Bio


Dr. Carmichael is a perinatal and nutritional epidemiologist and Professor of Pediatrics and Obstetrics and Gynecology at the Stanford University School of Medicine. Her research focuses on finding ways to improve maternal and infant health. Exposure themes include nutrition, social context, care, environmental contaminants and genetics. Outcomes include severe maternal morbidity, stillbirth, birth defects, and preterm delivery. She is particularly interested in understanding the intersection of these varied types of exposures and outcomes and how they interact to impact health and health disparities, for the mother-baby dyad, in domestic as well as global health settings.

Administrative Appointments


  • Co-Director, Perinatal Epidemiology & Population Health, Dunlevie Maternal Fetal Medicine Center, Stanford (2022 - Present)
  • Adjunct Professor, Dept. of Epidemiology, Tulane Univ. School of Public Health & Tropical Medicine (2022 - Present)
  • Fellow, Center for Emerging Reproductive & Perinatal Epidemiology (CERPE), Tulane Univ. School of Public Health & Tropical Medicine (2022 - Present)
  • Faculty Senator, Stanford University (2020 - 2022)
  • Head, Department of Pediatrics Research and Statistical Unit (2012 - 2018)
  • Epidemic Intelligence Service Officer, CDC (1996 - 1998)

Honors & Awards


  • Fulbright Scholar Award, University of Bergen (2023)
  • Scholars in Service Award, Stanford Impact Labs and Haas Center for Public Service (2022-2023)
  • Post-Doc Mentor Award, Dept. of Pediatrics, Stanford Univ. School of Medicine (2020)
  • F. Clarke Fraser New Investigator Award, Teratology Society (2005)
  • Public Health Citation, Public Health Service, DHHS (1997)
  • Warren Winkelstein Epidemiology Award, U.C., Berkeley (1996)
  • Regents Fellowship and Kaiser Fellowship, U.C., Berkeley (1994-95)
  • A.J. Bryan Scholarship, Kaiser Fellowship, U.C., Berkeley (1993-94)
  • Lechner Fellowship, Texas A&M University (1984-88)

Boards, Advisory Committees, Professional Organizations


  • President-Elect, President, Past President, Society for Pediatric and Perinatal Epidemiologic Research (2014 - 2017)
  • Associate Editor, Annals of Epidemiology (2009 - 2022)
  • Faculty Fellow, Stanford Center for Population Health Sciences (2017 - Present)
  • Member, Science Advisory Board, Developmental and Reproductive Toxicant Identification Committee, OEHHA, State of California (2015 - Present)
  • Epidemiology Section Editor, Cleft Palate-Craniofacial Journal (2014 - 2017)
  • Member at Large, Society for Pediatric and Perinatal Epidemiologic Research (2007 - 2011)
  • Secretary, Society for Pediatric and Perinatal Epidemiologic Research (1998 - 2002)

Professional Education


  • PhD, U.C., Berkeley, Epidemiology (1996)
  • M.S., U.C., Davis, International Agricultural Development (1992)
  • B.S., Texas A&M University, Scientific Nutrition (1988)

Community and International Work


  • Peace Corps Volunteer, Honduras, 1992

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

Current Research and Scholarly Interests


Dr. Carmichael is a perinatal and nutritional epidemiologist and Professor of Pediatrics and Obstetrics and Gynecology at the Stanford University School of Medicine.

Her team is committed to finding ways to improve maternal and infant health outcomes and equity by leading research that identifies effective leverage points for change, from upstream 'macro' social and structural factors, to downstream clinical factors (eg, related to care and morbidities) through a collaborative research approach that integrates epidemiologic approaches with community engagement and systems thinking.

Exposure themes include social context, nutrition, care, environmental contaminants and genetics. Outcome themes include severe maternal morbidity, stillbirth, birth defects, and preterm delivery. She is particularly interested in understanding the intersectionality of these varied types of exposures and outcomes and how they interact to impact health and health disparities, for the mother-baby dyad.

Please see the team web-site for further information!
https://med.stanford.edu/carmichaellab.html

2024-25 Courses


Stanford Advisees


All Publications


  • Hypertensive Disorders in Pregnancy: Differences by Hispanic Ethnicity and Black Race. Journal of racial and ethnic health disparities Atkinson, J. A., Carmichael, S. L., Leonard, S. A. 2024

    Abstract

    Black individuals carry the greatest burden of maternal mortality, with hypertensive disorders during pregnancy being a significant driving force to this disparity. However, research on maternal health disparities predominantly groups Hispanic Black individuals with all other individuals of Hispanic ethnicity. We hypothesized that this aggregation might obscure the risk patterns of hypertensive disorders in pregnancy for Hispanic-Black and non-Hispanic Black individuals.We analyzed a California statewide dataset of vital records linked to hospitalization discharge data for births from 2007 to 2018. Using multivariable logistic regression models adjusted for age, pre-pregnancy BMI, parity, smoking status, diabetes, and chronic renal disease, we compared the odds of hypertensive disorders in pregnancy between Hispanic Black, non-Hispanic Black, and non-Black Hispanic racial-ethnic groups. Hypertensive disorders were categorized into two groups: (1) any hypertensive disorder and (2) chronic hypertension alone, non-severe hypertensive disorders, and severe hypertensive disorders in pregnancy.Non-Hispanic Black people had 75% increased odds of developing a hypertensive disorder during pregnancy (adjusted odds ratio (aOR); 95% confidence interval (CI): 1.74, 1.78) and Hispanic-Black individuals had a 31% increased odds (95% CI: 1.24, 1.38) as compared with non-Black Hispanic individuals. When considering hypertensive disorders separately, the race-associated differences were largest for chronic hypertension alone, with non-Hispanic Black individuals showing an aOR of 2.35 (95% CI: 2.32, 2.38) and Hispanic-Black individuals an aOR of 1.80 (95% CI: 1.66, 1.95).Compared with non-Black Hispanic individuals, the prevalence of hypertensive disorders in pregnancy was higher in Black-Hispanic individuals and highest in non-Hispanic Black individuals. Racial/ethnic differences were larger for chronic hypertension alone than for preeclampsia.

    View details for DOI 10.1007/s40615-024-02224-5

    View details for PubMedID 39499430

    View details for PubMedCentralID 10144523

  • Historical Redlining, Contemporary Gentrification, and Severe Maternal Morbidity in California, 2005-2018. JAMA network open Gao, X., Morello-Frosch, R., Nuru-Jeter, A. M., Snowden, J. M., Carmichael, S. L., Mujahid, M. S. 2024; 7 (9): e2429428

    Abstract

    Historically redlined neighborhoods may experience disinvestment, influencing their likelihood of gentrification, a process of neighborhood (re-)development that unequally distributes harms and benefits by race and class. Understanding the combined outcomes of redlining and gentrification informs how the mutually constitutive systems of structural racism and racial capitalism affect pregnancy outcomes.To examine if historical redlining and contemporary gentrification is associated with increased severe maternal morbidity (SMM) odds.This cross-sectional study used data from a statewide population-based sample of all live hospital births at 20 weeks' gestation or more between 2005 and 2018 in California. Analysis was conducted from March 2023 to January 2024.Redlining (as characterized by the federal Home Owners' Loan Corporation mortgage security maps) and displacement (using present-day sociodemographic and housing market information).Mixed-effects logistic regression models were used to assess the association of census tract-level exposure to historical redlining and contemporary gentrification with increased SMM odds, adjusting for sociodemographic and pregnancy related factors. Outcome classification was based on the Centers for Disease Control and Prevention SMM index, which defines SMM as having any of the 21 procedures and diagnoses based on the International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes.The study sample included 1 554 837 births (median [SD] maternal age, 29.0 [6.4] years; 3464 American Indian or Alaskan Native [0.2%], 224 774 Asian [14.5%], 132 240 Black [8.5%], 880 104 Hispanic [56.6%], 312 490 White [20.1%]), with 22 993 cases of SMM (1.4%). Residents in historically redlined neighborhoods that were undergoing gentrification or displacement were more likely to be Black, Hispanic, and American Indian or Alaskan Native. Independent of individual-level characteristics, SMM odds were greater for individuals living in redlined neighborhoods that experienced displacement (OR, 1.21; 95% CI, 1.14-1.28) and in redlined neighborhoods undergoing gentrification (OR, 1.21; 95% CI, 1.13-1.29) compared with those in continuously advantaged neighborhoods.Findings from this cross-sectional study demonstrate that the legacies of redlining, intertwined with current dynamics of displacement and gentrification, affect SMM. Place-based sociopolitical mechanisms that inequitably distribute resources may be important intervention points to address structural drivers of adverse pregnancy outcomes and their racial inequities.

    View details for DOI 10.1001/jamanetworkopen.2024.29428

    View details for PubMedID 39312242

    View details for PubMedCentralID PMC11420692

  • Survival of Children With Critical Congenital Heart Defects in the National Birth Defects Prevention Study. Birth defects research Forestieri, N. E., Olshan, A. F., Oster, M. E., Ailes, E. C., Fundora, M. P., Fisher, S. C., Shumate, C., Romitti, P. A., F Liberman, R., Nembhard, W. N., Carmichael, S. L., Desrosiers, T. A. 2024; 116 (9): e2394

    Abstract

    Critical congenital heart defects (CCHDs) are associated with considerable morbidity and mortality. This study estimated survival of children with nonsyndromic CCHDs and evaluated relationships between exposures of interest and survival by CCHD severity (univentricular or biventricular function).This analysis included 4380 infants with CCHDs (cases) born during 1999-2011 and enrolled in the National Birth Defects Prevention Study, a multisite, population-based case-control study of major birth defects. Cases were linked to state death files. Nonparametric Kaplan-Meier survival functions were used to estimate 1- and 5-year survival probabilities overall and by severity group (univentricular/biventricular) stratified by demographic and clinical exposure variables of interest. The log-rank test was used to determine whether stratified survival curves were equivalent. Survival and 95% confidence intervals (CIs) were also estimated using Cox proportional hazards modeling adjusted for maternal age, education, race/ethnicity, study site, and birth year.One- and five-year survival rates were 85.8% (CI 84.7-86.8) and 83.7% (CI 82.5-84.9), respectively. Univentricular 5-year survival was lower than biventricular case survival [65.3% (CI 61.7-68.5) vs. 89.0% (CI 87.8-90.1; p < 0.001)]. Clinical factors (e.g. preterm birth, low birthweight, and complex/multiple defects) were associated with lower survival in each severity group. Sociodemographic factors (non-Hispanic Black race/ethnicity,

    View details for DOI 10.1002/bdr2.2394

    View details for PubMedID 39258453

  • Association of nutritional intake with clinical and imaging activity in pediatric multiple sclerosis MULTIPLE SCLEROSIS JOURNAL Mohan, S. D., Peterson, S., Brenton, J., Carmichael, S. L., Virupakshaiah, A., Rodriguez, M., Tillema, J., Mar, S., Rensel, M. R., Abrams, A., Chitnis, T., Benson, L., Gorman, M., Lotze, T., Shukla, N., Graves, J., Aaen, G., Casper, T., Waubant, E. 2024: 1056-1065

    Abstract

    Understanding nutrition's role in multiple sclerosis (MS) can guide recommendations and intervention-based studies.Evaluate the association between nutrition and pediatric-onset MS outcomes.Prospective longitudinal multicenter study conducted as part of the US Network of Pediatric MS centers. Predictors were collected using a food screener estimating intake of various dietary food groups (e.g. dairy and fruits) and additional calculated indices (e.g. Healthy Eating Index (HEI)). Outcomes included time-from-enrollment to clinical relapse, new magnetic resonance imaging (MRI) T2 lesions, and Expanded Disability Status Scale (EDSS) increase.353 children with MS were enrolled (mean ± SD age 15.4 ± 2.9, follow-up 3.9 ± 2.6 years). Multivariable analysis demonstrated that increased dairy by 50% of recommended intake was associated with increased relapse risk by 41% (adjusted hazard ratio (HR) 1.41, 95% CI 1.07-1.86), and risk of T2 progression by 40% (1.40, 1.12-1.74). Increased intake of fruit or vegetable above recommended, and every five-point HEI increase decreased relapse risk by 25% (0.75, 0.60-0.95), 45% (0.55, 0.32-0.96), and 15% (0.84, 0.74-0.96), respectively. No associations were found with EDSS.This work supports the influence of dietary intake on MS course, particularly with dairy intake. Future prospective study is required to establish causation.

