfs*67). We re-examined exome data from 20 other patients with structural eye defects and identified two additional PXDN mutations in a sporadic male with bilateral microphthalmia, cataracts and anterior segment dysgenesis--a maternally inherited, frameshift mutation, c.1192delT, predicting p.(Tyr398Thrfs*40) and a paternally inherited, missense substitution that was predicted to be deleterious, c.947 A>C, predicting p.(Gln316Pro). Mutations in PXDN were previously reported in three families with congenital cataracts, microcornea, sclerocornea and developmental glaucoma. The gene is expressed in corneal epithelium and is secreted into the extracellular matrix. Defective peroxidasin has been shown to impair sulfilimine bond formation in collagen IV, a constituent of the basement membrane, implying that the eye defects result because of loss of basement membrane integrity in the developing eye. Our finding of a broader phenotype than previously appreciated for PXDN mutations is typical for exome-sequencing studies, which have proven to be highly effective for mutation detection in patients with atypical presentations. We conclude that PXDN sequencing should be considered in microphthalmia with anterior segment dysgenesis.
View details for DOI 10.1038/ejhg.2014.119
View details for PubMedID 24939590
View details for PubMedCentralID PMC4326713
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Rare LRP6 Variants Identified in Spina Bifida Patients
HUMAN MUTATION
2015; 36 (3): 342-349
Abstract
Several single-nucleotide variants (SNVs) in low-density lipoprotein receptor-related protein 6 (Lrp6) cause neural tube defects (NTDs) in mice. We therefore examined LRP6 in 192 unrelated infants from California with the NTD, spina bifida, and found four heterozygous missense SNVs, three of which were predicted to be deleterious, among NTD cases and not in 190 ethnically matched nonmalformed controls. Parents and siblings could not be tested because of the study design. Like Crooked tail and Ringleschwanz mouse variants, the p.Tyr544Cys Lrp6 protein failed to bind the chaperone protein mesoderm development and impaired Lrp6 subcellular localization to the plasma membrane of MDCK II cells. Only the p.Tyr544Cys Lrp6 variant downregulated canonical Wnt signaling in a TopFlash luciferase reporter in vitro assay. In contrast, three Lrp6 mutants (p.Ala3Val, p.Tyr544Cys, and p.Arg1574Leu) increased noncanonical Wnt/planar cell polarity (PCP) signaling in an Ap1-luciferase assay. Thus, LRP6 variants outside of YWTD repeats could potentially predispose embryos to NTDs, whereas Lrp6 modulation of Wnt/PCP signaling would be more essential than its canonical pathway role in neural tube closure.
View details for DOI 10.1002/humu.22750
View details for Web of Science ID 000351399900010
View details for PubMedID 25546815
View details for PubMedCentralID PMC4361299
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Hospital variation and risk factors for bronchopulmonary dysplasia in a population-based cohort.
JAMA pediatrics
2015; 169 (2)
View details for DOI 10.1001/jamapediatrics.2014.3676
View details for PubMedID 25642906
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Hospital variation and risk factors for bronchopulmonary dysplasia in a population-based cohort.
JAMA pediatrics
2015; 169 (2)
Abstract
Bronchopulmonary dysplasia (BPD) remains a serious morbidity in very low-birth-weight (VLBW) infants (<1500 g). Deregionalization of neonatal care has resulted in an increasing number of VLBW infants treated in community hospitals with unknown impact on the development of BPD.To identify individual risk factors for BPD development and hospital variation of BPD rates across all levels of neonatal intensive care units (NICUs) within the California Perinatal Quality Care Collaborative.Retrospective cohort study (January 2007 to December 2011) from the California Perinatal Quality Care Collaborative including more than 90% of California's NICUs. Eligible VLBW infants born between 22 to 29 weeks' gestational age.Varying levels of intensive care.Bronchopulmonary dysplasia was defined as continuous supplemental oxygen use at 36 weeks' postmenstrual age. A combined outcome of BPD or mortality prior to 36 weeks was used. Multivariable logistic regression accounting for hospital as a random effect and gestational age as a risk factor was used to assess individual risk factors for BPD. This model was applied to determine risk-adjusted rates of BPD across hospitals and assess associations between levels of care and BPD rates.The study cohort included 15 779 infants, of which 1534 infants died prior to 36 weeks' postmenstrual age. A total of 7081 infants, or 44.8%, met the primary outcome of BPD or death prior to 36 weeks. Combined BPD or death rates across 116 NICUs varied from 17.7% to 73.4% (interquartile range, 38.7%-54.1%). Compared with level IV NICUs, the risk for developing BPD was higher for level II NICUs (odds ratio, 1.23; 95% CI, 1.02-1.49) and similar for level III NICUs (odds ratio, 1.04; 95% CI, 0.95-1.14).Bronchopulmonary dysplasia or death prior to 36 weeks' postmenstrual age affects approximately 45% of VLBW infants across California. The wide variability in BPD occurrence across hospitals could offer insights into potential risk or preventive factors. Additionally, our findings suggest that increased regionalization of NICU care may reduce BPD among VLBW infants.
View details for DOI 10.1001/jamapediatrics.2014.3676
View details for PubMedID 25642906
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Prevalence of Birth Defects among American-Indian Births in California, 1983-2010
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2015; 103 (2): 105-110
Abstract
Approximately 6.3 million live births and fetal deaths occurred during the ascertainment period in the California Birth Defects Monitoring Program registry. American-Indian and non-Hispanic white women delivered 40,268 and 2,044,118 births, respectively. While much information has been published about non-Hispanic white infants, little is known regarding the risks of birth defects among infants born to American-Indian women.This study used data from the California Birth Defects Monitoring Program to explore risks of selected birth defects in offspring of American-Indian relative to non-Hispanic white women in California. The study population included all live births and fetal deaths 20 weeks or greater from 1983 to 2010. Prevalence ratios and corresponding 95% confidence intervals (CI) were computed using Poisson regression for 51 groupings of birth defects.Prevalence ratios were estimated for 51 groupings of birth defects. Of the 51, nine had statistically precise results ranging from 0.78 to 1.85. The eight groups with elevated risks for American-Indian births were reduction deformities of brain, anomalies of anterior segments, specified anomalies of ear, ostium secundum type atrial septal defect, specified anomalies of heart, anomalies of the aorta, anomalies of great veins, and cleft lip with cleft palate.Our results suggest that American-Indian women having babies in California may be at higher risk for eight birth defect phenotypes compared with non-Hispanic whites. Further research is needed to determine whether these risks are observed among other populations of American-Indian women or when adjusted for potential covariates.
View details for DOI 10.1002/bdra.23341
View details for Web of Science ID 000350470500005
View details for PubMedID 25721951
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Prediction of early spontaneous preterm birth using placental, lipid, and immune related markers
MOSBY-ELSEVIER. 2015: S292
View details for DOI 10.1016/j.ajog.2014.10.792
View details for Web of Science ID 000361140900581
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Spina bifida.
Nature reviews. Disease primers
2015; 1: 15007
Abstract
Spina bifida is a birth defect in which the vertebral column is open, often with spinal cord involvement. The most clinically significant subtype is myelomeningocele (open spina bifida), which is a condition characterized by failure of the lumbosacral spinal neural tube to close during embryonic development. The exposed neural tissue degenerates in utero, resulting in neurological deficit that varies with the level of the lesion. Occurring in approximately 1 per 1,000 births worldwide, myelomeningocele is one of the most common congenital malformations, but its cause is largely unknown. The genetic component is estimated at 60-70%, but few causative genes have been identified to date, despite much information from mouse models. Non-genetic maternal risk factors include reduced folate intake, anticonvulsant therapy, diabetes mellitus and obesity. Primary prevention by periconceptional supplementation with folic acid has been demonstrated in clinical trials, leading to food fortification programmes in many countries. Prenatal diagnosis is achieved by ultrasonography, enabling women to seek termination of pregnancy. Individuals who survive to birth have their lesions closed surgically, with subsequent management of associated defects, including the Chiari II brain malformation, hydrocephalus, and urological and orthopaedic sequelae. Fetal surgical repair of myelomeningocele has been associated with improved early neurological outcome compared with postnatal operation. Myelomeningocele affects quality of life during childhood, adolescence and adulthood, posing a challenge for individuals, families and society as a whole. For an illustrated summary of this Primer, visit: http://go.nature.com/fK9XNa.
View details for PubMedID 27189655
View details for PubMedCentralID PMC4898641
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Lower rate of selected congenital heart defects with better maternal diet quality: a population-based study
ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION
2015; 101 (1): 43-49
Abstract
To evaluate whether better diet quality in mothers is associated with lower risk for major non-syndromic congenital heart defects in their children.Multicentre population-based case-control study, the National Birth Defects Prevention Study.Ten sites in the USA.Mothers of babies with major non-syndromic congenital heart defects (n=9885) and mothers with unaffected babies (n=9468) with estimated date of delivery from 1997 to 2009.Adjusted ORs for specific major congenital heart defects by quartiles of maternal diet quality in the year before pregnancy, assessed by the Diet Quality Index for pregnancy (DQI-P) and the Mediterranean Diet Score. Quartile 1 (Q1) reflecting the worst diet quality and Q4 the best diet quality.Better diet quality was associated with reduced risk for some conotruncal and atrial septal heart defects. For DQI-P, estimated risks reductions (Q4 vs Q1) for conotruncal defects were 37% for tetralogy of Fallot (OR 0.63, 95% CI 0.49 to 0.80) and 24% overall (OR 0.76, 95% CI 0.64 to 0.91); and for septal defects, 23% for atrial septal defects (OR 0.77, 95% CI 0.63 to 0.94) and 14% overall (OR 0.86, 95% CI 0.75 to 1.00). Risk reductions were weaker or minimal for most other major congenital heart defects.Better diet quality is associated with a reduced occurrence of some conotruncal and septal heart defects. This finding suggests that a reduction in certain cardiac malformations may be an additional benefit of improved maternal diet quality, reinforcing current preconception care recommendations.
View details for DOI 10.1136/archdischild-2014-308013
View details for Web of Science ID 000367479500010
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Evaluation of a cumulative first trimester characteristic and serum marker risk score for predicting early spontaneous preterm birth
MOSBY-ELSEVIER. 2015: S142
View details for DOI 10.1016/j.ajog.2014.10.305
View details for Web of Science ID 000361140900260
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Spontaneous preterm birth risk among inter-racial/ethnic couples
MOSBY-ELSEVIER. 2015: S82
View details for DOI 10.1016/j.ajog.2014.10.177
View details for Web of Science ID 000361140900133
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Maternal height and risk for spontaneous preterm birth across BMI categories
MOSBY-ELSEVIER. 2015: S83
View details for DOI 10.1016/j.ajog.2014.10.178
View details for Web of Science ID 000361140900134
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Traffic-related air pollution and risk of preterm birth in the San Joaquin Valley of California
ANNALS OF EPIDEMIOLOGY
2014; 24 (12): 888-895
Abstract
To evaluate associations between traffic-related air pollution during pregnancy and preterm birth in births in four counties in California during years 2000 to 2006.We used logistic regression to examine the association between the highest quartile of ambient air pollutants (carbon monoxide, nitrogen dioxide, particulate matter <10 and 2.5 μm) and traffic density during pregnancy and each of five levels of prematurity based on gestational age at birth (20-23, 24-27, 28-31, 32-33, and 34-36 weeks) versus term (37-42 weeks). We examined trimester averages and the last month and the last 6 weeks of pregnancy. Models were adjusted for birthweight, maternal age, race/ethnicity, education, prenatal care, and birth costs payment. Neighborhood socioeconomic status (SES) was evaluated as a potential effect modifier.There were increased odds ratios (ORs) for early preterm birth for those exposed to the highest quartile of each pollutant during the second trimester and the end of pregnancy (adjusted OR, 1.4-2.8). Associations were stronger among mothers living in low SES neighborhoods (adjusted OR, 2.1-4.3). We observed exposure-response associations for multiple pollutant exposures and early preterm birth. Inverse associations during the first trimester were observed.The results confirm associations between traffic-related air pollution and prematurity, particularly among very early preterm births and low SES neighborhoods.