    View details for DOI 10.1177/13524585241261556

    View details for Web of Science ID 001279795900001

    View details for PubMedID 39078111

  • A Counterfactual Analysis of Impact of Cesarean Birth in a First Birth on Severe Maternal Morbidity in the Subsequent Birth. Epidemiology (Cambridge, Mass.) Bane, S., Snowden, J. M., Simard, J. F., Odden, M., Kan, P., Main, E. K., Carmichael, S. L. 2024

    Abstract

    It is known that cesarean birth affects maternal outcomes in subsequent pregnancies, but specific effect estimates are lacking. We sought to quantify the effect of cesarean birth reduction among nulliparous, term, singleton, vertex (NTSV) births (i.e., preventable cesarean births) on severe maternal morbidity (SMM) in the second birth.We examined birth certificates linked with maternal hospitalization data (2007-19) from California for NTSV births with a second birth (N = 779,382). The exposure was cesarean delivery in first birth and the outcome was SMM in the second birth. We used adjusted Poisson regression models to calculate risk ratios and population attributable fraction for SMM in the second birth and conducted a counterfactual impact analysis to estimate how lowering NTSV cesarean births could reduce SMM in second birth.The adjusted risk ratio for SMM in the second birth given a prior cesarean birth was 1.7 (95% CI 1.5-1.9); 15.5% (95% CI 15.3%-15.7%) of this SMM may be attributable to prior cesarean birth. In a counterfactual analysis where 12% of the California population least likely to get a cesarean birth instead delivered vaginally, we observed 174 fewer SMM events in a population of individuals with a low-risk first birth and a subsequent birth.In our counterfactual analysis, lowering primary cesarean birth among a NTSV population was associated with fewer downstream SMM events in subsequent births and overall. Additionally, our findings reflect the importance of considering the cumulative accrual of risks across the reproductive life-course.

    View details for DOI 10.1097/EDE.0000000000001775

    View details for PubMedID 39058553

  • Considering pregnancies as repeated versus independent events: An empirical comparison of common approaches across selected perinatal outcomes. American journal of obstetrics & gynecology MFM Bane, S., Carmichael, S. L., Mathur, M. B., Simard, J. F. 2024: 101434

    Abstract

    In population-based research, pregnancy may be a repeated event. Despite published guidance on how to address repeated pregnancies to the same individual, a variety of approaches are observed in perinatal epidemiological studies. While some of these approaches are supported by the chosen research question, others are consequences of constraints inherent to a given dataset (e.g., missing parity information). These decisions determine how appropriately a given research question can be answered and overall generalizability.To compare common cohort selection and analytic approaches used for perinatal epidemiological research by assessing the prevalence of two perinatal outcomes and their association with a clinical and a social independent variable STUDY DESIGN: Using vital records linked to maternal hospital discharge records for singleton births, we created four cohorts: (1) all-births (2) randomly selected one birth per individual (3) first observed birth per individual (4) primiparous-births (parity 1). Sampling of births was not conditional on cluster (i.e., we did not sample all births by a given mother, but rather sampled individual births). Study outcomes were severe maternal morbidity and preeclampsia/eclampsia, and the independent variables were self-reported race/ethnicity (as a social factor) and systemic lupus erythematosus. Comparing the four cohorts, we assessed the distribution of maternal characteristics, the prevalence of outcomes, overall and stratified by parity, and risk ratios for the associations of outcomes with independent variables. Among all-births, we then compared risk ratios from three analytic strategies: with standard inference that assumes independently sampled births to the same mother in the model, with cluster-robust inference, and adjusting for parity.We observed minor differences in the population characteristics between the all-birth (N=2,736,693), random-selection, and first-observed birth cohorts (both N=2,284,660), with more substantial differences between these cohorts and the primiparous-births cohort (N=1,054,684). Outcome prevalence was consistently lowest among all-births and highest among primiparous-births (e.g., severe maternal morbidity 18.9 per 1,000 births among primiparous-births vs. 16.6 per 1,000 births among all-births). When stratified by parity, outcome prevalence was always the lowest in births of parity 2 and highest among births of parity 1 for both outcomes. Risk ratios differed for study outcomes across all four cohorts, with the most pronounced differences between the primiparous-birth cohort and other cohorts. Among all-births, robust inference minimally impacted the confidence bounds of estimates, compared to the standard inference, i.e., crude estimates (e.g., lupus-severe maternal morbidity association: 4.01, 95% CI 3.54-4.55 vs. 4.01, 95% CI 3.53-4.56 for crude estimate), while adjusting for parity slightly shifted estimates, towards the null for severe maternal morbidity and away from the null for preeclampsia/eclampsia.Researchers should consider the alignment between the methods they use, their sampling strategy, and their research question. This could include refining the research question to better match inference possible for available data, considering alternative data sources, and appropriately noting data limitations and resulting bias, as well as the generalizability of findings. If parity is an established effect modifier, stratified results should be presented.

    View details for DOI 10.1016/j.ajogmf.2024.101434

    View details for PubMedID 38996915

  • Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study. Birth defects research Blue, E. E., Moore, K. J., North, K. E., Desrosiers, T. A., Carmichael, S. L., White, J. J., Chong, J. X., Bamshad, M. J., Jenkins, M. M., Almli, L. M., Brody, L. C., Freedman, S. F., Reefhuis, J., Romitti, P. A., Shaw, G. M., Werler, M., Kay, D. M., Browne, M. L., Feldkamp, M. L., Finnell, R. H., Nembhard, W. N., Pangilinan, F., Olshan, A. F. 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

  • Socioeconomic disadvantage and racial/ethnic disparities in low-risk cesarean birth in California. American journal of epidemiology Bane, S., Mujahid, M. S., Main, E. K., Carmichael, S. L. 2024

    Abstract

    Our objective was to assess the relationship of socioeconomic disadvantage and race/ethnicity with low-risk cesarean birth. We examined birth certificates (2007-18) linked with maternal hospitalization data from California; the outcome was cesarean birth among low-risk deliveries (i.e., nulliparous, term, singleton, vertex [NTSV]). We used GEE Poisson regression with an interaction term for race/ethnicity (7 groups) and a measure of socioeconomic disadvantage (census tract-level neighborhood deprivation index [NDI], education, or insurance). Among 1,815,933 NTSV births, 26.6% were cesarean. When assessing the joint effect of race/ethnicity and socioeconomic disadvantage among low-risk births, risk of cesarean birth increased with socioeconomic disadvantage for most racial/ethnic groups, and disadvantaged Black individuals had the highest risks; e.g., Black individuals with a high school education or less had a risk ratio of 1.49 (95% CI 1.45-1.53), relative to White individuals with a college degree. The disparity in risk of cesarean birth between Black and White individuals was observed across all strata of socioeconomic disadvantage. Asian American and Hispanic individuals had higher risks than White individuals at lower socioeconomic disadvantage; this disparity was not observed at higher levels of disadvantage. Black individuals have a persistent, elevated risk of cesarean birth, relative to White individuals, regardless of socioeconomic disadvantage.

    View details for DOI 10.1093/aje/kwae157

    View details for PubMedID 38932570

  • Neighborhood-level Fatal Police Violence and Severe Maternal Morbidity in California. American journal of epidemiology Hailu, E. M., Riddell, C. A., Tucker, C., Ahern, J., Bradshaw, P. T., Carmichael, S. L., Mujahid, M. S. 2024

    Abstract

    Police violence is a pervasive issue that may have adverse implications for severe maternal morbidity (SMM). We assessed how the occurrence of fatal police violence (FPV) in one's neighborhood before/during pregnancy may influence SMM risk. Hospital discharge records from California between 2002-2018 were linked with the Fatal Encounters database (N=2,608,682). We identified 2,184 neighborhoods (census-tracts) with at least one FPV incident during the study period and used neighborhood fixed-effects models adjusting for individual sociodemographic characteristics to estimate odds of SMM associated with experiencing FPV in one's neighborhood anytime within the 24-months before childbirth. We did not find conclusive evidence on the link between FPV occurrence before delivery and SMM. However, estimates show that birthing people residing in neighborhoods where one or more FPV events had occurred within the preceding 24-months of giving birth may have a mildly elevated odds of SMM than those residing in the same neighborhoods with no FPV occurrence during the 24-months preceding childbirth (Odds Ratio (OR)=1.02; 95% Confidence Interval (CI): 0.99-1.05), particularly among those living in neighborhoods with fewer (1-2) FPV incidents throughout the study period (OR=1.03; 95% CI:1.00-1.06). Our findings provide evidence for the need to continue to examine the health consequences of police violence.

    View details for DOI 10.1093/aje/kwae124

    View details for PubMedID 38879741

  • Epidemiology of elective induction of labour: a timeless exposure. International journal of epidemiology Snowden, J. M., Bane, S., Osmundson, S. S., Odden, M. C., Carmichael, S. L. 2024; 53 (4)

    View details for DOI 10.1093/ije/dyae088

    View details for PubMedID 38964853

  • 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 Nicoletti, P., Zafer, S., Matok, L., Irron, I., Patrick, M., Haklai, R., Evangelista, J. E., Marino, G. B., Ma'ayan, A., Sewda, A., Holmes, G., Britton, S. R., Lee, W. J., Wu, M., Ru, Y., Arnaud, E., Botto, L., Brody, L. C., Byren, J. C., Caggana, M., Carmichael, S. L., Cilliers, D., Conway, K., Crawford, K., Cuellar, A., Di Rocco, F., Engel, M., Fearon, J., Feldkamp, M. L., Finnell, R., Fisher, S., Freudlsperger, C., Garcia-Fructuoso, G., Hagge, R., Heuzé, Y., Harshbarger, R. J., Hobbs, C., Howley, M., Jenkins, M. M., Johnson, D., Justice, C. M., Kane, A., Kay, D., Gosain, A. K., Langlois, P., Legal-Mallet, L., Lin, A. E., Mills, J. L., Morton, J. E., Noons, P., Olshan, A., Persing, J., Phipps, J. M., Redett, R., Reefhuis, J., Rizk, E., Samson, T. D., Shaw, G. M., Sicko, R., Smith, N., Staffenberg, D., Stoler, J., Sweeney, E., Taub, P. J., Timberlake, A. T., Topczewska, J., Wall, S. A., Wilson, A. F., Wilson, L. C., Boyadjiev, S. A., Wilkie, A. O., Richtsmeier, J. T., Jabs, E. W., Romitti, P. A., Karasik, D., Birnbaum, R. Y., Peter, I. 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

  • Trends in racial/ethnic disparities in postpartum hospital readmissions in California from 1997 to 2018. AJOG global reports Tucker, C. M., Ma, C., Mujahid, M. S., Butwick, A. J., Girsen, A. I., Gibbs, R. S., Carmichael, S. L. 2024; 4 (2): 100331

    Abstract

    BACKGROUND: Postpartum readmission is an important indicator of postpartum morbidity. The likelihood of postpartum readmission is highest for Black individuals. However, it is unclear whether the likelihood of postpartum readmission has changed over time according to race/ethnicity. Little is also known about the factors that contribute to these trends.OBJECTIVE: This study aimed to: (1) examine trends in postpartum readmission by race/ethnicity, (2) examine if prenatal or clinical factors explain the trends, and (3) investigate if racial/ethnic disparities changed over time.STUDY DESIGN: We examined trends in postpartum readmission, defined as hospitalization within 42 days after birth hospitalization discharge, using live birth and fetal death certificates linked to delivery discharge records from 10,711,289 births in California from 1997 to 2018. We used multivariable logistic regression models that included year and year-squared (to allow for nonlinear trends), overall and stratified by race/ethnicity, to estimate the annual change in postpartum readmission during the study period, represented by odds ratios and 95% confidence intervals. We then adjusted models for prenatal (eg, patient demographics) and clinical (eg, gestational age, mode of birth) factors. To determine whether racial/ethnic disparities changed over time, we calculated risk ratios for 1997 and 2018 by comparing the predicted probabilities from the race-specific, unadjusted logistic regression models.RESULTS: The overall incidence of postpartum readmission was 10 per 1000 births (17.4/1000 births for non-Hispanic Black, 10/1000 for non-Hispanic White, 7.9/1000 for non-Hispanic Asian/Pacific Islander, and 9.6/1000 for Hispanic individuals). Odds of readmission increased for all groups during the study period; the increase was greatest for Black individuals (42% vs 21%-29% for the other groups). After adjustment for prenatal and clinical factors, the increase in odds was similar for Black and White individuals (12%). The disparity in postpartum readmission rates relative to White individuals increased for Black individuals (risk ratio, 1.68 in 1997 and 1.90 in 2018) and more modestly for Hispanic individuals (risk ratio, 1.02 in 1997 and 1.05 in 2018) during the study period. Asian/Pacific Islander individuals continued to have lower risk than White individuals during the study period (risk ratio, 0.87 in 1997 and 0.82 in 2018).CONCLUSION: The rate of postpartum readmissions increased from 1997 to 2018 in California across all racial/ethnic groups, with the greatest increase observed for Black individuals. Racial/ethnic differences in the trend were more modest after adjustment for prenatal and clinical factors. It is important to find ways to prevent further increases in postpartum readmission, especially among groups at highest risk.

    View details for DOI 10.1016/j.xagr.2024.100331

    View details for PubMedID 38919705

  • Prevalence and Outcomes of Emergency Room Care for Postpartum Endometritis. Perlman, N., Mayo, J., Leonard, S., Carmichael, S., Gibbs, R. SPRINGER HEIDELBERG. 2024: 140A
  • Validity of Birth Certificate Data Compared With Hospital Discharge Data in Reporting Maternal Morbidity and Disparities. Obstetrics and gynecology Gemmill, A., Passarella, M., Phibbs, C. S., Main, E. K., Lorch, S. A., Kozhimannil, K. B., Carmichael, S. L., Leonard, S. A. 2024

    Abstract

    A growing number of studies are using birth certificate data, despite data-quality concerns, to study maternal morbidity and associated disparities. We examined whether conclusions about the incidence of maternal morbidity, including Black-White disparities, differ between birth certificate data and hospitalization data. Using linked birth certificate and hospitalization data from California and Michigan for 2018 (N=543,469), we found that maternal morbidity measures using birth certificate data alone are substantially underreported and have poor validity. Furthermore, the degree of underreporting in birth certificate data differs between Black and White individuals and results in erroneous inferences about disparities. Overall, Black-White disparities were more modest in the birth certificate data compared with the hospitalization data. Birth certificate data alone are inadequate for studies of maternal morbidity and associated racial disparities.

    View details for DOI 10.1097/AOG.0000000000005497

    View details for PubMedID 38176017

  • Structural Racism, Mass Incarceration, and Racial and Ethnic Disparities in Severe Maternal Morbidity. JAMA network open Hailu, E. M., Riddell, C. A., Bradshaw, P. T., Ahern, J., Carmichael, S. L., Mujahid, M. S. 2024; 7 (1): e2353626

    Abstract

    Importance: Racial and ethnic inequities in the criminal-legal system are an important manifestation of structural racism. However, how these inequities may influence the risk of severe maternal morbidity (SMM) and its persistent racial and ethnic disparities remains underinvestigated.Objective: To examine the association between county-level inequity in jail incarceration rates comparing Black and White individuals and SMM risk in California.Design, Setting, and Participants: This population-based cross-sectional study used state-wide data from California on all live hospital births at 20 weeks of gestation or later from January 1, 1997, to December 31, 2018. Data were obtained from hospital discharge and vital statistics records, which were linked with publicly available county-level data. Data analysis was performed from January 2022 to February 2023.Exposure: Jail incarceration inequity was determined from the ratio of jail incarceration rates of Black individuals to those of White individuals and was categorized as tertile 1 (low), tertile 2 (moderate), tertile 3 (high), with mean cutoffs across all years of 0 to 2.99, 3.00 to 5.22, and greater than 5.22, respectively.Main Outcome and Measures: This study used race- and ethnicity-stratified mixed-effects logistic regression models with birthing people nested within counties and adjusted for individual- and county-level characteristics to estimate the odds of non-blood transfusion SMM (NT SMM) and SMM including blood transfusion-only cases (SMM; as defined by the Centers for Disease Control and Prevention SMM index) associated with tertiles of incarceration inequity.Results: This study included 10 200 692 births (0.4% American Indian or Alaska Native, 13.4% Asian or Pacific Islander, 5.8% Black, 50.8% Hispanic or Latinx, 29.6% White, and 0.1% multiracial or other [individuals who self-identified with ≥2 racial groups and those who self-identified as "other" race or ethnicity]). In fully adjusted models, residing in counties with high jail incarceration inequity (tertile 3) was associated with higher odds of SMM for Black (odds ratio [OR], 1.14; 95% CI, 1.01-1.29 for NT SMM; OR, 1.20, 95% CI, 1.01-1.42 for SMM), Hispanic or Latinx (OR, 1.24; 95% CI, 1.14-1.34 for NT SMM; OR, 1.20; 95% CI, 1.14-1.27 for SMM), and White (OR, 1.02; 95% CI, 0.93-1.12 for NT SMM; OR, 1.09; 95% CI, 1.02-1.17 for SMM) birthing people, compared with residing in counties with low inequity (tertile 1).Conclusions and Relevance: The findings of this study highlight the adverse maternal health consequences of structural racism manifesting via the criminal-legal system and underscore the need for community-based alternatives to inequitable punitive practices.

    View details for DOI 10.1001/jamanetworkopen.2023.53626

    View details for PubMedID 38277143

  • Joint effects of epilepsy and mental health on severe maternal morbidity Perlman, N., Mayo, J. A., Leonard, S. A., Carmichael, S. L., McElrath, T., Meador, K., Druzin, M. L., Panelli, D. M. MOSBY-ELSEVIER. 2024: S161-S162
  • Hypertensive disorders of pregnancy and severe maternal morbidity according to race/ ethnicity, California 2007-2018 Mayo, J. A., Perlman, N., Girsen, A., Carmichael, S. L., Leonard, S. A. MOSBY-ELSEVIER. 2024: S411
  • Associations between antepartum anemia and uterine fibroids in pregnancy by race and ethnicity Igbinosa, I., Mayo, J. A., Leonard, S. A., Iwekaogwu, I., Carmichael, S. L., Lyell, D. J., Eunice Kennedy Shriver Natl Inst Child Hlth Human Dev MOSBY-ELSEVIER. 2024: S264
  • Trends and Disparities in Severe Maternal Morbidity Indicator Categories During Childbirth Hospitalization in California from 1997-2017. American journal of perinatology El Ayadi, A. M., Lyndon, A., Kan, P., Mujahid, M. S., Main, E. K., Carmichael, S. 2023

    Abstract

    Objective Severe maternal morbidity (SMM) is increasing and characterized by substantial racial and ethnic disparities. Analyzing trends and disparities across time by etiologic or organ system groups instead of an aggregated index may inform specific, actionable pathways to equitable care. We explored trends and racial and ethnic disparities in seven SMM categories at childbirth hospitalization. Study Design We analyzed California birth cohort data on all live and stillbirths ≥20 weeks gestation from 1997-2017 (n=10,580,096) using the Centers for Disease Control and Prevention's SMM index. Cases were categorized into seven non-mutually exclusive indicator categories (cardiac, renal, respiratory, hemorrhage, sepsis, other obstetric, and other medical SMM). We compared prevalence and trends in SMM indicator categories overall and by racial and ethnic group using logistic and linear regression. Results SMM occurred in 1.16% of births and non-transfusion SMM in 0.54%. Hemorrhage SMM occurred most frequently (27 per 10,000 births), followed by other obstetric (11), respiratory (7), and sepsis, cardiac, and renal SMM (5). Hemorrhage, renal, respiratory, and sepsis SMM increased over time for all racial and ethnic groups. The largest disparities were for Black individuals, including over three-fold increased odds of other medical SMM. Renal and sepsis morbidity had the largest relative increases over time (717% and 544%). Sepsis and hemorrhage SMM had the largest absolute changes over time (17 per 10,000 increase). Disparities increased over time for respiratory SMM among Black, US-born Hispanic, and non-US-born Hispanic individuals and for sepsis SMM among Asian or Pacific Islander individuals. Disparities decreased over time for sepsis SMM among Black individuals yet remained substantial. Conclusion Our research further supports the critical need to address SMM and disparities as a significant public health priority in the United States and suggests that examining SMM subgroups may reveal helpful nuance for understanding trends, disparities and potential needs for intervention.

    View details for DOI 10.1055/a-2223-3520

    View details for PubMedID 38057087

  • Assessing the relationship between census tract rurality and severe maternal morbidity in California (1997-2018). The Journal of rural health : official journal of the American Rural Health Association and the National Rural Health Care Association Berkowitz, R. L., Kan, P., Gao, X., Hailu, E. M., Board, C., Lyndon, A., Mujahid, M., Carmichael, S. L. 2023

    Abstract

    PURPOSE: Recent studies have demonstrated an increased risk of severe maternal morbidity (SMM) for people living in rural versus urban counties. Studies have not considered rurality at the more nuanced subcounty census-tract level. This study assessed the relationship between census-tract-level rurality and SMM for birthing people in California.METHODS: We used linked vital statistics and hospital discharge records for births between 1997 and 2018 in California. SMM was defined by at least 1 of 21 potentially fatal conditions and lifesaving procedures. Rural-Urban Commuting Area codes were used to characterize census tract rurality dichotomously (2-category) and at 4 levels (4-category). Covariates included sociocultural-demographic, pregnancy-related, and neighborhood-level factors. We ran a series of mixed-effects logistic regression models with tract-level clustering, reporting risk ratios and 95% confidence intervals (CIs). We used the STROBE reporting guidelines.FINDINGS: Of 10,091,415 births, 1.1% had SMM. Overall, 94.3% of participants resided in urban/metropolitan and 5.7% in rural tracts (3.9% micropolitan, 0.9% small town, 0.8% rural). In 2-category models, the risk of SMM was 10% higher for birthing people in rural versus urban tracts (95% CI: 6%, 13%). In 4-category models, the risk of SMM was 16% higher in micropolitan versus metropolitan tracts (95% CI: 12%, 21%).CONCLUSION: The observed rurality and SMM relationship was driven by living in a micropolitan versus metropolitan tract. Increased risk may result from resource access inequities within suburban areas. Our findings demonstrate the importance of considering rurality at a subcounty level to understand locality-related inequities in the risk of SMM.

    View details for DOI 10.1111/jrh.12814

    View details for PubMedID 38054697

  • Preconception dietary glycemic index and risk for large-for-gestational age births. Nutrition (Burbank, Los Angeles County, Calif.) Darling, A. M., Yazdy, M. M., Garcia, M. H., Carmichael, S. L., Shaw, G. M., Nestoridi, E., National Birth Defects Prevention Study 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

  • Neighborhood Deprivation and Neural Tube Defects. Epidemiology (Cambridge, Mass.) Pruitt Evans, S., Ailes, E. C., Kramer, M. R., Shumate, C. J., Reefhuis, J., Insaf, T. Z., Yazdy, M. M., Carmichael, S. L., Romitti, P. A., Feldkamp, M. L., Neo, D. T., Nembhard, W. N., Shaw, G. M., Palmi, E., Gilboa, S. M. 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

  • Is gastroschisis associated with county-level socio-environmental quality during pregnancy? Birth defects research Krajewski, A. K., Patel, A., Gray, C. L., Messer, L. C., Keeler, C. Y., Langlois, P. H., Reefhuis, J., Gilboa, S. M., Werler, M. M., Shaw, G. M., Carmichael, S. L., Nembhard, W. N., Insaf, T. Z., Feldkamp, M. L., Conway, K. M., Lobdell, D. T., Desrosiers, T. A. 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

  • Racial and Ethnic Disparities in Anemia and Severe Maternal Morbidity. Obstetrics and gynecology Igbinosa, I. I., Leonard, S. A., Noelette, F., Davies-Balch, S., Carmichael, S. L., Main, E., Lyell, D. J. 2023

    Abstract

    To evaluate antepartum anemia prevalence by race and ethnicity, to assess whether such differences contribute to severe maternal morbidity (SMM), and to estimate the contribution of antepartum anemia to SMM and nontransfusion SMM by race and ethnicity.We conducted a population-based cohort study using linked vital record and birth hospitalization data for singleton births at or after 20 weeks of gestation in California from 2011 through 2020. Pregnant patients with hereditary anemias, out-of-hospital births, unlinked records, and missing variables of interest were excluded. Antepartum anemia prevalence and trends were estimated by race and ethnicity. Centers for Disease Control and Prevention criteria were used for SMM and nontransfusion SMM indicators. Multivariable logistic regression modeling was used to estimate risk ratios (RRs) for SMM and nontransfusion SMM by race and ethnicity after sequential adjustment for social determinants, parity, obstetric comorbidities, delivery, and antepartum anemia. Population attributable risk percentages were calculated to assess the contribution of antepartum anemia to SMM and nontransfusion SMM by race and ethnicity.In total, 3,863,594 births in California were included. In 2020, Black pregnant patients had the highest incidence of antepartum anemia (21.5%), followed by Pacific Islander (18.2%), American Indian-Alaska Native (14.1%), multiracial (14.0%), Hispanic (12.6%), Asian (10.6%), and White pregnant patients (9.6%). From 2011 to 2020, the prevalence of anemia increased more than100% among Black patients, and there was a persistent gap in prevalence among Black compared with White patients. Compared with White patients, the adjusted risk for SMM was high among most racial and ethnic groups; adjustment for anemia after sequential modeling for known confounders decreased SMM risk most for Black pregnant patients (approximated RR 1.47, 95% CI 1.42-1.53 to approximated RR 1.27, 95% CI 1.22-1.37). Compared with White patients, the full adjusted nontransfusion SMM risk remained high for most groups except Hispanic and multiracial patients. Within each racial and ethnic group, the population attributable risk percentage for antepartum anemia and SMM was highest for multiracial patients (21.4%, 95% CI 17.5-25.0%), followed by Black (20.9%, 95% CI 18.1-23.4%) and Hispanic (20.9%, 95% CI 19.9-22.1%) patients. The nontransfusion SMM population attributable risk percentages for Asian, Black, and White pregnant patients were less than 8%.Antepartum anemia, most prevalent among Black pregnant patients, contributed to disparities in SMM by race and ethnicity. Nearly one in five to six SMM cases among Black, Hispanic, American Indian-Alaska Native, Pacific Islander, and multiracial pregnant patients is attributable in part to antepartum anemia.