View details for DOI 10.1016/j.annepidem.2014.10.004
View details for Web of Science ID 000345497100004
View details for PubMedCentralID PMC4355392
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Risk of selected structural abnormalities in infants after increased nuchal translucency measurement
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
2014; 211 (6)
Abstract
We sought to examine the association between increased first-trimester fetal nuchal translucency (NT) measurement and major noncardiac structural birth defects in euploid infants.Included were 75,899 singleton infants without aneuploidy or critical congenital heart defects born in California in 2009 through 2010 with NT measured between 11-14 weeks of gestation. Logistic binomial regression was employed to estimate relative risks (RRs) and 95% confidence intervals (CIs) for occurrence of birth defects in infants with an increased NT measurement (by percentile at crown-rump length [CRL] and by ≥3.5 mm compared to those with measurements <90th percentile for CRL).When considered by CRL adjusted percentile and by measurement ≥3.5 mm, infants with a NT ≥95th percentile were at risk of having ≥1 major structural birth defects (any defect, RR, 1.6; 95% CI, 1.3-1.9; multiple defects, RR, 2.1; 95% CI, 1.3-3.4). Infants with a NT measurement ≥95th percentile were at particularly high risk for pulmonary, gastrointestinal, genitourinary, and musculoskeletal anomalies (RR, 1.6-2.7; 95% CI, 1.1-5.4).Our findings demonstrate that risks of major pulmonary, gastrointestinal, genitourinary, and musculoskeletal structural birth defects exist for NT measurements ≥95th percentile. The ≥3-fold risks were observed for congenital hydrocephalus; agenesis, hypoplasia, and dysplasia of the lung; atresia and stenosis of the small intestine; osteodystrophies; and diaphragm anomalies.
View details for DOI 10.1016/j.ajog.2014.06.025
View details for Web of Science ID 000346585300030
View details for PubMedID 24949541
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Residential agricultural pesticide exposures and risk of selected congenital heart defects among offspring in the San Joaquin Valley of California.
Environmental research
2014; 135: 133-138
Abstract
Pesticide exposures are ubiquitous and of substantial public concern. We examined the potential association of congenital heart defects with residential proximity to commercial agricultural pesticide applications in the San Joaquin Valley, California.Study subjects included 569 heart defect cases and 785 non-malformed controls born from 1997 to 2006 whose mothers participated in a population-based case-control study. Associations with any versus no exposure to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for relevant covariates, for 8 heart defect phenotypes that included ≥50 cases and pesticide exposures with ≥5 exposed cases and controls, which resulted in 235 comparisons.38% of cases and controls were classified as exposed to pesticides within a 500m radius of mother׳s address during a 3-month periconceptional window. Adjusted odds ratios (AORs) with 95% CIs excluding 1.0 were observed for 18 comparisons; all were >1 and ranged from 1.9 to 7.1. They included tetralogy of Fallot (n=101 cases) and neonicotinoids; hypoplastic left heart syndrome (n=59) and strobins; coarctation of the aorta (n=74) and pyridazinones; pulmonary valve stenosis (n=53) and bipyridyliums and organophosphates; ventricular septal defects (n=93) and avermectins and pyrethroids; and atrial septal defects (n=132) and dichlorphenoxy acid or esters, organophosphates, organotins, and pyrethroids. No AORs met both of these criteria for d-transposition of the great arteries (n=58) or heterotaxia (n=53).Most pesticides were not associated with increased risk of specific heart defect phenotypes. For the few that were associated, results should be interpreted with caution until replicated in other study populations.
View details for DOI 10.1016/j.envres.2014.08.030
View details for PubMedID 25262086
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Better Diet Quality before Pregnancy Is Associated with Reduced Risk of Gastroschisis in Hispanic Women
JOURNAL OF NUTRITION
2014; 144 (11): 1781-1786
Abstract
Gastroschisis is unique because of its substantial risk in pregnancies of adolescent women. Adolescents may have poor diet quality, which places them at higher risk of gastroschisis.We investigated whether better maternal diet quality, measured by 2 different indices, reduced the risk of gastroschisis.We used case-control data from the National Birth Defects Prevention Study to investigate maternal diet quality among 1125 gastroschisis cases and 9483 controls (estimated delivery dates between 1997 and 2009). Cases were ascertained from 10 U.S. birth defect surveillance systems. Control subjects were randomly selected from birth certificates or hospital records. Using a 58-item food-frequency questionnaire, interviewers queried mothers about their average food and cereal intake during the year before conception. Diet quality scores [Diet Quality Index (DQI) and Mediterranean diet score (MDS)] were calculated using specific components. Women were excluded if they consumed <500 or >5000 kcal/d, reported pregestational diabetes, or had >1 missing food item. Quartile-specific adjusted ORs (aORs) were calculated, using as reference the lowest quartile.Overall, we observed a statistically significant decrease with increasing diet quality for both the DQI and MDS. When stratified by maternal race/ethnicity, this finding was confined to Hispanic women. Among Hispanic women, the risk of gastroschisis decreased significantly with increasing DQI quartiles: quartile 2, aOR = 0.58 (95% CI: 0.40, 0.86); quartile 3, aOR = 0.52 (95% CI: 0.36, 0.79); and quartile 4, aOR = 0.48 (95% CI: 0.32, 0.76). Increasing diet quality, as measured by the MDS, showed reduced risk of gastroschisis among women, mostly Hispanic, who were born outside the United States: quartile 2, aOR = 0.62 (95% CI: 0.33, 1.16); quartile 3, aOR = 0.51 (95% CI: 0.28, 0.94); and quartile 4, aOR = 0.50 (95% CI: 0.28, 0.90).Increasing diet quality was associated with a reduced risk of gastroschisis only among Hispanic and foreign-born women, but these findings require replication.
View details for DOI 10.3945/jn.114.201376
View details for Web of Science ID 000343681400016
View details for PubMedID 25332477
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Sociodemographic and Hispanic Acculturation Factors and Isolated Anotia/Microtia
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2014; 100 (11): 852-862
Abstract
It has been observed in several studies that infants with anotia/microtia are more common among Hispanics compared with other racial/ethnic groups. We examined the association between selected Hispanic ethnicity and acculturation factors and anotia/microtia in the National Birth Defects Prevention Study.We examined data from mothers of 351 infants with isolated anotia/microtia and 8435 unaffected infants from the National Birth Defects Prevention Study with an expected delivery date from 1997 to 2007. Sociodemographic, maternal, and acculturation factors (e.g., age, maternal education, household income, body mass index, gestational diabetes, folic acid, smoking, alcohol intake, study center, parental birthplace, and years lived in the United States, maternal language) were assessed as overall risk factors and also as risk factors among subgroups of Hispanics (United States- and foreign-born) versus non-Hispanic whites.Compared with non-Hispanic whites, both United States- and foreign-born Hispanic mothers demonstrated substantially higher odds of delivering infants with anotia/microtia across nearly all strata of sociodemographic and other maternal factors (adjusted odds ratios range: 2.1-11.9). The odds of anotia/microtia was particularly elevated among Hispanic mothers who emigrated from Mexico after age five (adjusted odds ratios = 4.88; 95% confidence interval = 2.93-8.11) or who conducted the interview in Spanish (adjusted odds ratios = 4.97; 95% confidence interval = 3.00-8.24).We observed that certain sociodemographic and acculturation factors are associated with higher risks of anotia/microtia among offspring of Hispanic mothers.
View details for DOI 10.1002/bdra.23282
View details for Web of Science ID 000345690600007
View details for PubMedID 25074828
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Exposure to airborne polycyclic aromatic hydrocarbons during pregnancy and risk of preterm birth
ENVIRONMENTAL RESEARCH
2014; 135: 221-226
Abstract
Preterm birth is an important marker of health and has a prevalence of 12-13% in the U.S. Polycyclic aromatic hydrocarbons (PAHs) are a group of organic contaminants that form during the incomplete combustion of hydrocarbons, such as coal, diesel and gasoline. Studies suggest that exposure to PAHs during pregnancy is related to adverse birth outcomes. The aim of this study is to evaluate the association between exposure to PAHs during the pregnancy and preterm birth.The study population included births from years 2001 to 2006 of women whose maternal residence was within 20km of the primary monitoring site in Fresno, California. Data in the Fresno area were used to form a spatio-temporal model to assign daily exposure to PAHs with 4, 5, or 6 rings at the maternal residence throughout pregnancy of all of the births in the study area. Gestational age at birth and relevant covariates were extracted from the birth certificate.We found an association between PAHs during the last 6 weeks of pregnancy and birth at 20-27 weeks (OR=2.74; 95% CI: 2.24-3.34) comparing the highest quartile to the lower three. The association was consistent when each quartile was compared to the lowest (OR2nd=1.49, 95% CI: 1.08-2.06; OR3rd=2.63, 95% CI:1.93-3.59; OR4th=3.94, 95% CI:3.03-5.12). Inverse associations were also observed for exposure to PAHs during the entire pregnancy and the first trimester and birth at 28-31 weeks and 20-27 weeks.An association between PAH exposure during the 6 weeks before delivery and early preterm birth was observed. However, the inverse association with early preterm birth offers an unclear, and potentially complex, inference of these associations.
View details for DOI 10.1016/j.envres.2014.09.014
View details for Web of Science ID 000346622800031
View details for PubMedID 25282280
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Maternal Periconceptional Occupational Pesticide Exposure and Neural Tube Defects
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2014; 100 (11): 877-886
Abstract
Adverse associations between maternal pesticide exposure and neural tube defects (NTDs) have been suggested but not consistently observed. This study used data from the multisite National Birth Defects Prevention Study to examine associations between maternal periconceptional (1 month preconception through 2 months postconception) occupational pesticide exposure and NTDs.Mothers of 502 NTD cases and 2950 unaffected live-born control infants with estimated delivery dates from 1997 through 2002 were included. Duration, categorical intensity scores, and categorical frequency scores for pesticide classes (e.g., insecticides) were assigned using a modified, literature-based job-exposure matrix and maternal-reported occupational histories. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated based on fitted multivariable logistic regression models that described associations between maternal periconceptional occupational pesticide exposure and NTDs. The aORs were estimated for pesticide exposure (any [yes/no] and cumulative exposure [intensity × frequency × duration] to any pesticide class, each pesticide class, or combination of pesticide classes) and all NTD cases combined and NTD subtypes.Positive, but marginally significant or nonsignificant, aORs were observed for exposure to insecticides + herbicides for all NTD cases combined and for spina bifida alone. Similarly, positive aORs were observed for any exposure and cumulative exposure to insecticides + herbicides + fungicides and anencephaly alone and encephalocele alone. All other aORs were near unity.Pesticide exposure associations varied by NTD subtype and pesticide class. Several aORs were increased, but not significantly. Future work should continue to examine associations between pesticide classes and NTD subtypes using a detailed occupational pesticide exposure assessment and examine pesticide exposures outside the workplace.