    View details for DOI 10.1097/AOG.0000000000005325

    View details for PubMedID 37678935

  • 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 Petersen, J. M., Smith-Webb, R. S., Shaw, G. M., Carmichael, S. L., Desrosiers, T. A., Nestoridi, E., Darling, A. M., Parker, S. E., Politis, M. D., Yazdy, M. M., Werler, M. M. 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

  • Neighborhood gentrification, displacement, and severe maternal morbidity in California. Social science & medicine (1982) Gao, X., Thomas, T. A., Morello-Frosch, R., Allen, A. M., Snowden, J. M., Carmichael, S. L., Mujahid, M. S. 2023; 334: 116196

    Abstract

    Gentrification, a racialized and profit-driven process in which historically disinvested neighborhoods experience an influx of development that contributes to the improvement of physical amenities, increasing housing costs, and the dispossession and displacement of existing communities, may influence the risk of severe maternal morbidity (SMM). Leveraging a racially diverse population-based sample of all live hospital births in California between 2006 and 2017, we examined associations between neighborhood-level gentrification and SMM. SMM was defined as having one of 21 procedures and diagnoses, as described in the SMM index developed by Centers for Disease Control and Prevention. We compared three gentrification measures to determine which operationalization best captures aspects of gentrification most salient to SMM: Freeman, Landis 3-D, and Urban Displacement Project Gentrification and Displacement Typology. Descriptive analysis assessed bivariate associations between gentrification and birthing people's characteristics. Overall and race and ethnicity-stratified mixed-effects logistic models assessed associations between gentrification and SMM, adjusting for individual sociodemographic and pregnancy factors while accounting for clustering by census tract. The study sample included 5,256,905 births, with 72,718 cases of SMM (1.4%). The percentage of individuals living in a gentrifying neighborhood ranged from 5.7% to 11.7% across exposure assessment methods. Net of individual and pregnancy-related factors, neighborhood-level gentrification, as measured by the Freeman method, was protective against SMM (OR = 0.89, 95% CI: 0.86-0.93); in comparison, gentrification, as measured by the Gentrification and Displacement Typology, was associated with greater risk of SMM (OR = 1.18, 95% CI: 1.14-1.23). These associations were significant among non-Hispanic White, non-Hispanic Black, and Hispanic individuals. Findings demonstrate that gentrification plays a role in shaping the risk of SMM among birthing people in California. Differences in how gentrification is conceptualized and measured, such as an emphasis on housing affordability compared to a broader characterization of gentrification's multiple aspects, may explain the heterogeneity in the directions of observed associations.

    View details for DOI 10.1016/j.socscimed.2023.116196

    View details for PubMedID 37678111

  • Are individual-level risk factors for gastroschisis modified by neighborhood-level socioeconomic factors? Birth defects research Neo, D. T., Martin, C. L., Carmichael, S. L., Gucsavas-Calikoglu, M., Conway, K. M., Evans, S. P., Feldkamp, M. L., Gilboa, S. M., Insaf, T. Z., Musfee, F. I., Shaw, G. M., Shumate, C., Werler, M. M., Olshan, A. F., Desrosiers, T. A. 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

  • Oxidative balance scores and neural crest cell-related congenital anomalies. Birth defects research Carmichael, S. L., Yang, W., Ma, C., Desrosiers, T. A., Weber, K., Collins, R. T., Nestoridi, E., Shaw, G. M. 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

  • Early postpartum hospital encounters among patients with genitourinary and wound infections during hospitalization for birth. American journal of perinatology Leonard, S. A., Girsen, A., Trepman, P., Carmichael, S. L., Darmawan, K., Butwick, A., Gibbs, R. 2023

    Abstract

    To assess the associations between genitourinary and wound infections during the birth hospitalization and early postpartum hospital encounters, and to evaluate clinical risk factors for early postpartum hospital encounters among patients with a genitourinary or wound infection during the birth hospitalization.We conducted a population-based cohort study of births in California during 2016-2018 and postpartum hospital encounters. We identified genitourinary and wound infections using diagnosis codes. Our main outcome was early postpartum hospital encounter, defined as a readmission or ED visit within 3 days after discharge from the birth hospitalization. We evaluated the association of genitourinary and wound infections (overall and subtypes) with early postpartum hospital encounter using logistic regression, adjusting for sociodemographic factors and comorbidities and stratified by mode of birth. We then evaluated factors associated with early postpartum hospital encounter among patients with genitourinary and wound infections.Among 1,217,803 birth hospitalizations, 5.5% were complicated by genitourinary and wound infections and 1.8% resulted in an early postpartum hospital encounter. Genitourinary or wound infection was associated with an early postpartum hospital encounter among patients with both vaginal births (aRR 1.26, 95% CI 1.17, 1.36) and cesarean births (aRR 1.23, 95% CI 1.15, 1.32). Major puerperal infection, followed by wound infection, among patients with a cesarean birth conferred the highest risk of an early postpartum hospital encounter (6.4% and 4.3%, respectively). Among patients with genitourinary and wound infections at birth hospitalization, factors associated with an early postpartum hospital encounter included severe maternal morbidity, major mental health condition, prolonged postpartum hospital stay, and, among cesarean births, postpartum hemorrhage (P-value < 0.05).Genitourinary and wound infections during hospitalization for birth may increase risk of a readmission or ED visit within the first few days after discharge, particularly among patients who have a major puerperal infection or wound infection.

    View details for DOI 10.1055/a-2097-1584

    View details for PubMedID 37216972

  • Racial and Ethnic Disparities in Primary Cesarean Birth and Adverse Outcomes Among Low-Risk Nulliparous People. Obstetrics and gynecology Carmichael, S. L., Snowden, J. 2023; 141 (5): 1024

    View details for DOI 10.1097/AOG.0000000000005158

    View details for PubMedID 37103537

  • Neighborhood-level socioeconomic position during early pregnancy and risk of gastroschisis. Epidemiology (Cambridge, Mass.) Neo, D. T., Desrosiers, T. A., Martin, C. L., Carmichael, S. L., Gucsavas-Calikoglu, M., Conway, K. M., Evans, S. P., Feldkamp, M. L., Gilboa, S. M., Insaf, T. Z., Musfee, F. I., Shaw, G. M., Shumate, C. J., Werler, M. M., Olshan, A. F. 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

  • 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 Sok, P., Sabo, A., Almli, L. M., Jenkins, M. M., Nembhard, W. N., Agopian, A. J., Bamshad, M. J., Blue, E. E., Brody, L. C., Brown, A. L., Browne, M. L., Canfield, M. A., Carmichael, S. L., Chong, J. X., Dugan-Perez, S., Feldkamp, M. L., Finnell, R. H., Gibbs, R. A., Kay, D. M., Lei, Y., Meng, Q., Moore, C. A., Mullikin, J. C., Muzny, D., Olshan, A. F., Pangilinan, F., Reefhuis, J., Romitti, P. A., Schraw, J. M., Shaw, G. M., Werler, M. M., Harpavat, S., Lupo, P. J. 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

  • Neighborhood Deprivation and Severe Maternal Morbidity in the State of California: An Examination of Effect Modification by Race/Ethnicity. American journal of obstetrics & gynecology MFM Mujahid, M. S., Wall-Wieler, E., Hailu, M. E., Berkowitz, R. L., Gao, M. X., Morris, M. C., Abrams, B., Lyndon, A., Carmichael, S. L. 2023: 100916

    Abstract

    Social determinants of health, including neighborhood context, may be a key driver of severe maternal morbidity and its related racial/ethnic inequities, but investigations remain limited.We examined associations between neighborhood socioeconomic characteristics and severe maternal morbidity and whether associations were modified by race/ethnicity.This study leveraged a California statewide data resource on all hospital births ≥20 weeks (1997-2018). Severe maternal morbidity was defined as having at least one of 21 diagnoses and procedures (for example, blood transfusion, hysterectomy) as outlined by the Centers for Disease Control and Prevention. Neighborhoods were defined as residential census tracts (N=8,022; average of 1,295 births per neighborhood), and neighborhood deprivation index was a summary measures of 8 census indicators (for example, percent poverty, unemployment, public assistance). Mixed-effects logistic regression models (individuals nested within neighborhoods) were used to compare odds of severe maternal morbidity across quartiles (Quartile 1= least deprived; Quartile 4 = most deprived) of neighborhood deprivation index before and after adjustment for maternal sociodemographic and pregnancy-related factors and co-morbidities. We also created cross-product terms to determine if associations were modified by race/ethnicity.Of 10,384,976 births, the prevalence of severe maternal morbidity was 1.2% (N=120,487). In fully adjusted mixed-effects models, odds of severe maternal morbidity increased with increasing neighborhood deprivation index (Odds Ratios and 95% Confidence Intervals, with Quartile 1 as reference: Quartile 4 =1.23 (1.20-1.26), Quartile 3=1.13 (1.10-1.16), Quartile 2=1.06 (1.03-1.08). Associations were modified by race/ethnicity such that associations (Quartile 4 vs. Quartile 1, 95% C.I.) were strongest among individuals in the "Other" racial/ethnic category (1.39, 1.03-1.86) and weakest among Black individuals (1.07, 0.98-1.16).These findings suggest that neighborhood deprivation contributes to an increased risk of severe maternal morbidity. Future research should examine which aspects of neighborhood environments matter most across racial/ethnic groups.

    View details for DOI 10.1016/j.ajogmf.2023.100916

    View details for PubMedID 36905984

  • Prepregnancy body mass index and gestational diabetes mellitus across Asian and Pacific Islander subgroups in California. AJOG global reports Sperling, M. M., Leonard, S. A., Blumenfeld, Y. J., Carmichael, S. L., Chueh, J. 2023; 3 (1): 100148

    Abstract

    The American College of Obstetricians and Gynecologists recommends early screening for gestational diabetes mellitus among pregnant Asian people with a prepregnancy body mass index ≥23.0 kg/m2, in contrast with the recommended screening at a body mass index ≥25 kg/m2 for other races and ethnicities. However, there is significant heterogeneity within Asian and Pacific Islander populations, and gestational diabetes mellitus and its association with body mass index among Asian and Pacific Islander subgroups may not be uniform across all groups.This study aimed to analyze the association between body mass index and gestational diabetes mellitus among Asian and Pacific Islander subgroups in California, specifically gestational diabetes mellitus rates among those with a body mass index above vs below 23 kg/m2, which is the cutoff point for the designation of being overweight among Asians populations.Using a linked delivery hospitalization discharge and vital records database, we identified patients who gave birth in California between 2007 and 2017 and who self-reported to be 1 of 13 Asian and Pacific Islander subgroups, which was collected from birth and fetal death certificates. In each subgroup, we evaluated the association between body mass index and gestational diabetes mellitus using multivariable logistic regression models adjusted for age, education, parity, payment method, the trimester in which prenatal care was initiated, and nativity. We fit body mass index nonlinearly with splines and categorized body mass index as being above or below 23 kg/m2. Predicted probabilities of gestational diabetes mellitus with 95% confidence intervals were calculated across body mass index values using the nonlinear regression models.The overall prevalence of gestational diabetes mellitus was 14.3% (83,400/584,032), ranging between 8.4% and 17.1% across subgroups. The highest prevalence was among Indian (17.1%), Filipino (16.7%), and Vietnamese (15.5%) subgroups. In these subgroups, gestational diabetes mellitus was diagnosed in 10% to 13% of those with a body mass index <23.0 kg/m2 and in 22% of those with a body mass index ≥23 kg/m2. Gestational diabetes mellitus was least common among Korean (8.4%), Japanese (9.0%), and Samoan (9.8%) subgroups with a gestational diabetes mellitus rate of 5% to 7% among those with a body mass index <23.0 kg/m2 and in 10% to 15% among those with a body mass index ≥23 kg/m2. Although Samoan patients had the highest rate of obesity, defined as body mass index ≥30 kg/m2 (57.4%), they had the third lowest prevalence of gestational diabetes mellitus. Conversely, Vietnamese patients had the second lowest rate of obesity (2.4%) but the highest rate of gestational diabetes mellitus at a body mass index of ≥23 kg/m2 (22.3%).Gestational diabetes mellitus and its association with body mass index varied among Asian subgroups but increased as body mass index increased. Subgroups with the lowest prevalence of obesity trended toward a higher prevalence of gestational diabetes mellitus and those with a higher prevalence of obesity trended toward a lower prevalence of gestational diabetes mellitus.

    View details for DOI 10.1016/j.xagr.2022.100148

    View details for PubMedID 36632428

    View details for PubMedCentralID PMC9826825

  • Factors Associated with Transfer Distance from Birth Hospital to Repair Hospital for First Surgical Repair among Infants with Myelomeningocele in California. American journal of perinatology Kancherla, V., Ma, C., Purkey, N. J., Hintz, S. R., Lee, H. C., Grant, G., Carmichael, S. L. 2023

    Abstract

     The objective of our study was to examine factors associated with distance to care for first surgical repair among infants with myelomeningocele in California. A total of 677 eligible cases with complete geocoded data were identified for birth years 2006 to 2012 using data from the California Perinatal Quality Care Collaborative linked to hospital and vital records. The median distance from home to birth hospital among eligible infants was 9 miles, and from birth hospital to repair hospital was 15 miles. We limited our analysis to infants who lived close to the birth hospital, creating two study groups to examine transfer distance patterns: "lived close and had a short transfer" (i.e., lived <9 miles from birth hospital and traveled <15 miles from birth hospital to repair hospital; n = 92), and "lived close and had a long transfer" (i.e., lived <9 miles from birth hospital and traveled ≥15 miles from birth hospital to repair hospital; n = 96). Log-binomial regression was used to estimate crude and adjusted risk ratios (aRRs and 95% confidence intervals (CIs). Selected maternal, infant, and birth hospital characteristics were compared between the two groups. We found that low birth weight (aRR = 1.44; 95% CI = 1.04, 1.99) and preterm birth (aRR = 1.41; 95% CI = 1.01, 1.97) were positively associated, whereas initiating prenatal care early in the first trimester was inversely associated (aRR = 0.64; 95% CI = 0.46, 0.89) with transferring a longer distance (≥15 miles) from birth hospital to repair hospital. No significant associations were noted by maternal race-ethnicity, socioeconomic indicators, or the level of hospital care at the birth hospital. Our study identified selected infant factors associated with the distance to access surgical care for infants with myelomeningocele who had to transfer from birth hospital to repair hospital. Distance-based barriers to care should be identified and optimized when planning deliveries of at-risk infants in other populations.· Low birth weight predicted long hospital transfer distance.. · Preterm birth was associated with transfer distance.. · Prenatal care was associated with transfer distance..

    View details for DOI 10.1055/s-0042-1760431

    View details for PubMedID 36646096

  • Linked Birth Cohort Files for Perinatal Health Research: California as a Model for Methodology and Implementation. Annals of epidemiology Danielsen, B. H., Carmichael, S. L., Jb, G., Hc, L. 2023

    Abstract

    PURPOSE: Rigorous perinatal epidemiologic research depends on population-based parental and neonatal sociodemographic and clinical data. Here we describe the creation of linked birth cohort files (LBCF), an enriched data source that combines information from vital records with maternal delivery and infant hospital encounter records.METHODS: Probabilistic linkage techniques were used to link vital records (i.e., birth and fetal death certificates) from the California Department of Public Health with hospital inpatient, ambulatory surgery and emergency department encounter data for mothers and infants from the California Department of Health Care Access and Information.RESULTS: From 2012 to 2018, 95% of live birth records were successfully linked to maternal and newborn hospital records while 85% of fetal death records were linked to a maternal delivery record. Overall, 93% of postnatal hospital encounters of infants (i.e., <1 year old) were matched to a linked record.CONCLUSION: The LBCF is a rich resource opening many possibilities for understanding perinatal health outcomes and opportunities for linkage to longitudinal, social determinant, and environmental data. To optimally use this file for research, analysts should evaluate possible shortcomings or biases of the data sources being linked.

    View details for DOI 10.1016/j.annepidem.2022.12.014

    View details for PubMedID 36603709

  • Increased rates of postpartum emergency department visits and inpatient readmissions in people with epilepsy Darmawan, K. F., Leonard, S. A., Meador, K., McElrath, T. F., Carmichael, S. L., Lyell, D. J., El-Sayed, Y. Y., Herrero, T., Druzin, M. L., Panelli, D. M. MOSBY-ELSEVIER. 2023: S163
  • Severe maternal morbidity among people with cardiac disease: getting to the heart of the problem Darmawan, K. F., Panelli, D. M., Mayo, J. A., Leonard, S. A., Girsen, A., Carmichael, S. L., Bianco, K. MOSBY-ELSEVIER. 2023: S163-S164
  • Increased primary cesarean delivery rate among people with epilepsy: Risks, drivers and future directions Darmawan, K. F., Leonard, S. A., Meador, K., McElrath, T. F., Carmichael, S. L., Lyell, D. J., El-Sayed, Y. Y., Herrero, T., Druzin, M. L., Panelli, D. M. MOSBY-ELSEVIER. 2023: S162-S163
  • Adverse Pregnancy Outcomes Among Asian Subgroups - Does Gestational Diabetes Mellitus Increase the Risk? Perlman, N. C., Sperling, M. M., Mayo, J., Leonard, S. A., Blumenfeld, Y. J., Carmichael, S. L., Maine, E., Chueh, J., Bianco, K. SPRINGER HEIDELBERG. 2023: 131A-132A
  • Remapping racial and ethnic inequities in severe maternal morbidity: The legacy of redlining in California. Paediatric and perinatal epidemiology Gao, X., Snowden, J. M., Tucker, C. M., Allen, A., Morello-Frosch, R., Abrams, B., Carmichael, S. L., Mujahid, M. S. 2022

    Abstract

    BACKGROUND: Historical mortgage redlining, a racially discriminatory policy designed to uphold structural racism, may have played a role in producing the persistently elevated rate of severe maternal morbidity (SMM) among racialised birthing people.OBJECTIVE: This study examined associations between Home-Owner Loan Corporation (HOLC) redlining grades and SMM in a racially and ethnically diverse birth cohort in California.METHODS: We leveraged a population-based cohort of all live hospital births at ≥20weeks of gestation between 1997 and 2017 in California. SMM was defined as having one of 21 procedures and diagnoses, per an index developed by Centers for Disease Control and Prevention. We characterised census tract-level redlining using HOLC's security maps for eight California cities. We assessed bivariate associations between HOLC grades and participant characteristics. Race and ethnicity-stratified mixed effects logistic regression models assessed the risk of SMM associated with HOLC grades within non-Hispanic Black, Asian/Pacific Islander, American Indian/Alaskan Nativeand Hispanic groups, adjusting for sociodemographic information, pregnancy-related factors, co-morbidities and neighbourhood deprivation index.RESULTS: The study sample included 2,020,194 births, with 24,579 cases of SMM (1.2%). Living in a census tract that was graded as "Hazardous," compared to census tracts graded "Best" and "Still Desirable," was associated with 1.15 (95% confidence interval [CI] 1.03, 1.29) and 1.17 (95% CI 1.09, 1.25) times the risk of SMM among Black and Hispanic birthing people, respectively, independent of sociodemographic factors. These associations persisted after adjusting for pregnancy-related factors and neighbourhood deprivation index.CONCLUSIONS: Historical redlining, a tool of structural racism that influenced the trajectory of neighbourhood social and material conditions, is associated with increased risk of experiencing SMM among Black and Hispanic birthing people in California. These findings demonstrate that addressing the enduring impact of macro-level and systemic mechanisms that uphold structural racism is a vital step in achieving racial and ethnic equity in birthing people's health.

    View details for DOI 10.1111/ppe.12935

    View details for PubMedID 36420897

  • Structural racism and adverse maternal health outcomes: A systematic review. Health & place Hailu, E. M., Maddali, S. R., Snowden, J. M., Carmichael, S. L., Mujahid, M. S. 2022; 78: 102923

    Abstract

    In the United States, racial disparities in adverse maternal health outcomes remain a pressing issue, with Black women experiencing a 3-4 times higher risk of maternal mortality and a 2-3 times higher risk of severe maternal morbidity. Despite recent encouraging efforts, fundamental determinants of these alarming inequities (e.g. structural racism) remain understudied. Approaches that address these structural drivers are needed to then intervene upon root causes of adverse maternal outcomes and their disparities and to ultimately improve maternal health across the U.S. In this paper, we offer a conceptual framework for studies of structural racism and maternal health disparities and systematically synthesize the current empirical epidemiologic literature on the links between structural racism measures and adverse maternal health outcomes. For the systematic review, we searched electronic databases (Pubmed, Web of Science, and EMBASE) to identify peer-reviewed U.S. based quantitative articles published between 1990 and 2021 that assessed the link between measures of structural racism and indicators of maternal morbidity/mortality. Our search yielded 2394 studies and after removing duplicates, 1408 were included in the title and abstract screening, of which 18 were included in the full text screening. Only 6 studies met all the specified inclusion criteria for this review. Results revealed that depending on population sub-group analyzed, measures used, and covariates considered, there was evidence that structural racism may increase the risk of adverse maternal health outcomes. This review also highlighted several areas for methodological and theoretical development in this body of work. Future work should more comprehensively assess structural racism in a way that informs policy and interventions, which can ameliorate its negative consequences on racial/ethnic disparities in maternal morbidity/mortality.

    View details for DOI 10.1016/j.healthplace.2022.102923

    View details for PubMedID 36401939

  • Assessing associations between residential proximity to greenspace and birth defects in the National Birth Defects Prevention Study. Environmental research Weber, K. A., Yang, W., Carmichael, S. L., Collins, R. T., Luben, T. J., Desrosiers, T. A., Insaf, T. Z., Le, M. T., Evans, S. P., Romitti, P. A., Yazdy, M. M., Nembhard, W. N., Shaw, G. M., National Birth Defects Prevention Study 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

  • ASSOCIATION BETWEEN INFERTILITY SUBTYPES AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE AMONG POSTMENOPAUSAL PARTICIPANTS FROM THE WOMEN'S HEALTH INITIATIVE. Murugappan, G., Leonard, S., Lathi, R. B., Farland, L. V., Carmichael, S. L., Parikh, N. J., Stefanick, M. L. ELSEVIER SCIENCE INC. 2022: E4-E5
  • Early postpartum readmissions: identifying risk factors at birth hospitalization. AJOG global reports Girsen, A. I., Leonard, S. A., Butwick, A. J., Joudi, N., Carmichael, S. L., Gibbs, R. S. 2022; 2 (4): 100094

    Abstract

    BACKGROUND: The high maternal mortality and severe morbidity rates in the United States compared with other high-income countries have received national attention. Characterization of postpartum hospital readmissions within the first days after delivery hospitalization discharge could help to identify patients who need additional preparedness for discharge.OBJECTIVE: This study aimed to investigate conditions at birth associated with postpartum readmissions occurring within 0 to 6 days and at 7 to 29 days after discharge from the delivery hospitalization.STUDY DESIGN: We analyzed linked vital statistics and hospital discharge records of patients who gave birth in California during 2007 to 2018. We investigated hospital readmissions within 30 days after birth hospitalization discharge. We used multivariable logistic regression to investigate factors associated with early readmission (0-6 days) and later readmission (7-29 days) compared with no readmission within 30 days (reference). The risk factors assessed included maternal medical or obstetrical conditions before and at birth, birth hospitalization length of stay, and mode of delivery. Severe maternal morbidity was defined as the presence of any of the 21 indicators recommended by the Centers for Disease Control and Prevention.RESULTS: Among 5,248,746 pregnant patients, 23,636 (0.45%) had an early postpartum readmission, whereas 24,712 (0.47%) had a later postpartum readmission. After adjustments, early readmission was most strongly associated with sepsis (adjusted odds ratio, 4.63; 95% confidence interval, 3.87-5.53), severe maternal morbidity (adjusted odds ratio, 3.46; 95% confidence interval, 3.28-3.65) at birth hospitalization, or preeclampsia before birth hospitalization (adjusted odds ratio, 3.67; 95% confidence interval, 3.54-3.81). The associations between later readmission and sepsis and severe maternal morbidity were similar, whereas the association between preeclampsia and later readmission was less strong (adjusted odds ratio, 1.65; 95% confidence interval, 1.57-1.73).CONCLUSION: Pregnant patients with sepsis or severe maternal morbidity during delivery hospitalization or preeclampsia before birth hospitalization were at the highest risk for readmission within 6 days of discharge. These findings may be informative for efforts to improve postpartum care.