View details for DOI 10.1002/bdra.23293
View details for Web of Science ID 000345690600009
View details for PubMedID 25124525
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Copy Number Variation in Bronchopulmonary Dysplasia
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2014; 164 (10): 2672–75
View details for DOI 10.1002/ajmg.a.36659
View details for Web of Science ID 000342279600041
View details for PubMedID 24975634
View details for PubMedCentralID PMC4167221
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Corticosteroid Use and Risk for Orofacial Clefts EDITORIAL COMMENT
OBSTETRICAL & GYNECOLOGICAL SURVEY
2014; 69 (10): 573-575
View details for DOI 10.1097/01.ogx.0000456345.09228.f3
View details for Web of Science ID 000344453200003
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Early Pregnancy Agricultural Pesticide Exposures and Risk of Gastroschisis among Offspring in the San Joaquin Valley of California
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2014; 100 (9): 686-694
Abstract
Prevalence of gastroschisis has inexplicably been increasing over the past few decades. Our intent was to explore whether early gestational exposures to pesticides were associated with risk of gastroschisis.We used population-based data, accompanied by detailed information from maternal interviews as well as information on residential proximity to a large number of commercial pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley of California (). Cases were 156 infants/fetuses with gastroschisis and controls were 785 infants without birth defects.Among 22 chemical pesticide groups analyzed, none had an elevated odds ratio with an associated confidence interval that excluded 1.0, although exposure to the triazine group showed borderline significance. Among 36 specific pesticide chemicals analyzed, only exposure to petroleum distillates was associated with an elevated risk, odds ratio = 2.5 (1.1-5.6). In general, a substantially different inference was not derived when analyses were stratified by maternal age or when risk estimation included adjustment for race/ethnicity, body mass index, folic acid supplement use, and smoking.Our study rigorously adds to the scant literature on this topic. Our a priori expectation was that we would observe certain pesticide compounds to be particularly associated with young age owing to the disproportionate risk observed for young women to have offspring with gastroschisis. We did not observe an exposure profile unique to young women. Birth Defects Research (Part A), 100:686-694, 2014. © 2014 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23263
View details for Web of Science ID 000342625200006
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Early pregnancy agricultural pesticide exposures and risk of gastroschisis among offspring in the San Joaquin Valley of California.
Birth defects research. Part A, Clinical and molecular teratology
2014; 100 (9): 686-694
Abstract
Prevalence of gastroschisis has inexplicably been increasing over the past few decades. Our intent was to explore whether early gestational exposures to pesticides were associated with risk of gastroschisis.We used population-based data, accompanied by detailed information from maternal interviews as well as information on residential proximity to a large number of commercial pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley of California (). Cases were 156 infants/fetuses with gastroschisis and controls were 785 infants without birth defects.Among 22 chemical pesticide groups analyzed, none had an elevated odds ratio with an associated confidence interval that excluded 1.0, although exposure to the triazine group showed borderline significance. Among 36 specific pesticide chemicals analyzed, only exposure to petroleum distillates was associated with an elevated risk, odds ratio = 2.5 (1.1-5.6). In general, a substantially different inference was not derived when analyses were stratified by maternal age or when risk estimation included adjustment for race/ethnicity, body mass index, folic acid supplement use, and smoking.Our study rigorously adds to the scant literature on this topic. Our a priori expectation was that we would observe certain pesticide compounds to be particularly associated with young age owing to the disproportionate risk observed for young women to have offspring with gastroschisis. We did not observe an exposure profile unique to young women. Birth Defects Research (Part A), 100:686-694, 2014. © 2014 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23263
View details for PubMedID 24910073
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Combined elevated midpregnancy tumor necrosis factor alpha and hyperlipidemia in pregnancies resulting in early preterm birth.
American journal of obstetrics and gynecology
2014; 211 (2): 141 e1-9
Abstract
The objective of the study was to determine whether pregnancies resulting in early preterm birth (PTB) (<30 weeks) were more likely than term pregnancies to have elevated midtrimester serum tumor necrosis factor alpha (TNF-α) levels combined with lipid patterns suggestive of hyperlipidemia.In 2 nested case-control samples drawn from California and Iowa cohorts, we examined the frequency of elevated midpregnancy serum TNF-α levels (in the fourth quartile [4Q]) and lipid patterns suggestive of hyperlipidemia (eg, total cholesterol, low-density-lipoproteins, or triglycerides in the 4Q, high-density lipoproteins in the first quartile) (considered independently and by co-occurrence) in pregnancies resulting in early PTB compared with those resulting in term birth (n = 108 in California and n = 734 in Iowa). Odds ratios (ORs) and 95% confidence intervals (CIs) estimated in logistic regression models were used for comparisons.Early preterm pregnancies were 2-4 times more likely than term pregnancies to have a TNF-α level in the 4Q co-occurring with indicators of hyperlipidemia (37.5% vs 13.9% in the California sample (adjusted OR, 4.0; 95% CI, 1.1-16.3) and 26.3% vs 14.9% in the Iowa sample (adjusted OR, 2.7; 95% CI, 1.1-6.3). No differences between early preterm and term pregnancies were observed when TNF-α or target lipid abnormalities occurred in isolation. Observed differences were not explicable to any maternal or infant characteristics.Pregnancies resulting in early PTB were more likely than term pregnancies to have elevated midpregnancy TNF-α levels in combination with lipid patterns suggestive of hyperlipidemia.
View details for DOI 10.1016/j.ajog.2014.02.019
View details for PubMedID 24831886
View details for PubMedCentralID PMC4117727
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Irf6 regulates Tfap2a and is required for neurulation
WILEY-BLACKWELL. 2014: 1883-1884
View details for Web of Science ID 000340667900030
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Association between maternal characteristics, abnormal serum aneuploidy analytes, and placental abruption.
American journal of obstetrics and gynecology
2014; 211 (2): 144 e1-9
View details for DOI 10.1016/j.ajog.2014.03.027
View details for PubMedID 24631707
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Combined elevated midpregnancy tumor necrosis factor alpha and hyperlipidemia in pregnancies resulting in early preterm birth.
American journal of obstetrics and gynecology
2014; 211 (2): 141 e1-9
View details for DOI 10.1016/j.ajog.2014.02.019
View details for PubMedID 24831886
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Maternal occupational exposure to polycyclic aromatic hydrocarbons and small for gestational age offspring.
Occupational and environmental medicine
2014; 71 (8): 529-535
Abstract
While some of the highest maternal exposures to polycyclic aromatic hydrocarbons (PAHs) occur in the workplace, there is only one previous study of occupational PAH exposure and adverse pregnancy outcomes. We sought to extend this literature using interview data combined with detailed exposure assessment.Data for 1997-2002 were analysed from mothers of infants without major birth defects in the National Birth Defects Prevention Study, a large population-based case-control study in the USA. Maternal telephone interviews yielded information on jobs held in the month before conception through delivery. From 6252 eligible control mothers, 2803 completed the interview, had a job, met other selection criteria, and were included in the analysis. Two industrial hygienists independently assessed occupational exposure to PAHs from the interview and reviewed results with a third to reach consensus. Small for gestational age (SGA) was the only adverse pregnancy outcome with enough exposed cases to yield meaningful results. Logistic regression estimated crude and adjusted ORs.Of the 2803 mothers, 221 (7.9%) had infants who were SGA. Occupational PAH exposure was found for 17 (7.7%) of the mothers with SGA offspring and 102 (4.0%) of the remaining mothers. Almost half the jobs with exposure were related to food preparation and serving. After adjustment for maternal age, there was a significant association of occupational exposure with SGA (OR=2.2, 95% CI 1.3 to 3.8).Maternal occupational exposure to PAHs was found to be associated with increased risk of SGA offspring.
View details for DOI 10.1136/oemed-2013-101833
View details for PubMedID 24893704
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Maternal Exposure to Criteria Air Pollutants and Congenital Heart Defects in Offspring: Results from the National Birth Defects Prevention Study
ENVIRONMENTAL HEALTH PERSPECTIVES
2014; 122 (8): 863-872
Abstract
Epidemiologic literature suggests that exposure to air pollutants is associated with fetal development.We investigated maternal exposures to air pollutants during weeks 2-8 of pregnancy and their associations with congenital heart defects.Mothers from the National Birth Defects Prevention Study, a nine-state case-control study, were assigned 1-week and 7-week averages of daily maximum concentrations of carbon monoxide, nitrogen dioxide, ozone, and sulfur dioxide and 24-hr measurements of fine and coarse particulate matter using the closest air monitor within 50 km to their residence during early pregnancy. Depending on the pollutant, a maximum of 4,632 live-birth controls and 3,328 live-birth, fetal-death, or electively terminated cases had exposure data. Hierarchical regression models, adjusted for maternal demographics and tobacco and alcohol use, were constructed. Principal component analysis was used to assess these relationships in a multipollutant context.Positive associations were observed between exposure to nitrogen dioxide and coarctation of the aorta and pulmonary valve stenosis. Exposure to fine particulate matter was positively associated with hypoplastic left heart syndrome but inversely associated with atrial septal defects. Examining individual exposure-weeks suggested associations between pollutants and defects that were not observed using the 7-week average. Associations between left ventricular outflow tract obstructions and nitrogen dioxide and between hypoplastic left heart syndrome and particulate matter were supported by findings from the multipollutant analyses, although estimates were attenuated at the highest exposure levels.Using daily maximum pollutant levels and exploring individual exposure-weeks revealed some positive associations between certain pollutants and defects and suggested potential windows of susceptibility during pregnancy.
View details for DOI 10.1289/ehp.1307289
View details for Web of Science ID 000341713800024
View details for PubMedID 24727555
View details for PubMedCentralID PMC4123026
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Association between maternal characteristics, abnormal serum aneuploidy analytes, and placental abruption.
American journal of obstetrics and gynecology
2014; 211 (2): 144 e1-9
Abstract
The objective of the study was to examine the association between placental abruption, maternal characteristics, and routine first- and second-trimester aneuploidy screening analytes.The study consisted of an analysis of 1017 women with and 136,898 women without placental abruption who had first- and second-trimester prenatal screening results, linked birth certificate, and hospital discharge records for a live-born singleton. Maternal characteristics and first- and second-trimester aneuploidy screening analytes were analyzed using logistic binomial regression.Placental abruption was more frequent among women of Asian race, age older than 34 years, women with chronic and pregnancy-associated hypertension, preeclampsia, preexisting diabetes, previous preterm birth, and interpregnancy interval less than 6 months. First-trimester pregnancy-associated plasma protein-A of the fifth percentile or less, second-trimester alpha fetoprotein of the 95th percentile or greater, unconjugated estriol of the fifth percentile or less, and dimeric inhibin-A of the 95th percentile or greater were associated with placental abruption as well. When logistic models were stratified by the presence or absence of hypertensive disease, only maternal age older than 34 years (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.0-2.0), pregnancy-associated plasma protein-A of the 95th percentile or less (OR, 1.9; 95% CI, 1.2-3.1), and alpha fetoprotein of the 95th percentile or greater (OR, 2.3; 95% CI, 1.4-3.8) remained statistically significantly associated for abruption.In this large, population-based cohort study, abnormal maternal aneuploidy serum analyte levels were associated with placental abruption, regardless of the presence of hypertensive disease.
View details for DOI 10.1016/j.ajog.2014.03.027
View details for PubMedID 24631707
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Maternal prepregnancy body mass index and risk of spontaneous preterm birth.
Paediatric and perinatal epidemiology
2014; 28 (4): 302-311
Abstract
Findings from studies examining risk of preterm birth associated with elevated prepregnancy body mass index (BMI) have been inconsistent.Within a large population-based cohort, we explored associations between prepregnancy BMI and spontaneous preterm birth across a spectrum of BMI, gestational age, and racial/ethnic categories. We analysed data for 989 687 singleton births in California, 2007-09. Preterm birth was grouped as 20-23, 24-27, 28-31, or 32-36 weeks gestation (compared with 37-41 weeks). BMI was categorised as <18.5 (underweight); 18.5-24.9 (normal); 25.0-29.9 (overweight); 30.0-34.9 (obese I); 35.0-39.9 (obese II); and ≥40.0 (obese III). We assessed associations between BMI and spontaneous preterm birth of varying severity among non-Hispanic White, Hispanic, and non-Hispanic Black women.Analyses of mothers without hypertension and diabetes, adjusted for age, education, height, and prenatal care initiation, showed obesity categories I-III to be associated with increased risk of spontaneous preterm birth at 20-23 and 24-27 weeks among those of parity 1 in each race/ethnic group. Relative risks for obese III and preterm birth at 20-23 weeks were 6.29 [95% confidence interval (CI) 3.06, 12.9], 4.34 [95% CI 2.30, 8.16], and 4.45 [95% CI 2.53, 7.82] for non-Hispanic Whites, non-Hispanic Blacks, and Hispanics, respectively. A similar, but lower risk, pattern was observed for women of parity ≥2 and preterm birth at 20-23 weeks. Underweight was associated with modest risks for preterm birth at ≥24 weeks among women in each racial/ethnic group regardless of parity.The association between women's prepregnancy BMI and risk of spontaneous preterm birth is complex and is influenced by race/ethnicity, gestational age, and parity.