    View details for DOI 10.1016/j.xagr.2022.100094

    View details for PubMedID 36536841

  • Postpartum Readmissions With and Without Severe Maternal Morbidity Within 1 Year of Birth, Oregon, 2012-2017. American journal of epidemiology Kaufman, M., McConnell, K. J., Carmichael, S. L., Rodriguez, M. I., Richardson, D., Snowden, J. M. 2022

    Abstract

    Postpartum readmissions (PPR) represent a critical marker of maternal morbidity. Most Severe Maternal Morbidity (SMM) events result in a hospital admission, but most PPRs do not have evidence of SMM. Little is known about PPR and SMM beyond the first six weeks postpartum. We examined the associations of maternal demographic and clinical factors with PPR within 12 months postpartum. We categorized PPR as with and without evidence of SMM to assess whether risk factors and timing differed. Using the Oregon All Payer All Claims database, we analyzed hospital births from 2012-2017. We used log-binomial regression to estimate associations between maternal factors and PPR. Our final analytic sample included 158,653 births. Overall, 2.7% (N = 4,141) of births had at least one readmission within 12 months postpartum (808 (19.5% of PPRs) with SMM). SMM at delivery was the strongest risk factor for PPR with SMM (Risk Ratio (RR): 5.55, 95% Confidence Interval (CI): 4.14, 7.44). PPR without SMM had numerous risk factors, including any mental health diagnosis (RR: 2.10, CI: 1.91, 2.30), chronic hypertension (RR: 2.17, CI: 1.85, 2.55), and prepregnancy diabetes (RR: 2.85, CI: 2.47, 3.30), all which were on par with SMM at delivery (RR: 1.89, CI: 1.49, 2.40).

    View details for DOI 10.1093/aje/kwac183

    View details for PubMedID 36269008

  • Antihypertensive Medication Use before and during Pregnancy and the Risk of Severe Maternal Morbidity in Individuals with Prepregnancy Hypertension. American journal of perinatology Bane, S., Wall-Wieler, E., Druzin, M. L., Carmichael, S. L. 2022

    Abstract

    OBJECTIVE: Our objective is to examine severe maternal morbidity (SMM) and patterns of antihypertensive medication use before and during pregnancy among individuals with chronic hypertension.STUDY DESIGN: We examined 11,759 pregnancies resulting in a live birth or stillbirth to individuals with chronic hypertension and one or more antihypertensive prescription 6 months before pregnancy (Optum, 2007-17). We examined whether study outcomes were associated with the use of medication as compared to no use during pregnancy. In addition, patterns of medication use based on the Food and Drug Administration guidance and literature were evaluated. Medication use was divided into prepregnancy and during pregnancy use and classified as pregnancy recommended (PR) or not pregnancy recommended (nPR) or no medication use. SMM was defined per the Centers for Disease Control and Prevention definition of 21 indicators. Risk ratios (RR) reflecting the association of SMM with the use of antihypertensive medications were computed using modified Poisson regression with robust standard errors and adjusted for maternal age, education, and birth year.RESULTS: Overall, 83% of individuals filled an antihypertensive prescription during pregnancy and 6.3% experienced SMM. The majority of individuals with a prescription prior to pregnancy had a prescription for the same medication in pregnancy. Individuals with any versus no medication use in pregnancy had increased adjusted RR (aRR) of SMM (1.18, 95% confidence interval [CI]: 0.96-1.44). Compared to the use of PR medications before and during pregnancy, aRRs were 1.42 (95% CI: 1.18-1.69, 12.4% of sample) for nPR use before and during pregnancy, 1.52 (1.23-1.86; 12.4%) for nPR (before) and PR (during) use, and 2.67 (1.73-4.15) for PR and nPR use. Patterns with no medication use during pregnancy were not statistically significant.CONCLUSION: Pattern of antihypertensive medication use before and during pregnancy may be associated with an elevated risk of SMM. Further research is required to elucidate whether this association is related to the severity of hypertension, medication effectiveness, or suboptimal quality of care.KEY POINTS: · Individuals with any medication use compared to no medication use in pregnancy had an increased risk of SMM.. · Specific medication use patterns were associated with an elevated risk of SMM.. · Pattern of antihypertensive medication use before and during pregnancy may be associated with an increased risk of SMM..

    View details for DOI 10.1055/s-0042-1757354

    View details for PubMedID 36261063

  • Differential newborn DNA methylation among individuals with complex congenital heart defects and childhood lymphoma. Birth defects research Richard, M. A., Yang, W., Sok, P., Li, M., Carmichael, S. L., von Behren, J., Reynolds, P., Fisher, P. G., Collins, R. T., Hobbs, C. A., Luke, B., Shaw, G. M., Lupo, P. J. 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

  • Early pregnancy vitamin D status and risk of select congenital anomalies in the National Birth Defects Prevention Study. Birth defects research Adrien, N., Orta, O. R., Nestoridi, E., Carmichael, S. L., Yazdy, M. M., For The National Birth Defects Prevention Study 2022

    Abstract

    INTRODUCTION: Vitamin D deficiency is associated with adverse pregnancy events. However, its role in the etiology of congenital anomalies remains unclear. We examined the association between vitamin D status, measured through prepregnancy diet, UV exposure, season of conception, and congenital anomalies.METHODS: We used data from the National Birth Defects Prevention Study, a U.S. population-based case-control study (1997-2011). Prepregnancy dietary vitamin D was calculated from food frequency questionnaires and evaluated using tertiles, based on the distribution in controls. We used the National Oceanic and Atmospheric Administration Weather Service to assign UV indices based on location and estimated date of conception, then dichotomized UV exposure (low vs. high). Seasons of conception was categorized as fall/winter spring/summer. We used logistic regression to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI).RESULTS: Lower prepregnancy dietary vitamin D intake (<65.21IU/d vs. >107.55IU/d) was associated with increased odds of anencephaly (aOR=1.28, 95% CI 1.01, 1.63), hypospadias (aOR=1.21, 95% CI 1.04, 1.40), septal defects (aOR=1.16, 95% CI 1.05, 1.30), diaphragmatic hernia (aOR=1.42, 95% CI 1.13, 1.79), and gastroschisis (aOR=1.27, 95% CI 1.07, 1.52). Findings were consistent when we stratified by UV exposure and season of conception.CONCLUSIONS: Our findings suggest lower dietary intake of vitamin D may be associated with increased risk of select congenital anomalies. Further investigations are warranted to evaluate the effects of other nutrients and appropriate thresholds and sources of vitamin D using serum.

    View details for DOI 10.1002/bdr2.2101

    View details for PubMedID 36203383

  • Racial/ethnic disparities in severe maternal morbidity: An intersectional lifecourse approach. Annals of the New York Academy of Sciences Hailu, E. M., Carmichael, S. L., Berkowitz, R. L., Snowden, J. M., Lyndon, A., Main, E., Mujahid, M. S. 2022

    Abstract

    Despite long-existing calls to address alarming racial/ethnic gaps in severe maternal morbidity (SMM), research that considers the impact of intersecting social inequities on SMM risk remains scarce. Invoking intersectionality theory, we sought to assess SMM risk at the nexus of racial/ethnic marginalization, weathering, and neighborhood/individual socioeconomic disadvantage. We used birth hospitalization records from California across 20 years (1997-2017, N = 9,806,406) on all live births ≥20 weeks gestation. We estimated adjusted average predicted probabilities of SMM at the combination of levels of race/ethnicity, age, and neighborhood deprivation or individual socioeconomic status (SES). The highest risk of SMM was observed among Black birthing people aged ≥35 years who either resided in the most deprived neighborhoods or had the lowest SES. Black birthing people conceptualized to be better off due to their social standing (aged 20-34 years and living in the least deprived neighborhoods or college graduates) had comparable and at times worse risk than White birthing people conceptualized to be worse off (aged ≥35 years and living in the most deprived neighborhoods or had a high-school degree or less). Our findings highlight the need to explicitly address structural racism as the driver of racial/ethnic health inequities and the imperative to incorporate intersectional approaches.

    View details for DOI 10.1111/nyas.14901

    View details for PubMedID 36166238

  • Risk factors and pregnancy outcomes vary among Asian American, Native Hawaiian, and Pacific Islander individuals giving birth in California. Annals of epidemiology Bane, S., Abrams, B., Mujahid, M., Ma, C., Shariff-Marco, S., Main, E., Profit, J., Xue, A., Palaniappan, L., Carmichael, S. L. 2022

    Abstract

    OBJECTIVE: To compare frequencies of risk factors and pregnancy outcomes in ethnic groups versus the combined total of Asian American, Native Hawaiian, and Pacific Islander (AANHPI) populations.METHODS: Using linked birth and fetal death certificate and maternal hospital discharge data (California 2007-2018), we estimated frequencies of 15 clinical and sociodemographic exposures and 11 pregnancy outcomes. Variability across 15 AANHPI groups was compared using a heat map and compared to frequencies for the total group (n=904,232).RESULTS: AANHPI groups varied significantly from each other and the combined total regarding indicators of social disadvantage (e.g., range for high school-level educational or less: 6.4% Korean-55.8% Samoan) and sociodemographic factors (e.g., maternal age <20 years: 0.2% Chinese-8.8% Guamanian) that are related to adverse pregnancy outcomes. Perinatal outcomes varied significantly (e.g., severe maternal morbidity: 1.2% Korean-1.9% Filipino). No single group consistently had risk factors or outcome prevalence at the extremes, i.e., no group was consistently better or worse off across examined factors.CONCLUSIONS: Substantial variability in perinatal risk factors and outcomes exists across AANHPI groups. Aggregation into "AANHPI" is not appropriate for outcome reporting.

    View details for DOI 10.1016/j.annepidem.2022.09.004

    View details for PubMedID 36115627

  • Using Longitudinally Linked Data to Measure Severe Maternal Morbidity Beyond the Birth Hospitalization in California. Obstetrics and gynecology Carmichael, S. L., Girsen, A. I., Ma, C., Main, E. K., Gibbs, R. S. 2022

    Abstract

    Most studies of severe maternal morbidity (SMM) include only cases that occur during birth hospitalizations. We examined the increase in cases when including SMM during antenatal and postpartum (within 42 days of discharge) hospitalizations, using longitudinally linked data from 1,010,250 births in California from September 1, 2016, to December 31, 2018. For total SMM, expanding the definition resulted in 22.8% more cases; for nontransfusion SMM, 45.1% more cases were added. Sepsis accounted for 55.5% of the additional cases. The increase varied for specific indicators, for example, less than 2% for amniotic fluid embolism, 7.0% for transfusion, 112.9% for sepsis, and 155.6% for acute myocardial infarction. These findings reiterate the importance of considering SMM beyond just the birth hospitalization and facilitating access to longitudinally linked data to facilitate a more complete understanding of SMM.

    View details for DOI 10.1097/AOG.0000000000004902

    View details for PubMedID 35926198

  • Distance from home to birth hospital, transfer, and mortality in neonates with hypoplastic left heart syndrome in California. Birth defects research Purkey, N. J., Ma, C., Lee, H. C., Hintz, S. R., Shaw, G. M., McElhinney, D. B., Carmichael, S. L. 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

  • Subsequent risk of stillbirth, preterm birth, and small for gestational age: A cross-outcome analysis of adverse birth outcomes. Paediatric and perinatal epidemiology Bane, S., Simard, J. F., Wall-Wieler, E., Butwick, A. J., Carmichael, S. L. 2022

    Abstract

    BACKGROUND: Stillbirth, preterm birth, and small for gestational age (SGA) birth have an increased recurrence risk. The occurrence of one of these biologically related outcomes could also increase the risk for another one of these outcomes in a subsequent pregnancy.OBJECTIVES: We assessed cross-outcome risks for subsequent stillbirth, preterm birth, and SGA.METHODS: We used live birth and fetal death records to identify singleton, sequential birth pairs in California (1997-2017). Stillbirth was defined as delivery at ≥20weeks of gestation of a foetus that died in utero; preterm birth as live birth at 20-36weeks; and small for gestational age as sex-specific birthweight <10th percentile for gestational age. Risk ratios (RR) were computed using modified Poisson regression and adjusted for potential confounders. Sensitivity analyses included analysing a cohort restricted to primiparous index births and using inverse-probability censoring weights.RESULTS: Of 3,108,532 birth pairs, 16,668 (0.5%), 260,596 (8.4%) and 331,109 (10.7%) of index births were stillborn, preterm and SGA, respectively. Among individuals with an index stillbirth, the adjusted RRs were 1.90 (95% confidence interval [CI] 1.83, 1.98) for subsequent preterm and 1.35 (95% CI 1.28, 1.41) for subsequent SGA. Among those with index preterm birth, the adjusted RRs were 2.02 (95% CI 1.92, 2.13) for stillbirth and 1.42 (95%CI1.41, 1.44) for SGA. Among those with index SGA, the adjusted RRs were 1.54 (95% CI 1.46, 1.63) for stillbirth and 1.45 (95% CI 1.44, 1.47) for preterm birth. Similar results were reported for sensitivity analyses.CONCLUSIONS: Individuals experiencing stillbirth, preterm birth, or SGA in one pregnancy had an increased risk of one of these biologically related outcomes in a subsequent pregnancy. These findings could encourage enhanced surveillance for individuals who experience stillbirth, preterm birth, or SGA and desire a subsequent pregnancy.