View details for DOI 10.1111/ppe.12125
View details for PubMedID 24810721
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Haploinsufficiency of insulin gene enhancer protein 1 (ISL1) is associated with d-transposition of the great arteries.
Molecular genetics & genomic medicine
2014; 2 (4): 341-351
Abstract
Congenital heart defects are the most common malformation, and are the foremost causes of mortality in the first year of life. Among congenital heart defects, conotruncal defects represent about 20% and are severe malformations with significant morbidity. Insulin gene enhancer protein 1 (ISL1) has been considered a candidate gene for conotruncal heart defects based on its embryonic expression pattern and heart defects induced in Isl1 knockout mice. Nevertheless no mutation of ISL1 has been reported from any human subject with a heart defect. From a population base of 974,579 births during 1999-2004, we used multiplex ligation-dependent probe amplification to screen for microdeletions/duplications of ISL1 among 389 infants with tetralogy of Fallot or d-transposition of the great arteries (d-TGA). We also sequenced all exons of ISL1. We identified a novel 20-kb microdeletion encompassing the entire coding region of ISL1, but not including either flanking gene, from an infant with d-TGA. We confirmed that the deletion was caused by nonhomologous end joining mechanism. Sequencing of exons of ISL1 did not reveal any subject with a novel nonsynonymous mutation. This is the first report of an ISL1 mutation of a child with a congenital heart defect.
View details for DOI 10.1002/mgg3.75
View details for PubMedID 25077177
View details for PubMedCentralID PMC4113275
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Maternal stressors and social support as risks for delivering babies with structural birth defects.
Paediatric and perinatal epidemiology
2014; 28 (4): 338-344
Abstract
We examined the association of maternal stressful life events and social support with risks of birth defects using National Birth Defects Prevention Study data, a population-based case-control study.We examined seven stressful life events and three social support questions applicable to the periconceptional period, among mothers of 552 cases with neural tube defects (NTDs), 413 cleft palate (CP), 797 cleft lip ± cleft palate (CLP), 189 d-transposition of the great arteries (dTGA), 311 tetralogy of Fallot (TOF), and 2974 non-malformed controls. A stressful life events index equalled the sum of 'yes' responses to the seven questions. Social support questions were also summed to form an index. Data were analyzed using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusted for maternal race-ethnicity, age, education, body mass index, smoking, drinking, and intake of vitamin supplements.Associations with the stress index tended to be higher with higher scores, but few 95% CIs excluded one. A four-point increase in the index was moderately associated with NTDs (OR 1.5, [95% CI 1.1, 2.0]) and CLP (OR 1.3, [95% CI 1.0, 1.7]). The social support index tended to be associated with reduced risk but most 95% CIs included one, with the exception of dTGA (OR for a score of 3 vs 0 was 0.5 [95% CI 0.3, 0.8]).Maternal periconceptional stressful life events, social support, and the two factors in combination were at most modestly, if at all, associated with risks of the studied birth defects.
View details for DOI 10.1111/ppe.12123
View details for PubMedID 24697924
View details for PubMedCentralID PMC4057295
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Swedish and American studies show that initiatives to decrease maternal obesity could play a key role in reducing preterm birth.
Acta paediatrica (Oslo, Norway : 1992)
2014; 103 (6): 586-591
Abstract
Maternal obesity is a major source of preventable perinatal morbidity, but studies of the relationship between obesity and preterm birth have been inconsistent. This review looks at two major studies covering just under 3.5 million births, from California, USA, and Sweden.Inconsistent findings in previous studies appear to stem from the complex relationship between obesity and preterm birth. Initiatives to decrease maternal obesity represent an important strategy in reducing preterm birth.
View details for DOI 10.1111/apa.12616
View details for PubMedID 24575829
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Corticosteroid Use and Risk of Orofacial Clefts
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2014; 100 (6): 499-506
Abstract
Maternal use of corticosteroids during early pregnancy has been inconsistently associated with orofacial clefts in the offspring. A previous report from the National Birth Defect Prevention Study (NBDPS), using data from 1997 to 2002, found an association with cleft lip and palate (odds ratio, 1.7; 95% confidence interval [CI], 1.1-2.6), but not cleft palate only (odds ratio, 0.5, 95%CI, 0.2-1.3). From 2003 to 2009, the study population more than doubled in size, and our objective was to assess this association in the more recent data.The NBDPS is an ongoing multi-state population-based case-control study of birth defects, with ascertainment of cases and controls born since 1997. We assessed the association of corticosteroids and orofacial clefts using data from 2372 cleft cases and 5922 controls born from 2003 to 2009. Maternal corticosteroid exposure was based on telephone interviews.The overall association of corticosteroids and cleft lip and palate in the new data was 1.0 (95% CI, 0.7-1.4). There was little evidence of associations between specific corticosteroid components or timing and clefts.In contrast to the 1997 to 2002 data from the NBDPS, the 2003 to 2009 data show no association between maternal corticosteroid use and cleft lip and palate in the offspring.
View details for DOI 10.1002/bdra.23248
View details for Web of Science ID 000338036300006
View details for PubMedCentralID PMC4283705
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Investigation of maternal environmental exposures in association with self-reported preterm birth.
Reproductive toxicology
2014; 45: 1-7
Abstract
Identification of maternal environmental factors influencing preterm birth risks is important to understand the reasons for the increase in prematurity since 1990. Here, we utilized a health survey, the US National Health and Nutrition Examination Survey (NHANES) to search for personal environmental factors associated with preterm birth. 201 urine and blood markers of environmental factors, such as allergens, pollutants, and nutrients were assayed in mothers (range of N: 49-724) who answered questions about any children born preterm (delivery <37 weeks). We screened each of the 201 factors for association with any child born preterm adjusting by age, race/ethnicity, education, and household income. We attempted to verify the top finding, urinary bisphenol A, in an independent study of pregnant women attending Lucile Packard Children's Hospital. We conclude that the association between maternal urinary levels of bisphenol A and preterm birth should be evaluated in a larger epidemiological investigation.
View details for DOI 10.1016/j.reprotox.2013.12.005
View details for PubMedID 24373932
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Congenital heart defects after maternal fever
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
2014; 210 (4)
Abstract
The purpose of this study was to evaluate whether maternal febrile illnesses in early pregnancy are associated with increased risk for congenital heart defects in the offspring and whether such risk is mitigated by multivitamin supplement use.From a multistate population-based case-control study (National Birth Defects Prevention Study), we compared maternal reports of first-trimester febrile illness from 7020 subjects with heart defects and 6746 unaffected control subjects who were born from 1997 through 2005. Relative risks were computed with no fever or infection during the first trimester as reference group and were adjusted for potential confounders.First-trimester febrile illness was reported by 7.4% of control mothers (1 in 13). Febrile genitourinary infections were associated with selected heart defects, particularly right-sided obstructive defects (odds ratios, >3) and possibly others, whereas common respiratory illnesses were associated with low-to-negligible risks for most heart defects. When risk estimates were elevated, they tended to be mitigated when multivitamin supplements had been taken in the periconceptional period.The source of fever and the use of supplements appear to influence the risk for heart defects. This information can be helpful in counseling and research, in particular with regard to primary prevention.
View details for DOI 10.1016/j.ajog.2013.10.880
View details for Web of Science ID 000333401900023
View details for PubMedID 24184180
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Genetic Epidemiology and Nonsyndromic Structural Birth Defects From Candidate Genes to Epigenetics
JAMA PEDIATRICS
2014; 168 (4): 371-377
Abstract
Birth defects are a leading cause of infant morbidity and mortality worldwide. The vast majority of birth defects are nonsyndromic, and although their etiologies remain mostly unknown, evidence supports the hypothesis that they result from the complex interaction of genetic, epigenetic, environmental, and lifestyle factors. Since our last review published in 2002 describing the basic tools of genetic epidemiology used to study nonsyndromic structural birth defects, many new approaches have become available and have been used with varying success. Through rapid advances in genomic technologies, investigators are now able to investigate large portions of the genome at a fraction of previous costs. With next-generation sequencing, research has progressed from assessing a small percentage of single-nucleotide polymorphisms to assessing the entire human protein-coding repertoire (exome)-an approach that is starting to uncover rare but informative mutations associated with nonsyndromic birth defects. Herein, we report on the current state of the genetic epidemiology of birth defects and comment on future challenges and opportunities. We consider issues of study design, and we discuss common variant approaches, including candidate gene studies and genome-wide association studies. We also discuss the complexities embedded in exploring interactions between genes and the environment. We complete our review by describing new and promising next-generation sequencing technologies and examining how the study of epigenetic mechanisms could become the key to unraveling the complex etiologies of nonsyndromic structural birth defects.
View details for DOI 10.1001/jamapediatrics.2013.4858
View details for Web of Science ID 000336839200014
View details for PubMedID 24515445
View details for PubMedCentralID PMC3981910
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Late Detection of Critical Congenital Heart Disease Among US Infants: Estimation of the Potential Impact of Proposed Universal Screening Using Pulse Oximetry.
JAMA pediatrics
2014; 168 (4): 361-370
Abstract
IMPORTANCE Critical congenital heart disease (CCHD) was added to the Recommended Uniform Screening Panel for Newborns in the United States in 2011. Many states have recently adopted or are considering requirements for universal CCHD screening through pulse oximetry in birth hospitals. Limited previous research is directly applicable to the question of how many US infants with CCHD might be identified through screening. OBJECTIVES To estimate the proportion of US infants with late detection of CCHD (>3 days after birth) based on existing clinical practice and to investigate factors associated with late detection. DESIGN, SETTING, AND PARTICIPANTS Descriptive and multivariable analysis. Data were obtained from a multisite population-based study of birth defects in the United States, the National Birth Defects Prevention Study (NBDPS). We included all live-born infants with estimated dates of delivery from January 1, 1998, through December 31, 2007, and nonsyndromic, clinically verified CCHD conditions potentially detectable through screening via pulse oximetry. MAIN OUTCOMES AND MEASURES The main outcome measure was the proportion of infants with late detection of CCHD through echocardiography or at autopsy under the assumption that universal screening at birth hospitals might reduce the number of such late diagnoses. Secondary outcome measures included prevalence ratios for associations between selected demographic and clinical factors and late detection of CCHD. RESULTS Of 3746 live-born infants with nonsyndromic CCHD, late detection occurred in 1106 (29.5% [95% CI, 28.1%-31.0%]), including 6 (0.2%) (0.1%-0.4%) first receiving a diagnosis at autopsy more than 3 days after birth. Late detection varied by CCHD type from 9 of 120 infants (7.5% [95% CI, 3.5%-13.8%]) with pulmonary atresia to 497 of 801 (62.0% [58.7%-65.4%]) with coarctation of the aorta. In multivariable analysis, late detection varied significantly by CCHD type and study site, and infants with extracardiac defects were significantly less likely to have late detection of CCHD (adjusted prevalence ratio, 0.58 [95% CI, 0.49-0.69]). CONCLUSIONS AND RELEVANCE We estimate that 29.5% of live-born infants with nonsyndromic CCHD in the NBDPS received a diagnosis more than 3 days after birth and therefore might have benefited from routine CCHD screening at birth hospitals. The number of infants in whom CCHD was detected through screening likely varies by several factors, including CCHD type. Additional population-based studies of screening in practice are needed.
View details for DOI 10.1001/jamapediatrics.2013.4779
View details for PubMedID 24493342
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Residential Agricultural Pesticide Exposures and Risk of Neural Tube Defects and Orofacial Clefts Among Offspring in the San Joaquin Valley of California
AMERICAN JOURNAL OF EPIDEMIOLOGY
2014; 179 (6): 740-748
Abstract
We examined whether early gestational exposures to pesticides were associated with an increased risk of anencephaly, spina bifida, cleft lip with or without cleft palate (CLP), or cleft palate only. We used population-based data along with detailed information from maternal interviews. Exposure estimates were based on residential proximity to agricultural pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley, California (1997-2006). Analyses included 73 cases with anencephaly, 123 with spina bifida, 277 with CLP, and 117 with cleft palate only in addition to 785 controls. A total of 38% of the subjects were exposed to 52 chemical groups and 257 specific chemicals. There were relatively few elevated odds ratios with 95% confidence intervals that excluded 1 after adjustment for relevant covariates. Those chemical groups included petroleum derivatives for anencephaly, hydroxybenzonitrile herbicides for spina bifida, and 2,6-dinitroaniline herbicides and dithiocarbamates-methyl isothiocyanate for CLP. The specific chemicals included 2,4-D dimethylamine salt, methomyl, imidacloprid, and α-(para-nonylphenyl)-ω-hydroxypoly(oxyethylene) phosphate ester for anencephaly; the herbicide bromoxynil octanoate for spina bifida; and trifluralin and maneb for CLP. Adjusted odds ratios ranged from 1.6 to 5.1. Given that such odds ratios might have arisen by chance because of the number of comparisons, our study showed a general lack of association between a range of agricultural pesticide exposures and risks of selected birth defects.
View details for DOI 10.1093/aje/kwt324
View details for Web of Science ID 000333246800011
View details for PubMedID 24553680
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Identification of Novel CELSR1 Mutations in Spina Bifida
PLOS ONE
2014; 9 (3)
Abstract
Spina bifida is one of the most common neural tube defects (NTDs) with a complex etiology. Variants in planar cell polarity (PCP) genes have been associated with NTDs including spina bifida in both animal models and human cohorts. In this study, we sequenced all exons of CELSR1 in 192 spina bifida patients from a California population to determine the contribution of CELSR1 mutations in the studied population. Novel and rare variants identified in these patients were subsequently genotyped in 190 ethnically matched control individuals. Six missense mutations not found in controls were predicted to be deleterious by both SIFT and PolyPhen. Two TG dinucleotide repeat variants were individually detected in 2 spina bifida patients but not detected in controls. In vitro functional analysis showed that the two TG dinucleotide repeat variants not only changed subcellular localization of the CELSR1 protein, but also impaired the physical association between CELSR1 and VANGL2, and thus diminished the ability to recruit VANGL2 for cell-cell contact. In total, 3% of our spina bifida patients carry deleterious or predicted to be deleterious CELSR1 mutations. Our findings suggest that CELSR1 mutations contribute to the risk of spina bifida in a cohort of spina bifida patients from California.
View details for DOI 10.1371/journal.pone.0092207
View details for Web of Science ID 000332858400150
View details for PubMedID 24632739
View details for PubMedCentralID PMC3954890
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Maternal Characteristics and Mid-Pregnancy Serum Markers in Spontaneous and Medically Indicated Preterm Birth
SAGE PUBLICATIONS INC. 2014: 239A
View details for Web of Science ID 000333813002170
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Association between Eclampsia, Maternal Characteristics, and Abnormal Levels of First and Second Trimester Serum Biomarkers.
SAGE PUBLICATIONS INC. 2014: 297A
View details for Web of Science ID 000333813002340
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Maternal Body Mass and Risk for Premature Birth among 1.2 Million California Births
SAGE PUBLICATIONS INC. 2014: 340A
View details for Web of Science ID 000333813003131
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Identification of Novel Candidate Gene Loci and Increased Sex Chromosome Aneuploidy Among Infants With Conotruncal Heart Defects
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2014; 164 (2): 397-406
Abstract
Congenital heart defects (CHDs) are common malformations, affecting four to eight per 1,000 total births. Conotruncal defects are an important pathogenetic subset of CHDs, comprising nearly 20% of the total. Although both environmental and genetic factors are known to contribute to the occurrence of conotruncal defects, the causes remain unknown for most. To identify novel candidate genes/loci, we used array comparative genomic hybridization to detect chromosomal microdeletions/duplications. From a population base of 974,579 total births born during 1999-2004, we screened 389 California infants born with tetralogy of Fallot or d-transposition of the great arteries. We found that 1.7% (5/288) of males with a conotruncal defect had sex chromosome aneuploidy, a sevenfold increased frequency (relative risk = 7.0; 95% confidence interval 2.9-16.9). We identified eight chromosomal microdeletions/duplications for conotruncal defects. From these duplications and deletions, we found five high priority candidate genes (GATA4, CRKL, BMPR1A, SNAI2, and ZFHX4). This is the initial report that sex chromosome aneuploidy is associated with conotruncal defects among boys. These chromosomal microduplications/deletions provide evidence that GATA4, SNAI2, and CRKL are highly dosage sensitive genes involved in outflow tract development. Genome wide screening for copy number variation can be productive for identifying novel genes/loci contributing to non-syndromic common malformations.
View details for DOI 10.1002/ajmg.a.36291
View details for Web of Science ID 000331067100017
View details for PubMedCentralID PMC3946915
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Identification of novel candidate gene loci and increased sex chromosome aneuploidy among infants with conotruncal heart defects.
American journal of medical genetics. Part A
2014; 164A (2): 397-406
Abstract
Congenital heart defects (CHDs) are common malformations, affecting four to eight per 1,000 total births. Conotruncal defects are an important pathogenetic subset of CHDs, comprising nearly 20% of the total. Although both environmental and genetic factors are known to contribute to the occurrence of conotruncal defects, the causes remain unknown for most. To identify novel candidate genes/loci, we used array comparative genomic hybridization to detect chromosomal microdeletions/duplications. From a population base of 974,579 total births born during 1999-2004, we screened 389 California infants born with tetralogy of Fallot or d-transposition of the great arteries. We found that 1.7% (5/288) of males with a conotruncal defect had sex chromosome aneuploidy, a sevenfold increased frequency (relative risk = 7.0; 95% confidence interval 2.9-16.9). We identified eight chromosomal microdeletions/duplications for conotruncal defects. From these duplications and deletions, we found five high priority candidate genes (GATA4, CRKL, BMPR1A, SNAI2, and ZFHX4). This is the initial report that sex chromosome aneuploidy is associated with conotruncal defects among boys. These chromosomal microduplications/deletions provide evidence that GATA4, SNAI2, and CRKL are highly dosage sensitive genes involved in outflow tract development. Genome wide screening for copy number variation can be productive for identifying novel genes/loci contributing to non-syndromic common malformations.
View details for DOI 10.1002/ajmg.a.36291
View details for PubMedID 24127225
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One-carbon metabolite levels in mid-pregnancy and risks of conotruncal heart defects.
Birth defects research. Part A, Clinical and molecular teratology
2014; 100 (2): 107-115
Abstract
Evidence exists for an association between use of vitamin supplements with folic acid in early pregnancy and reduced risk for offspring with conotruncal heart defects. A few observations have been made about nutrients related to one-carbon metabolism other than folate. Our prospective study attempted to extend information on nutrition and conotruncal heart defects by measuring analytes in mid-pregnancy sera.This study included data from a repository of women's mid-pregnancy serum specimens based on screened pregnancies in California from 2002-2007. Each woman's specimen was linked with delivery information to determine whether her fetus had a conotruncal heart defect or another structural malformation, or was nonmalformed. We identified 140 conotruncal cases and randomly selected 280 specimens as nonmalformed controls. Specimens were tested for a variety of analytes, including homocysteine, methylmalonic acid, folate, vitamin B12 , pyridoxal phosphate, pyridoxal, pyridoxic acid, riboflavin, total choline, betaine, methionine, cysteine, cystathionine, arginine, asymmetric and symmetric dimethylarginine.We did not observe statistical evidence for substantial differences between cases and controls for any of the measured analytes. Analyses specifically targeting B-vitamins also did not reveal differences between cases and controls. Birth Defects Research (Part A) 100:107-115, 2014. © 2014 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23224
View details for PubMedID 24532477
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Population-Level Correlates of Preterm Delivery among Black and White Women in the U.S.
PloS one
2014; 9 (4)
View details for DOI 10.1371/journal.pone.0094153
View details for PubMedID 24740117
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Placental accreta and first and second trimester maternal serum markers and characteristics
MOSBY-ELSEVIER. 2014: S62
View details for DOI 10.1016/j.ajog.2013.10.129
View details for Web of Science ID 000330322600099
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Association between severe early onset preeclampsia (PE) and serum measures of first trimester pregnancy associated plasma protein A (PAPP-A) and human chorionic gonadotrophin (hCG)
MOSBY-ELSEVIER. 2014: S143
View details for DOI 10.1016/j.ajog.2013.10.302
View details for Web of Science ID 000330322600270
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Elevated mid-pregnancy tumor necrosis factor-alpha (TNF-alpha) and lipid patterns suggestive of hyperlipidemia in pregnancies resulting in early preterm birth
MOSBY-ELSEVIER. 2014: S375–S376
View details for DOI 10.1016/j.ajog.2013.10.798
View details for Web of Science ID 000330322600765
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Population-level correlates of preterm delivery among black and white women in the U.S.
PloS one
2014; 9 (4)
Abstract
This study examined the ability of social, demographic, environmental and health-related factors to explain geographic variability in preterm delivery among black and white women in the US and whether these factors explain black-white disparities in preterm delivery.We examined county-level prevalence of preterm delivery (20-31 or 32-36 weeks gestation) among singletons born 1998-2002. We conducted multivariable linear regression analysis to estimate the association of selected variables with preterm delivery separately for each preterm/race-ethnicity group.The prevalence of preterm delivery varied two- to three-fold across U.S. counties, and the distributions were strikingly distinct for blacks and whites. Among births to blacks, regression models explained 46% of the variability in county-level risk of delivery at 20-31 weeks and 55% for delivery at 32-36 weeks (based on R-squared values). Respective percentages for whites were 67% and 71%. Models included socio-environmental/demographic and health-related variables and explained similar amounts of variability overall.Much of the geographic variability in preterm delivery in the US can be explained by socioeconomic, demographic and health-related characteristics of the population, but less so for blacks than whites.
View details for DOI 10.1371/journal.pone.0094153
View details for PubMedID 24740117
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Hypospadias and variants in genes related to sex hormone biosynthesis and metabolism
ANDROLOGY
2014; 2 (1): 130-137
Abstract
We examined whether variants in genes related to sex hormone biosynthesis and metabolism were associated with hypospadias in humans. We examined 332 relatively common tag single-nucleotide polymorphisms (tagSNPs) in 20 genes. Analyses included 633 cases (84 mild, 322 moderate, 212 severe and 15 undetermined severity) and 855 population-based non-malformed male controls born in California from 1990 to 2003. We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for each SNP. Several of the 332 studied SNPs had p < 0.01: one in CYP3A4, four in HSD17B3, one in HSD3B1, two in STARD3, 10 in SRD5A2 and seven in STS. In addition, haplotype analyses gave several associations with p < 0.01. For HSD17B3, 14-SNP and 5-SNP blocks had ORs of 1.5 (95% CI 1.1, 2.0, p < 0.001) and 2.8 (95% CI 1.6, 4.8, p < 0.001) respectively. For SRD5A2, 9-SNP, 3-SNP and 8-SNP blocks had ORs of 1.7 (95% CI 1.3, 2.2, p < 0.001), 1.4 (95% CI 1.1, 1.8, p = 0.008) and 1.5 (95% CI 1.2, 1.9, p = 0.002) respectively. Our study indicates that several genes that contribute to sex hormone biosynthesis and metabolism are associated with hypospadias risk.