    View details for DOI 10.1111/ppe.12881

    View details for PubMedID 35437809

  • Does active treatment in infants born at 22-23 weeks correlate with outcomes of more mature infants at the same hospital? An analysis of California NICU data, 2015-2019. Journal of perinatology : official journal of the California Perinatal Association Bane, S., Rysavy, M. A., Carmichael, S. L., Lu, T., Bennett, M., Lee, H. C. 2022

    Abstract

    OBJECTIVE: To investigate whether hospital rates of active treatment for infants born at 22-23 weeks is associated with survival of infants born at 24-27 weeks.STUDY DESIGN: We included all liveborn infants 22-27 weeks of gestation delivered at California Perinatal Quality Care Collaborative hospitals from 2015 to 2019. We assessed (1) the correlation of active treatment (e.g., endotracheal intubation, epinephrine) in 22-23 week infants and survival until discharge for 24-27 week infants and (2) the association of active treatment with survival using multilevel models.RESULT: The 22-23 week active treatment rate was associated with infant outcomes at 22-23 weeks but not 24-27 weeks. A 10% increase in active treatment did not relate to 24-25 week (adjusted OR: 1.00 [95% CI: 0.95-1.05]), or 26-27 week survival (aOR: 1.02 [0.95-1.09]).CONCLUSION: The hospital rate of active treatment for infants born at 22-23 weeks was not associated with improved survival for 24-27 week infants.

    View details for DOI 10.1038/s41372-022-01381-x

    View details for PubMedID 35361887

  • Association of infertility with atherosclerotic cardiovascular disease among postmenopausal participants in the Women's Health Initiative. Fertility and sterility Murugappan, G., Leonard, S. A., Farland, L. V., Lau, E. S., Shadyab, A. H., Wild, R. A., Schnatz, P., Carmichael, S. L., Stefanick, M. L., Parikh, N. I. 2022

    Abstract

    OBJECTIVE: To investigate the association of infertility with atherosclerotic cardiovascular disease (ASCVD) among postmenopausal participants in the Women's Health Initiative (WHI). We hypothesized that nulliparity and pregnancy loss may reveal more extreme phenotypes of infertility, enabling further understanding of the association of infertility with ASCVD.DESIGN: Prospective cohort study.SETTING: Forty clinical centers in the United States.PATIENT(S): A total of 158,787 postmenopausal participants in the Women's Health Initiative cohort.INTERVENTION(S): Infertility, parity, and pregnancy loss.MAIN OUTCOME MEASURE(S): The primary outcome was risk of ASCVD among women with and without a history of infertility, stratified by history of live birth and pregnancy loss. Cox proportional-hazards models were adjusted for demographics and risk factors for ASCVD.RESULT(S): Among 158,787 women, 25,933 (16.3%) reported a history of infertility; 20,427 (80%) had at least 1 live birth; and 9,062 (35%) had at least 1 pregnancy loss. There was a moderate overall association between infertility and ASCVD (adjusted hazard ratio, 1.02; 95% confidence interval [CI], 0.99-1.06) over 19 years of follow-up. Among nulliparous women, infertility was associated with a 13% higher risk of ASCVD (95% CI, 1.04-1.23). Among nulliparous women who had a pregnancy loss, infertility was associated with a 36% higher risk of ASCVD (95% CI, 1.09-1.71).CONCLUSION(S): Women with a history of infertility overall had a moderately higher risk of ASCVD compared with women without a history of infertility. Atherosclerotic cardiovascular disease risk was much higher among nulliparous infertile women and among nulliparous infertile women who also had a pregnancy loss, suggesting that in these more extreme phenotypes, infertility may be associated with ASCVD risk.

    View details for DOI 10.1016/j.fertnstert.2022.02.005

    View details for PubMedID 35305814

  • Clinical and Hospital Factors Associated with Increased Cesarean Birth Rate Among People with Epilepsy Darmawan, K., Cruz, G., Leonard, S., Meador, K., McElrath, T., Carmichael, S., Lyell, D., El Sayed, Y., Herrero, T., Druzin, M., Panelli, D. SPRINGER HEIDELBERG. 2022: 216
  • Interpregnancy Weight Change: Associations with Severe Maternal Morbidity and Neonatal Outcomes. American journal of obstetrics & gynecology MFM Abrams, B. F., Leonard, S. A., Kan, P., Lyell, D. J., Carmichael, S. L. 2022: 100596

    Abstract

    INTRODUCTION: Prepregnancy body mass index (BMI) and gestational weight gain have been linked with severe maternal morbidity (SMM), suggesting that weight change between pregnancies may also play a role, as it does for neonatal outcomes. We assessed the association of changes in prepregnancy BMI between two consecutive singleton pregnancies with the outcomes of SMM, stillbirth, small for gestational age (SGA) and large for gestational age (LGA) in the subsequent pregnancy.METHODS: This observational study was based on birth records from 1,111,032 consecutive pregnancies linked to hospital discharge records in California (2007-2017). Interpregnancy BMI change between the beginning of an index pregnancy and the beginning of the subsequent pregnancy was calculated from self-reported weight and height. SMM was defined based on the CDC index, including and excluding transfusion-only cases. We used multivariable log-binomial regression models to estimate adjusted risks, overall and stratified by prepregnancy BMI at index birth.RESULTS: Substantial interpregnancy BMI gain (≥4 kg/m2) was associated with SMM in crude but not adjusted analyses. Substantial interpregnancy BMI loss (>2 kg/m2) was associated with increased risk of SMM (adjusted relative risk (aRR) 1.13, 95% CI (1.07-1.19), and both substantial loss (aRR 1.11 (1.02-1.19)) and gain (≥4 kg/m2; aRR 1.09 (1.02-1.17)) were associated with non-transfusion SMM. Substantial loss (aRR 1.17 (1.05-1.31)) and gain (1.26 (1.14-1.40)) were associated with stillbirth. BMI gain was positively associated with LGA, and inversely associated with SGA.CONCLUSIONS: Substantial interpregnancy BMI changes were associated with modestly increased risk of SMM, stillbirth, SGA and LGA.

    View details for DOI 10.1016/j.ajogmf.2022.100596

    View details for PubMedID 35181513

  • Impact of Medicaid Expansion on Interpregnancy Interval. Women's health issues : official publication of the Jacobs Institute of Women's Health Liu, C., Snowden, J. M., Rossin-Slater, M., Torche, F., DiTosto, J. D., Carmichael, S. L. 1800

    Abstract

    OBJECTIVES: Medicaid expansion under the Affordable Care Act (ACA) improved access to reproductive health care for low-income women and birthing people who were previously ineligible for Medicaid. We aimed to evaluate if the expansion affected the risk of having a short interpregnancy interval (IPI), a preventable risk factor for adverse pregnancy outcomes.METHODS: We evaluated parous singleton births to mothers aged 19 or older from U.S. birth certificate data 2009-2018. We estimated the effect of residing in a state that expanded Medicaid access (expansion status determined at 60days after the prior live birth) on the risk of having a short IPI (<12months) using difference-in-differences (DID) methods in linear probability models. We stratified the analyses by maternal characteristics and county-level reproductive health care access.RESULTS: Overall risk of short IPI was 14.9% in expansion states and 16.3% in non-expansion states. The expansion was not associated with a significant change in risk of having a short IPI (adjusted mean percentage point change 1.24 [-1.64, 4.12]). Stratified results also did not provide support for an association.CONCLUSIONS: ACA Medicaid expansion did not have an impact on risk of short IPI. Preventing short IPI may require more comprehensive policy interventions in addition to health care access.

    View details for DOI 10.1016/j.whi.2021.12.004

    View details for PubMedID 35016841

  • Hospital Readmissions after Postpartum Emergency Department Visit Girsen, A., Leonard, S. A., Carmichael, S. L., Gibbs, R. S., Butwick, A. MOSBY-ELSEVIER. 2022: S517-S518
  • Ways Forward in Preventing Severe Maternal Morbidity and Maternal Health Inequities: Conceptual Frameworks, Definitions, and Data, from a Population Health Perspective. Women's health issues : official publication of the Jacobs Institute of Women's Health Carmichael, S. L., Abrams, B., El Ayadi, A., Lee, H. C., Liu, C., Lyell, D. J., Lyndon, A., Main, E. K., Mujahid, M., Tian, L., Snowden, J. M. 1800

    View details for DOI 10.1016/j.whi.2021.11.006

    View details for PubMedID 34972599

  • Association of Epilepsy and Severe Maternal Morbidity. Obstetrics and gynecology Panelli, D. M., Leonard, S. A., Kan, P., Meador, K. J., McElrath, T. F., Darmawan, K. F., Carmichael, S. L., Lyell, D. J., El-Sayed, Y. Y., Druzin, M. L., Herrero, T. C. 2021

    Abstract

    OBJECTIVE: To evaluate severe maternal morbidity (SMM) among patients with epilepsy and patients without epilepsy.METHODS: We retrospectively examined SMM using linked birth certificate and maternal hospital discharge records in California between 2007 and 2012. Epilepsy present at delivery admission was the exposure and was subtyped into generalized, focal and other less specified, or unspecified. The outcomes were SMM and nontransfusion SMM from delivery up to 42 days' postpartum, identified using Centers for Disease Control and Prevention indicators. Multivariable logistic regression models were used to adjust for confounders, which were selected a priori. We also estimated the association between epilepsy and SMM independent of comorbidities by using a validated obstetric comorbidity score. Severe maternal morbidity indicators were then compared using the same multivariable logistic regression models.RESULTS: Of 2,668,442 births, 8,145 (0.3%) were to patients with epilepsy; 637 (7.8%) had generalized, 6,250 (76.7%) had focal or other less specified, and 1,258 (15.4%) had unspecified subtypes. Compared with patients without epilepsy, patients with epilepsy had greater odds of SMM (4.3% vs 1.4%, adjusted odds ratio [aOR] 2.91, 95% CI 2.61-3.24) and nontransfusion SMM (2.9% vs 0.7%, aOR 4.16, 95% CI 3.65-4.75). Epilepsy remained significantly associated with increased SMM and nontransfusion SMM after additional adjustment for the obstetric comorbidity score, though the effects were attenuated. When grouped by organ system, all SMM indicators were significantly more common among patients with epilepsy-most notably those related to hemorrhage and transfusion.CONCLUSION: Severe maternal morbidity was significantly increased in patients with epilepsy, and SMM indicators across all organ systems contributed to this.

    View details for DOI 10.1097/AOG.0000000000004562

    View details for PubMedID 34619720

  • INFERTILITY AND RISK OF CARDIOVASCULAR DISEASE AMONG POSTMENOPAUSAL PARTICIPANTS IN THE WOMEN'S HEALTH INITIATIVE. Murugappan, G., Leonard, S. A., Carmichael, S. L., Stefanick, M. L., Parikh, N. I. ELSEVIER SCIENCE INC. 2021: E15
  • Does Severe Maternal Morbidity impact the probability of subsequent birth? A population-based study of women in California from 1997-2012. Annals of epidemiology Bane, S., Carmichael, S. L., Snowden, J. M., Liu, C., Lyndon, A., Wall-Wieler, E. 2021

    Abstract

    Complications during pregnancy and birth can impact whether an individual has more children. Our objective was to assess whether experiencing severe maternal morbidity (SMM) during first birth affected the probability of having another child. This study used linked vital records and maternal discharges from 1997 to 2012 for all California births, and SMM was identified using a Centers for Disease Control and Prevention index. Individuals whose first birth was a singleton live birth (n = 3,062,619) were followed until their second birth or December 31, 2012, whichever came first. Hazard ratios for having a subsequent birth were estimated using Cox proportional hazard regression models. This association was assessed overall and stratified by maternal factors of a priori interest: age, race/ethnicity, and payer. Of the 3,062,619individuals in our study, 34,729 (1.1%) experienced SMM at first birth. Compared to those who do not experience SMM, individuals who had SMM had a lower hazard, or instantaneous rate, of subsequent birth (adjusted HR 0.81, 95% CI: 0.80, 0.83); this association was observed in all levels of stratification and all indicators of SMM. Individuals who experience SMM at the time of their first birth are less likely to have another child.