View details for DOI 10.1111/j.2047-2927.2013.00165.x
View details for Web of Science ID 000328729900019
View details for PubMedID 24281767
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Maternal-fetal metabolic gene-gene interactions and risk of neural tube defects
MOLECULAR GENETICS AND METABOLISM
2014; 111 (1): 46-51
Abstract
Single-gene analyses indicate that maternal genes associated with metabolic conditions (e.g., obesity) may influence the risk of neural tube defects (NTDs). However, to our knowledge, there have been no assessments of maternal-fetal metabolic gene-gene interactions and NTDs. We investigated 23 single nucleotide polymorphisms among 7 maternal metabolic genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, and TCF7L2) and 2 fetal metabolic genes (SLC2A2 and UCP2). Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study for birth years 1999-2007. We used a 2-step approach to evaluate maternal-fetal gene-gene interactions. First, a case-only approach was applied to screen all potential maternal and fetal interactions (n = 76), as this design provides greater power in the assessment of gene-gene interactions compared to other approaches. Specifically, ordinal logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each maternal-fetal gene-gene interaction, assuming a log-additive model of inheritance. Due to the number of comparisons, we calculated a corrected p-value (q-value) using the false discovery rate. Second, we confirmed all statistically significant interactions (q < 0.05) using a log-linear approach among case-parent triads. In step 1, there were 5 maternal-fetal gene-gene interactions with q < 0.05. The "top hit" was an interaction between maternal ENPP1 rs1044498 and fetal SLC2A2 rs6785233 (interaction OR = 3.65, 95% CI: 2.32-5.74, p = 2.09×10(-8), q=0.001), which was confirmed in step 2 (p = 0.00004). Our findings suggest that maternal metabolic genes associated with hyperglycemia and insulin resistance and fetal metabolic genes involved in glucose homeostasis may interact to increase the risk of NTDs.
View details for DOI 10.1016/j.ymgme.2013.11.004
View details for Web of Science ID 000330158100007
View details for PubMedID 24332798
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Could genetic polymorphisms related to oxidative stress modulate effects of heavy metals for risk of human preterm birth?
Reproductive toxicology
2013; 42: 24-26
Abstract
Human preterm birth (PTB) is a complex medical outcome influenced by a combination of genetic and environmental factors. Research on the causative factors of PTB has mostly focused on demographic, socio-behavioral and environmental risk factors. Recent studies turn the spotlight on the effects of heavy metals exposure on adverse pregnancy outcomes. Here we present and evaluate the hypothesis that heavy metals may cause PTB through oxidative stress, and that this effect may be modified by polymorphisms in genes related to oxidative stress. Indeed, accumulating data suggest that the risk of PTB is correlated with polymorphisms in genes involved in detoxification, oxidative stress and lipid metabolism. These and other polymorphisms have independently been associated with susceptibility to the adverse effects of heavy metals.
View details for DOI 10.1016/j.reprotox.2013.06.072
View details for PubMedID 23811355
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Hypospadias and Genes Related to Genital Tubercle and Early Urethral Development
JOURNAL OF UROLOGY
2013; 190 (5): 1884-1892
Abstract
PURPOSE: We determined whether variants in genes associated with genital tubercle (the anlage for the penis) and early urethral development were associated with hypospadias in humans. MATERIALS AND METHODS: We examined 293 relatively common tagSNPs in BMP4, BMP7, FGF8, FGF10, FGFR2, HOXA13, HOXD13, HOXA4, HOXB6, SRY, WT1, WTAP, SHH, GLI1, GLI2, and GLI3. The analysis included 624 cases (81 mild, 319 moderate, 209 severe, 15 undetermined severity) and 844 population-based non-malformed male controls born in California from 1990-2003. RESULTS: There were 28 SNPs for which any of the comparisons (i.e., overall or for a specific severity) had a p-value <0.01. The homozygous variant genotypes for four SNPs in BMP7were associated with at least 2-fold increased risk of hypospadias, regardless of severity. Five SNPs for FGF10were associated with 3- to 4-fold increased risks, regardless of severity; for four of them, results were restricted to whites. For GLI1, GLI2and GLI3, there were 12 associated SNPs but results were inconsistent by severity and race-ethnicity. For SHH, one SNP was associated with 2.4-fold increased risk of moderate hypospadias. For WT1, six SNPs were associated with approximately 2-fold increased risks, primarily for severe hypospadias. CONCLUSIONS: This study provides evidence that SNPs in several genes that contribute to genital tubercle and early urethral development are associated with hypospadias risk.
View details for DOI 10.1016/j.juro.2013.05.061
View details for Web of Science ID 000325471400089
View details for PubMedID 23727413
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Hypospadias and residential proximity to pesticide applications.
Pediatrics
2013; 132 (5): e1216-26
Abstract
Experimental evidence suggests pesticides may be associated with hypospadias.Examine the association of hypospadias with residential proximity to commercial agricultural pesticide applications.The study population included male infants born from 1991 to 2004 to mothers residing in 8 California counties. Cases (n = 690) were ascertained by the California Birth Defects Monitoring Program; controls were selected randomly from the birth population (n = 2195). We determined early pregnancy exposure to pesticide applications within a 500-m radius of mother's residential address, using detailed data on applications and land use. Associations with exposures to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for maternal race or ethnicity and age and infant birth year.Forty-one percent of cases and controls were classified as exposed to 57 chemical groups and 292 chemicals. Despite >500 statistical comparisons, there were few elevated odds ratios with confidence intervals that excluded 1 for chemical groups or specific chemicals. Those that did were for monochlorophenoxy acid or ester herbicides; the insecticides aldicarb, dimethoate, phorate, and petroleum oils; and adjuvant polyoxyethylene sorbitol among all cases; 2,6-dinitroaniline herbicides, the herbicide oxyfluorfen, and the fungicide copper sulfate among mild cases; and chloroacetanilide herbicides, polyalkyloxy compounds used as adjuvants, the insecticides aldicarb and acephate, and the adjuvant nonyl-phenoxy-poly(ethylene oxy)ethanol among moderate and severe cases. Odds ratios ranged from 1.9 to 2.9.Most pesticides were not associated with elevated hypospadias risk. For the few that were associated, results should be interpreted with caution until replicated in other study populations.
View details for DOI 10.1542/peds.2013-1429
View details for PubMedID 24167181
View details for PubMedCentralID PMC3813401
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Hypospadias and residential proximity to pesticide applications.
Pediatrics
2013; 132 (5): e1216-26
Abstract
Experimental evidence suggests pesticides may be associated with hypospadias.Examine the association of hypospadias with residential proximity to commercial agricultural pesticide applications.The study population included male infants born from 1991 to 2004 to mothers residing in 8 California counties. Cases (n = 690) were ascertained by the California Birth Defects Monitoring Program; controls were selected randomly from the birth population (n = 2195). We determined early pregnancy exposure to pesticide applications within a 500-m radius of mother's residential address, using detailed data on applications and land use. Associations with exposures to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for maternal race or ethnicity and age and infant birth year.Forty-one percent of cases and controls were classified as exposed to 57 chemical groups and 292 chemicals. Despite >500 statistical comparisons, there were few elevated odds ratios with confidence intervals that excluded 1 for chemical groups or specific chemicals. Those that did were for monochlorophenoxy acid or ester herbicides; the insecticides aldicarb, dimethoate, phorate, and petroleum oils; and adjuvant polyoxyethylene sorbitol among all cases; 2,6-dinitroaniline herbicides, the herbicide oxyfluorfen, and the fungicide copper sulfate among mild cases; and chloroacetanilide herbicides, polyalkyloxy compounds used as adjuvants, the insecticides aldicarb and acephate, and the adjuvant nonyl-phenoxy-poly(ethylene oxy)ethanol among moderate and severe cases. Odds ratios ranged from 1.9 to 2.9.Most pesticides were not associated with elevated hypospadias risk. For the few that were associated, results should be interpreted with caution until replicated in other study populations.
View details for DOI 10.1542/peds.2013-1429
View details for PubMedID 24167181
View details for PubMedCentralID PMC3813401
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Traffic-related air pollution and selected birth defects in the San Joaquin Valley of California.
Birth defects research. Part A, Clinical and molecular teratology
2013; 97 (11): 730-735
Abstract
Birth defects are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some structural anomalies, although evidence is limited and several anomalies have not been investigated previously.We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 26 congenital birth defect phenotypes with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997 to 2006 (874 cases and 849 controls). We calculated odds ratios (adjusted for maternal race/ethnicity, education, and vitamin use; aOR) for 11 phenotypes that had at least 40 cases.Few odds ratios had confidence intervals that did not include 1.0. Odds of esophageal atresia were increased for the highest versus lowest of traffic density (aOR = 2.8, 95% confidence interval [CI], 1.1-7.4) and PM10 exposure (aOR 4.9; 95% CI, 1.4-17.2). PM10 was associated with a decreased risk of hydrocephaly (aOR= 0.3; 95% CI, 0.1-0.9) and CO with decreased risk of anotia/microtia (aOR = 0.4; 95% CI, 0.2-0.8) and transverse limb deficiency (aOR = 0.4; 95% CI, 0.2-0.9), again reflecting highest versus lowest quartile comparisons.Most analyses showed no substantive association between air pollution and the selected birth defects with few exceptions of mixed results. Birth Defects Research (Part A) 97:730-735, 2013. © 2013 Wiley Periodicals, Inc.
View details for DOI 10.1002/bdra.23175
View details for PubMedID 24108522
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Periconceptional nutrient intakes and risks of orofacial clefts in California.
Pediatric research
2013; 74 (4): 457-465
Abstract
Background:Evidence indicates that maternal nutrient intake may play a role in the development of birth defects. We investigated the association of maternal periconceptional intake of vitamin supplements and dietary nutrients with risk of developing cleft palate (CP) and cleft lip with or without cleft palate (CLP).Methods:Data were from a population-based, case-control study of fetuses and liveborn infants delivered in California,1999-2003. Analyses included 170 cases with CP, 425 with CLP, and 534 nonmalformed controls. Dietary intake was estimated from a food frequency questionnaire.Results:Vitamin supplement intake was associated with a modestly decreased risk of clefts, but the confidence intervals include one. Among women who did not use vitamin supplements, dietary intake of several micronutrients was associated with risk of clefts. We found at least a two-fold elevated risk of CP with low intake of riboflavin, magnesium, calcium, vitamin B12, and zinc; all CIs excluded 1.0. For CLP, we found at least a two-fold elevated risk with low intake of niacin, riboflavin, vitamin B12, and calcium, and a decreased risk with high intake of folate and cryptoxanthin; all CIs excluded 1.0.Conclusion:Results suggest that periconceptional nutrient intake may be associated with risk of CP and CLP.Pediatric Research (2013); doi:10.1038/pr.2013.115.
View details for DOI 10.1038/pr.2013.115
View details for PubMedID 23823175
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A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia.
Pediatrics
2013; 132 (2): 290-297
Abstract
Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD.The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip.Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative.We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.
View details for DOI 10.1542/peds.2013-0533
View details for PubMedID 23897914
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Hypospadias and Maternal Intake of Phytoestrogens
AMERICAN JOURNAL OF EPIDEMIOLOGY
2013; 178 (3): 434-440
Abstract
Experimental data indicate that gestational exposures to estrogenic compounds impact risk of hypospadias. We examined whether risk of hypospadias (i.e., a congenital malformation in which the opening of the penile urethra occurs on the ventral side of the penis) was associated with maternal intake of phytoestrogens, given their potential impact on estrogen metabolism. The analysis included data on mothers of 1,250 hypospadias cases and 3,118 controls who delivered their infants from 1997 to 2005 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. After adjustment for several covariates, high intakes of daidzein, genistein, glycetin, secoisolariciresinol, total isoflavones, total lignans, and total phytoestrogens were associated with reduced risks; odds ratios comparing intakes ≥90th percentile with intakes between the 11th and 89th percentiles ranged from 0.6 to 0.8. For example, the odds ratio for total phytoestrogen intake was 0.7 (95% confidence interval: 0.5, 1.0). This study represents the first large-scale analysis of phytoestrogen intake and hypospadias. The observed associations merit investigation in additional populations before firm conclusions can be reached.
View details for DOI 10.1093/aje/kws591
View details for Web of Science ID 000322734500012
View details for PubMedID 23752918
View details for PubMedCentralID PMC3727340
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Maternal Dietary Nutrient Intake and Risk of Preterm Delivery
AMERICAN JOURNAL OF PERINATOLOGY
2013; 30 (7): 579-588
Abstract
Objective To examine maternal dietary intake and preterm delivery.Study Design Data included 5738 deliveries from the National Birth Defects Prevention Study. Odds ratios (ORs) reflected risks of delivery at <32, 32-34, or 35-36 versus ≥37 weeks for maternal intake in the lowest or highest quartile of nutrient intake compared with the middle two.Results Among deliveries < 32 weeks, many ORs were ≥1.5 or ≤0.7, but few confidence intervals excluded one. ORs were ≥1.5 for lowest quartiles of protein, thiamin, riboflavin, choline, vitamin A, α-carotene, β-carotene, vitamin E, iron, copper, and zinc and for highest quartiles of carbohydrate, glycemic index, and Mediterranean Diet Score. ORs were ≤0.7 for lowest quartiles of glycemic index and betaine and for highest quartiles of protein, alanine, methionine, vitamin B6, betaine, and calcium. Few ORs met these criteria for later preterm deliveries.Conclusions Results suggested an association of nutrient intake with earlier preterm deliveries.
View details for DOI 10.1055/s-0032-1329686
View details for Web of Science ID 000322021900009
View details for PubMedID 23208764
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Mutations in Planar Cell Polarity Gene SCRIB Are Associated with Spina Bifida
PLOS ONE
2013; 8 (7)
Abstract
Neural tube defects (NTDs) (OMIM #182940) including anencephaly, spina bifida and craniorachischisis, are severe congenital malformations that affect 0.5-1 in 1,000 live births in the United States, with varying prevalence around the world. Mutations in planar cell polarity (PCP) genes are believed to cause a variety of NTDs in both mice and humans. SCRIB is a PCP-associated gene. Mice that are homozygous for the Scrib p.I285K and circletail (Crc) mutations, present with the most severe form of NTDs, namely craniorachischisis. A recent study reported that mutations in SCRIB were associated with craniorachischisis in humans, but whether SCRIB mutations contribute to increased spina bifida risk is still unknown. We sequenced the SCRIB gene in 192 infants with spina bifida and 190 healthy controls. Among the spina bifida patients, we identified five novel missense mutations that were predicted-to-be-deleterious by the PolyPhen software. Of these five mutations, three of them (p.P1043L, p.P1332L, p.L1520R) significantly affected the subcellular localization of SCRIB. In addition, we demonstrated that the craniorachischisis mouse line-90 mutation I285K, also affected SCRIB subcellular localization. In contrast, only one novel missense mutation (p.A1257T) was detected in control samples, and it was predicted to be benign. This study demonstrated that rare deleterious mutations of SCRIB may contribute to the multifactorial risk for human spina bifida.
View details for DOI 10.1371/journal.pone.0069262
View details for Web of Science ID 000322838900029
View details for PubMedID 23922697
View details for PubMedCentralID PMC3724847
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Ambient air pollution and traffic exposures and congenital heart defects in the san joaquin valley of california.
Paediatric and perinatal epidemiology
2013; 27 (4): 329-339
Abstract
Congenital anomalies are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited.We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 27 congenital heart defects with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997-2006 (n = 822 cases and n = 849 controls).Particulate matter < 10 microns (PM10 ) was associated with pulmonary valve stenosis [adjusted odds ratio (aOR)Fourth Quartile = 2.6] [95% confidence intervals (CI) 1.2, 5.7] and perimembranous ventricular septal defects (aORThird Quartile = 2.1) [95% CI 1.1, 3.9] after adjusting for maternal race/ethnicity, education and multivitamin use. PM2.5 was associated with transposition of the great arteries (aORThird Quartile = 2.6) [95% CI 1.1, 6.5] and inversely associated with perimembranous ventricular septal defects (aORFourth Quartile = 0.5) [95% CI 0.2, 0.9]. Secundum atrial septal defects were inversely associated with carbon monoxide (aORFourth Quartile = 0.4) [95% CI 0.2, 0.8] and PM2.5 (aORFourth Quartile = 0.5) [95% CI 0.3, 0.8]. Traffic density was associated with muscular ventricular septal defects (aORFourth Quartile = 3.0) [95% CI 1.2, 7.8] and perimembranous ventricular septal defects (aORThird Quartile = 2.4) [95% CI 1.3, 4.6], and inversely associated with transposition of the great arteries (aORFourth Quartile = 0.3) [95% CI 0.1, 0.8].PM10 and traffic density may contribute to the occurrence of pulmonary valve stenosis and ventricular septal defects, respectively. The results were mixed for other pollutants and had little consistency with previous studies.
View details for DOI 10.1111/ppe.12055
View details for PubMedID 23772934
View details for PubMedCentralID PMC3694598
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A Pilot Study Using Residual Newborn Dried Blood Spots to Assess the Potential Role of Cytomegalovirus and Toxoplasma gondii in the Etiology of Congenital Hydrocephalus
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2013; 97 (7): 431-436
Abstract
Congenital hydrocephalus is a condition characterized by accumulation of cerebrospinal fluid in the ventricles of the brain. Prenatal infections are risk factors for some birth defects. This pilot study investigated whether residual dried blood spots (DBS) could be used to assess infections as risk factors for birth defects by examining the associations between prenatal infection with Toxoplasma gondii (T. gondii) or cytomegalovirus (CMV) with congenital hydrocephalus.Case-infants with hydrocephalus (N=410) were identified among live-born infants using birth defects surveillance systems in California, North Carolina, and Texas. Control-infants without birth defects were randomly selected from the same geographic areas and time periods as case-infants (N=448). We tested residual DBS from case- and control-infants for T. gondii immunoglobulin M and CMV DNA. When possible, we calculated crude odds ratios (cORs) and confidence intervals (CIs).Evidence for prenatal T. gondii infection was more common among case-infants (1.2%) than control-infants (0%; p=0.11), and evidence for prenatal CMV infection was higher among case-infants (1.5%) than control-infants (0.7%; cOR: 2.3; 95% CI: 0.48, 13.99).Prenatal infections with T. gondii and CMV occurred more often among infants with congenital hydrocephalus than control-infants, although differences were not statistically significant. This pilot study highlighted some challenges in using DBS to examine associations between certain infections and birth defects, particularly related to reduced sensitivity and specimen storage conditions. Further study with increased numbers of specimens and higher quality specimens should be considered to understand better the contribution of these infections to the occurrence of congenital hydrocephalus.
View details for DOI 10.1002/bdra.23138
View details for Web of Science ID 000326397800001
View details for PubMedID 23716471
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Association of early-preterm birth with abnormal levels of routinely collected first- and second-trimester biomarkers
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
2013; 208 (6)
Abstract
The purpose of this study was to examine the relationship between typically measured prenatal screening biomarkers and early-preterm birth in euploid pregnancies.The study included 345 early-preterm cases (<30 weeks of gestation) and 1725 control subjects who were drawn from a population-based sample of California pregnancies who had both first- and second-trimester screening results. Logistic regression analyses were used to compare patterns of biomarkers in cases and control subjects and to develop predictive models. Replicability of the biomarker early-preterm relationships that was revealed by the models was evaluated by examination of the frequency and associated adjusted relative risks (RRs) for early-preterm birth and for preterm birth in general (<37 weeks of gestation) in pregnancies with identified abnormal markers compared with pregnancies without these markers in a subsequent independent California cohort of screened pregnancies (n = 76,588).The final model for early-preterm birth included first-trimester pregnancy-associated plasma protein A in the ≤5th percentile, second-trimester alpha-fetoprotein in the ≥95th percentile, and second-trimester inhibin in the ≥95th percentile (odds ratios, 2.3-3.6). In general, pregnancies in the subsequent cohort with a biomarker pattern that were found to be associated with early-preterm delivery in the first sample were at an increased risk for early-preterm birth and preterm birth in general (<37 weeks of gestation; adjusted RR, 1.6-27.4). Pregnancies with ≥2 biomarker abnormalities were at particularly increased risk (adjusted RR, 3.6-27.4).When considered across cohorts and in combination, abnormalities in routinely collected biomarkers reveal predictable risks for early-preterm birth.
View details for DOI 10.1016/j.ajog.2013.02.012
View details for Web of Science ID 000320596600029
View details for PubMedID 23395922
View details for PubMedCentralID PMC3672244
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The Association of Ambient Air Pollution and Traffic Exposures With Selected Congenital Anomalies in the San Joaquin Valley of California
AMERICAN JOURNAL OF EPIDEMIOLOGY
2013; 177 (10): 1074-1085
Abstract
Congenital anomalies are a leading cause of infant mortality and are important contributors to subsequent morbidity. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. We aimed to investigate whether ambient air pollutant and traffic exposures in early gestation contribute to the risk of selected congenital anomalies in the San Joaquin Valley of California, 1997-2006. Seven exposures and 5 outcomes were included for a total of 35 investigated associations. We observed increased odds of neural tube defects when comparing the highest with the lowest quartile of exposure for several pollutants after adjusting for maternal race/ethnicity, education, and multivitamin use. The adjusted odds ratio for neural tube defects among those with the highest carbon monoxide exposure was 1.9 (95% confidence interval: 1.1, 3.2) compared with those with the lowest exposure, and there was a monotonic exposure-response across quartiles. The highest quartile of nitrogen oxide exposure was associated with neural tube defects (adjusted odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). The adjusted odds ratio for the highest quartile of nitrogen dioxide exposure was 1.7 (95% confidence interval: 1.1, 2.7). Ozone was associated with decreased odds of neural tube defects. Our results extend the limited body of evidence regarding air pollution exposure and adverse birth outcomes.
View details for DOI 10.1093/aje/kws367
View details for Web of Science ID 000318801200006
View details for PubMedID 23538941
View details for PubMedCentralID PMC3697063
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Maternal occupational exposure to polycyclic aromatic hydrocarbons and risk of oral cleft-affected pregnancies.
Cleft palate-craniofacial journal
2013; 50 (3): 337-346
Abstract
Objective : To evaluate whether there is an association between maternal occupational exposure to polycyclic aromatic hydrocarbons and oral clefts in offspring. This is the first human study of polycyclic aromatic hydrocarbons and clefts of which the authors are aware. Design : Case-control study. Setting, Participants : Data for 1997 to 2002 from the National Birth Defects Prevention Study, a large population-based case-control study in the United States, were analyzed. Maternal telephone interviews yielded information on jobs held in the month before through 3 months after conception. Two industrial hygienists independently assessed occupational exposure to polycyclic aromatic hydrocarbons; all jobs rated as exposed or with rating difficulty were reviewed with a third industrial hygienist to reach consensus on all exposure parameters. Logistic regression estimated crude and adjusted odds ratios with 95% confidence intervals for cleft lip with or without cleft palate and cleft palate alone. Results : There were 2989 controls (3.5% exposed), 805 cases of cleft lip with or without cleft palate (5.8% exposed), and 439 cases of cleft palate alone (4.6% exposed). The odds of maternal occupational exposure to polycyclic aromatic hydrocarbons (any versus none) during pregnancy was increased for cleft lip with or without cleft palate cases as compared with controls (odds ratio, 1.69; 95% confidence interval, 1.18 to 2.40); the odds ratio was 1.47 (95% confidence interval 1.02 to 2.12) when adjusted for maternal education. There was a statistically significant adjusted exposure-response relationship for cleft lip with or without cleft palate (Ptrend = .02). Odd ratios for cleft palate alone were not statistically significant. Conclusions : Maternal occupational exposure to polycyclic aromatic hydrocarbons was associated with increased risk of cleft lip with or without cleft palate in offspring.
View details for DOI 10.1597/12-104
View details for PubMedID 23136939
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Transdisciplinary translational science and the case of preterm birth
JOURNAL OF PERINATOLOGY
2013; 33 (4): 251-258
Abstract
Medical researchers have called for new forms of translational science that can solve complex medical problems. Mainstream science has made complementary calls for heterogeneous teams of collaborators who conduct transdisciplinary research so as to solve complex social problems. Is transdisciplinary translational science what the medical community needs? What challenges must the medical community overcome to successfully implement this new form of translational science? This article makes several contributions. First, it clarifies the concept of transdisciplinary research and distinguishes it from other forms of collaboration. Second, it presents an example of a complex medical problem and a concrete effort to solve it through transdisciplinary collaboration: for example, the problem of preterm birth and the March of Dimes effort to form a transdisciplinary research center that synthesizes knowledge on it. The presentation of this example grounds discussion on new medical research models and reveals potential means by which they can be judged and evaluated. Third, this article identifies the challenges to forming transdisciplines and the practices that overcome them. Departments, universities and disciplines tend to form intellectual silos and adopt reductionist approaches. Forming a more integrated (or 'constructionist'), problem-based science reflective of transdisciplinary research requires the adoption of novel practices to overcome these obstacles.
View details for DOI 10.1038/jp.2012.133
View details for PubMedID 23079774
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Progress in understanding the genetics of bronchopulmonary dysplasia
SEMINARS IN PERINATOLOGY
2013; 37 (2): 85-93
Abstract
Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in infants. Its treatment imposes considerable healthcare burden and costs in the perinatal and early childhood period and patients are usually left with lifelong deficits in lung function. Evidence exists for different pathophysiologic pathways that can promote the structural changes that characterize BPD, including the impairment in alveolarization; however, there is increasing interest regarding heritable factors that may predispose very low birth weight infants to BPD. Our review focuses on recent publications that have investigated genetic factors that may potentially contribute to such reported heritability. These publications point us toward some possible genomic candidates for further study, but certainly do not identify any particular gene or gene pathway that would be inferred to be contributing substantially to the underlying etiology of BPD.
View details for DOI 10.1053/j.semperi.2013.01.004
View details for Web of Science ID 000317870800005
View details for PubMedID 23582962
View details for PubMedCentralID PMC3628629
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Considering the vascular hypothesis for the pathogenesis of small intestinal atresia: A case control study of genetic factors
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2013; 161A (4): 702-710
Abstract
Small intestinal atresia (SIA) is a rare congenital occlusion of the small intestine. SIA development, particularly in the jejunum and ileum, has been associated with in utero disruption of vascular supply. However, the number of studies of the vascular hypothesis is limited. This study considers the vascular hypothesis by exploring risks associated with 32 SNPs of genes involved in vascular processes of homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. A total of 206 SIA cases were ascertained by the California Birth Defects Monitoring Program, and 573 infants with no major congenital anomalies by their first birthday were selected as controls. Genomic DNA was genotyped for 32 SNPs involving the following genes: MTHFR, F2, F5, F7, SERPINE1, FGB, ITGA2, ITGB3, SELE, ICAM1, MMP3, TNF, LTA, NOS3, AGTR1, AGT, NPPA, ADD1, SCNN1A, GNB3, and ADRB2. Risks were estimated as odds ratios, adjusted for maternal age and race, with 95% confidence intervals. Cases were considered collectively and by subgroups based on atresia location (duodenal/jejunum/ileum). Three SNPs had reduced risk: SERPINE1 11053 T/G, MMP3 (-1171) A6/A5, and ADRB2 gln27glu. Two had increased risk: ITGA2 873 G/A and NPPA 2238 T/C. No intestinal subphenotypes showed a unique pattern of SNP associations. The association of two SNPs with increased risk lends some, albeit limited, support to vascular impairment as a possible mechanism leading to SIA. These results also identify genes meriting further exploration in SIA studies. Hence, this study makes an important contribution by exploring the long-held but not well-investigated vascular hypothesis.
View details for DOI 10.1002/ajmg.a.35775
View details for Web of Science ID 000316631300012
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The Continuing Challenge of Understanding, Preventing, and Treating Neural Tube Defects
SCIENCE
2013; 339 (6123)
Abstract
Human birth defects are a major public health burden: The Center for Disease Control estimates that 1 of every 33 United States newborns presents with a birth defect, and worldwide the estimate approaches 6% of all births. Among the most common and debilitating of human birth defects are those affecting the formation of the neural tube, the precursor to the central nervous system. Neural tube defects (NTDs) arise from a complex combination of genetic and environmental interactions. Although substantial advances have been made in the prevention and treatment of these malformations, NTDs remain a substantial public health problem, and we are only now beginning to understand their etiology. Here, we review the process of neural tube development and how defects in this process lead to NTDs, both in humans and in the animal models that serve to inform our understanding of these processes. The insights we are gaining will help generate new intervention strategies to tackle the clinical challenges and to alleviate the personal and societal burdens that accompany these defects.
View details for DOI 10.1126/science.1222002
View details for Web of Science ID 000315452000032
View details for PubMedID 23449594
View details for PubMedCentralID PMC3677196
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An Innovative Approach to Recruitment and Biospecimen Collection: A Study of Spina Bifida Genetics
SAGE PUBLICATIONS INC. 2013: 207A
View details for Web of Science ID 000329543100491
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Thymidylate synthase polymorphisms and risks of human orofacial clefts
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2013; 97 (2): 95-100
Abstract
Underlying mechanisms are unknown by which folic acid use in early pregnancy may reduce risks of orofacial clefts. Thymidylate synthase (TYMS) is a folate-dependent enzyme that catalyzes reductive methylation of deoxyuridylate to thymidylate, thereby playing a central role in DNA synthesis and repair. We investigated two TYMS functional variants (a 28-bp tandem repeat in the promoter enhancer region of the 5'-UTR; and TYMS 1494del6 (rs16430): a 6-bp deletion in the 3'-UTR) for their risk of cleft palate (CP) and of cleft lip with/without CP (CLP). We investigated effect measure modification between these variants and maternal folate intake for cleft risk.This case-control study included deliveries from July 1999 to June 2003 from select areas of California. Case groups included CLP or CP alone. Nonmalformed, liveborn controls were randomly selected. Maternal interviews provided information on vitamin use and dietary folate intake. DNA was derived from newborn bloodspots.Data were available for 304 CLP cases, 123 CP cases, and 581 controls. 1496del6 variants did not appear to influence risk of CP or CLP. Homozygosity for the 28-bp VNTR variant influenced CP risk (odds ratios, OR = 1.8, 95% confidence interval, 1.1-3.1), particularly among Hispanic infants, OR 2.1 (1.0-4.6). Effect measure modification was observed between the 28-bp VNTR and combined folate intake for CP with an OR of 10.0 (1.6-60.9).Although these findings are consistent with biological mechanisms, they were based on relatively small sample sizes and may represent false-positive discoveries. Replication is warranted in other populations.
View details for DOI 10.1002/bdra.23114
View details for Web of Science ID 000314982400004
View details for PubMedID 23404871
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High quality genome-wide genotyping from archived dried blood spots without DNA amplification.
PloS one
2013; 8 (5)
Abstract
Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA.
View details for DOI 10.1371/journal.pone.0064710
View details for PubMedID 23737996
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Thoughts on the Future of Reproductive and Perinatal Epidemiology
PAEDIATRIC AND PERINATAL EPIDEMIOLOGY
2013; 27 (1): 11-19
View details for DOI 10.1111/ppe.12017
View details for Web of Science ID 000312142900004
View details for PubMedID 23215705
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Diacylglycerol Kinase K Variants Impact Hypospadias in a California Study Population
JOURNAL OF UROLOGY
2013; 189 (1): 305-311
Abstract
A recent genome wide association study demonstrated the novel finding that variants in DGKK are associated with hypospadias. Our objectives were to determine whether this finding could be replicated in a more racially/ethnically diverse study population of California births and to provide a more comprehensive investigation of variants.We examined the association of 27 DGKK single nucleotide polymorphisms with hypospadias relative to population based nonmalformed controls born in selected California counties from 1990 to 2003. Analyses included a maximum of 928 controls and 665 cases (mild in 91, moderate in 336, severe in 221 and undetermined in 17). Results for mild and moderate cases were similar, so they were grouped together.For mild and moderate cases OR for 15 of the 27 single nucleotide polymorphisms had p values less than 0.05, with 2 less than 1 and the others ranging from 1.3 to 1.8. Among severe cases ORs tended to be closer to 1, and none of the p values were less than 0.05. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and 2 blocks were generated. These analyses identified a set of 8 variants associated with a threefold to fourfold increased risk relative to the most common haplotype, regardless of severity of the phenotype (OR 4.1, p <10(-4) for mild to moderate cases and 3.3, p = 0.001 for severe cases).This study confirms that DGKK variants are associated with hypospadias. Additional studies are needed to allow a more thorough investigation of DGKK variability and to delineate the mechanism by which DGKK contributes to urethral development.
View details for DOI 10.1016/j.juro.2012.09.002
View details for Web of Science ID 000312604800107
View details for PubMedID 23177175
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High Quality Genome-Wide Genotyping from Archived Dried Blood Spots without DNA Amplification.
PloS one
2013; 8 (5): e64710
Abstract
Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA.
View details for DOI 10.1371/journal.pone.0064710
View details for PubMedID 23737996
View details for PubMedCentralID PMC3667813
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Diabetes and Obesity-Related Genes and the Risk of Neural Tube Defects in the National Birth Defects Prevention Study
AMERICAN JOURNAL OF EPIDEMIOLOGY
2012; 176 (12): 1101-1109
Abstract
Few studies have evaluated genetic susceptibility related to diabetes and obesity as a risk factor for neural tube defects (NTDs). The authors investigated 23 single nucleotide polymorphisms among 9 genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, SLC2A2, TCF7L2, and UCP2) associated with type 2 diabetes or obesity. Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study during 1999-2007. Log-linear models were used to evaluate maternal and offspring genetic effects. After application of the false discovery rate, there were 5 significant maternal genetic effects. The less common alleles at the 4 FTO single nucleotide polymorphisms showed a reduction of NTD risk (for rs1421085, relative risk (RR) = 0.73 (95% confidence interval (CI): 0.62, 0.87); for rs8050136, RR = 0.79 (95% CI: 0.67, 0.93); for rs9939609, RR = 0.79 (95% CI: 0.67, 0.94); and for rs17187449, RR = 0.80 (95% CI: 0.68, 0.95)). Additionally, maternal LEP rs2071045 (RR = 1.31, 95% CI: 1.08, 1.60) and offspring UCP2 rs660339 (RR = 1.32, 95% CI: 1.06, 1.64) were associated with NTD risk. Furthermore, the maternal genotype for TCF7L2 rs3814573 suggested an increased NTD risk among obese women. These findings indicate that maternal genetic variants associated with glucose homeostasis may modify the risk of having an NTD-affected pregnancy.
View details for DOI 10.1093/aje/kws190
View details for Web of Science ID 000312634900006
View details for PubMedID 23132673
View details for PubMedCentralID PMC3571234
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Dietary Glycemic Index and the Risk of Birth Defects
AMERICAN JOURNAL OF EPIDEMIOLOGY
2012; 176 (12): 1110-1120
Abstract
Prepregnancy diabetes and obesity have been identified as independent risk factors for several birth defects, providing support for a mechanism that involves hyperglycemia and hyperinsulinemia in the development of malformations. Data from the National Birth Defects Prevention Study from 1997 to 2007 were used to investigate the association between the maternal dietary glycemic index (DGI) and the risk of birth defects among nondiabetic women. DGI was categorized by using spline regression models and quartile distributions. Adjusted odds ratios and 95% confidence intervals were calculated. The joint effect of DGI and obesity was also examined. Among the 53 birth defects analyzed, high DGI, categorized by spline regression, was significantly associated with encephalocele (adjusted odds ratio (aOR) = 2.68), diaphragmatic hernia (aOR = 2.58), small intestinal atresia/stenosis (aOR = 2.97) including duodenal atresia/stenosis (aOR = 2.48), and atrial septal defect (aOR = 1.37). Using quartiles to categorize DGI, the authors identified associations with cleft lip with cleft palate (aOR = 1.23) and anorectal atresia/stenosis (aOR = 1.40). The joint effect of high DGI and obesity provided evidence of a synergistic effect on the risk of selected birth defects. High DGI is associated with an increased risk of a number of birth defects under study. Obesity coupled with high DGI appears to increase the risk further for some birth defects.
View details for DOI 10.1093/aje/kws201
View details for Web of Science ID 000312634900007
View details for PubMedID 23171874