    View details for DOI 10.1016/j.annepidem.2021.08.017

    View details for PubMedID 34418536

  • Maternal exposure to hydroxychloroquine and birth defects. Birth defects research Howley, M. M., Werler, M. M., Fisher, S. C., Van Zutphen, A. R., Carmichael, S. L., Broussard, C. S., Heinke, D., Ailes, E. C., Pruitt, S. M., Reefhuis, J., Mitchell, A. A., Browne, M. L., National Birth Defects Prevention Study 2021

    Abstract

    BACKGROUND: Hydroxychloroquine is a treatment for rheumatic disease and considered safe during pregnancy. Interest in hydroxychloroquine has increased as it is being examined as a potential treatment and prophylaxis for coronavirus disease 2019. Data on the risks of specific birth defects associated with hydroxychloroquine use are sparse.METHODS: Using data from two case-control studies (National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study), we described women who reported hydroxychloroquine use in pregnancy and the presence of specific major birth defects in their offspring. Cases had at least one major birth defect and controls were live-born healthy infants. Women self-reported medication use information in the few months before pregnancy through delivery.RESULTS: In total, 0.06% (19/31,468) of case and 0.04% (5/11,614) of control mothers in National Birth Defects Prevention Study, and 0.04% (11/29,838) of case and 0.05% (7/12,868) of control mothers in Birth Defects Study reported hydroxychloroquine use. Hydroxychloroquine users had complicated medical histories and frequent medication use for a variety of conditions. The observed birth defects among women taking hydroxychloroquine were varied and included nine oral cleft cases; the elevated observed:expected ratios for specific oral cleft phenotypes and for oral clefts overall had 95% confidence intervals that included 1.0.CONCLUSION: While teratogens typically produce a specific pattern of birth defects, the observed birth defects among the hydroxychloroquine-exposed women did not present a clear pattern, suggesting no meaningful evidence for the risk of specific birth defects. The number of exposed cases is small; results should be interpreted cautiously.

    View details for DOI 10.1002/bdr2.1943

    View details for PubMedID 34296811

  • Implementing health communication tools at scale: mobile audio messaging and paper-based job aids for front-line workers providing community health education to mothers in Bihar, India. BMJ global health Ward, V., Abdalla, S., Raheel, H., Weng, Y., Godfrey, A., Dutt, P., Mitra, R., Sastry, P., Chamberlain, S., Shannon, M., Mehta, K., Bentley, J., Darmstadt Md, G. L., Ananya Study Group, Atmavilas, Y., Bentley, J., Bhattacharya, D., Borkum, E., Carmichael, S. L., Chaudhuri, I., Creanga, A., Darmstadt, G. L., Dutt, P., Irani, L., Krishnan, S., Mahapatra, T., Mehta, K. M., Mitra, R., Munar, W., Nanda, P., Pepper, K., Raheel, H., Rangarajan, A., Saggurti, N., Sastry, P., Schooley, J., Shah, H., Srikantiah, S., Tarigopula, U. K., Ward, V., Walker, D., Weng, Y., Wilhelm, J. 2021; 6 (Suppl 5)

    Abstract

    INTRODUCTION: As part of an investment by the Bill & Melinda Gates Foundation to support the Government of Bihar to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) statewide, BBC Media Action implemented multiple communication tools to support front-line worker (FLW) outreach. We analyse the impacts of a package of mHealth audio messaging and paper-based job aids used by FLWs during government-sponsored village health, sanitation and nutrition days (VHSNDs) on knowledge and practices of childbearing women across the RMNCHN continuum of care.METHODS: Data from two surveys collected between July and September 2016 were analysed using logistic regression to compare health-related knowledge and behaviours between women who had been exposed at VHSNDs to the mHealth GupShup Potli (GSP) audio recordings or interpersonal communication (IPC) tools versus those who were unexposed.RESULTS: Exposure to GSP recordings (n=2608) was associated with improved knowledge across all continuum-of-care domains, as well as improved health-related behaviours in some domains. The odds of having taken iron-folic acid (IFA) tablets were significantly higher in exposed women (OR 1.5, 95% CI 1.1 to 2.2), as was contraceptive use (OR 2.0, 95% CI 1.2 to 3.2). There were no differences in birth preparedness or complementary feeding practices between groups. Exposure to IPC paper-based tools (n=2002) was associated with a twofold increased odds of IFA consumption (OR 2.3, 95% CI 1.7 to 3.2) and contraceptive use (OR 1.8, 95% CI 1.2 to 2.8). Women exposed to both tools were generally at least twice as likely to subsequently discuss the messages with others.CONCLUSION: BBC Media Action's mHealth audio messaging job aids and paper-based IPC tools were associated with improved knowledge and practices of women who were exposed to them across multiple domains, suggesting their important potential for improving health outcomes for beneficiaries at scale in low-resource settings.TRIAL REGISTRATION NUMBER: NCT02726230.

    View details for DOI 10.1136/bmjgh-2021-005538

    View details for PubMedID 34312155

  • Drinking water contaminants in California and hypertensive disorders in pregnancy. Environmental epidemiology (Philadelphia, Pa.) Padula, A. M., Ma, C., Huang, H., Morello-Frosch, R., Woodruff, T. J., Carmichael, S. L. 2021; 5 (2): e149

    Abstract

    Environmental pollutants have been associated with hypertensive disorders in pregnancy including gestational hypertension, preeclampsia, and eclampsia, though few have focused on drinking water contamination. Water pollution can be an important source of exposures that may contribute to adverse pregnancy outcomes.Methods: We linked water quality data on 13 contaminants and two violations from the California Communities Environmental Health Screening Tool to birth records from vital statistics and hospital discharge records (2007-2012) to examine the relationship between drinking water contamination and hypertensive disorders in pregnancy. We examined contaminants in single- and multipollutant models. Additionally, we examined if the relationship between water contamination and hypertensive disorders in pregnancy differed by neighborhood poverty, individual socioeconomic status, and race/ethnicity.Results: Arsenic, nitrate, trihalomethane, hexavalent chromium, and uranium were detected in a majority of water systems. Increased risk of hypertensive disorders in pregnancy was modestly associated with exposure to cadmium, lead, trihalomethane, and hexavalent chromium in drinking water after adjusting for covariates in single pollutant models with odds ratios ranging from 1.01 to 1.08. In multipollutant models, cadmium was consistent, lead and trihalomethane were stronger, and additional contaminants were associated with hypertensive disorders in pregnancy including trichloroethylene, 1,2-Dibromo-3-chloropropane, nitrate, and tetrachloroethylene. Other contaminants either showed null results or modest inverse associations. The relationship between water contaminants and hypertensive disorders in pregnancy did not differ by neighborhood poverty.Conclusions: We found increased risk of hypertensive disorders in pregnancy associated with exposure to several contaminants in drinking water in California. Results for cadmium, lead, trihalomethane, and hexavalent chromium were robust in multipollutant models.

    View details for DOI 10.1097/EE9.0000000000000149

    View details for PubMedID 33870020

  • Severe Maternal Morbidity: A Comparison of Definitions and Data Sources. American journal of epidemiology Snowden, J. M., Lyndon, A., Kan, P., El Ayadi, A., Main, E., Carmichael, S. L. 2021

    Abstract

    Severe maternal morbidity (SMM) is a composite outcome measure that indicates serious, potentially life-threatening maternal health problems. There is great interest in defining SMM using administrative data for surveillance and research. In the US, one common way of defining SMM at the population level is an index developed by the Centers for Disease Control and Prevention. Modifications have been proposed to this index (e.g., excluding maternal transfusion); some research defines SMM using an index introduced by Bateman et al. Birth certificate data are also increasingly being used to define SMM. We compared commonly used US definitions of SMM to each other among all California births, 2007-2012, using the Kappa statistic and other measures. We also evaluated agreement between maternal morbidity fields on the birth certificate compared to claims data. Concordance was generally low between the 7 definitions of SMM analyzed (i.e., kappa < 0.4 for 13 of 21 two-way comparisons), Low concordance was particularly driven by presence/absence of transfusion and claims data versus birth certificate definitions. Low agreement between administrative data-based definitions of SMM highlights that results can be expected to differ between them. Further research is needed on validity of SMM definitions, using more fine-grained data sources.

    View details for DOI 10.1093/aje/kwab077

    View details for PubMedID 33755046

  • Risk Factors for Postpartum Readmission Among Women After Having a Stillbirth. American journal of obstetrics & gynecology MFM DiTosto, J. D., Liu, C., Wall-Wieler, E., Gibbs, R. S., Girsen, A. I., El-Sayed, Y. Y., Butwick, A. J., Carmichael, S. L. 2021: 100345

    Abstract

    BACKGROUND: Compared to women with a livebirth, women with a stillbirth are more likely to have maternal complications during pregnancy and at birth, but risk factors related to their postpartum health are uncertain.OBJECTIVE: This study aimed to identify patient-level risk factors for postpartum hospital readmission among women after having a stillbirth.STUDY DESIGN: This is a population-based cohort study of 29,654 women with a stillbirth in California from 1997-2011. Using logistic regression models, we examined the association of maternal patient-level factors with postpartum readmission among women after a stillbirth within six weeks of hospital discharge and between six weeks and nine months after birth.RESULTS: Within six weeks after a stillbirth, 642 (2.2%) women had a postpartum readmission. Risk factors for postpartum readmission after a stillbirth were: severe maternal morbidity excluding transfusion (aOR= 3.02, 95% CI 2.28-4.00), transfusion at delivery but no other indication of severe maternal morbidity (aOR= 1.95, 95% CI 1.35-2.81), gestational hypertension or preeclampsia (aOR=1.93, 95% CI 1.54-2.42), pre-pregnancy hypertension (aOR= 1.80, 95% CI 1.36-2.37), diabetes (aOR= 1.78, 95% CI = 1.33-2.37), an antenatal hospitalization (aOR= 1.78, 95% CI 1.43-2.21), cesarean birth (aOR= 1.73, 95% CI 1.43-2.21), long (> 2 days for vaginal birth, > 4 days for cesarean birth) birth hospitalization length of stay (aOR= 1.59, 95% CI 1.33-1.89), non- Hispanic black race/ ethnicity (aOR= 1.38, 95% CI 1.08-1.76), and having less than a high school education (aOR= 1.35, 95% CI 1.02-1.80). From 6 weeks to 9 months, 1,169 (3.90%) women had a postpartum readmission; significantly associated risk factors were largely similar to those for earlier readmission.CONCLUSION: Women with comorbidities, birth-related complications, of non-Hispanic black race/ ethnicity, or with less education had increased odds of postpartum readmission after having a stillbirth, highlighting the importance of continued care for these women after birth hospitalization.TRIAL REGISTRATION: Not applicable.

    View details for DOI 10.1016/j.ajogmf.2021.100345

    View details for PubMedID 33705999

  • Interpregnancy Interval and Subsequent Severe Maternal Morbidity: A Population-based Study from California over 16 years. American journal of epidemiology Liu, C., Snowden, J. M., Lyell, D. J., Wall-Wieler, E., Abrams, B., Kan, P., Stephansson, O., Lyndon, A., Carmichael, S. L. 2021

    Abstract

    Interpregnancy interval (IPI) associates with adverse perinatal outcomes, but its contribution to severe maternal morbidity (SMM) remains unclear. We examined the association between IPI and SMM, using data linked across sequential pregnancies to women in California 1997-2012. Adjusting for confounders measured at the index pregnancy (i.e. the first in a pair of consecutive pregnancies), we estimated adjusted risk ratios (aRRs) of SMM related to the subsequent pregnancy. We further conducted within-mother comparisons and analyses stratified by parity and maternal age at the index pregnancy. Compared to 18-23 months, IPI<6 months had same risk for SMM in between-mother comparison (aRR=0.96, 95%CI 0.91, 1.02) but lower risk in within-mother comparison (aRR=0.76, 95% confidence interval (CI) 0.67, 0.86). IPI 24-59 months and IPI≥60 months associated with increased risk of SMM in both between-mother (aRR=1.18, 95%CI 1.13, 1.23 and aRR=1.76, 95% CI 1.68, 1.85 respectively) and within-mother comparisons (aRR=1.22, 95%CI 1.11, 1.34 and aRR=1.88, 95% CI 1.66, 2.13 respectively). The association between IPI and SMM did not substantially differ by maternal age and parity. Longer IPI was associated with increased risk of SMM, which may be partly attributed to interpregnancy health.

    View details for DOI 10.1093/aje/kwab020

    View details for PubMedID 33543241

  • Timing of Transfer and Mortality in Neonates with Hypoplastic Left Heart Syndrome in California. Pediatric cardiology Purkey, N. J., Ma, C., Lee, H. C., Hintz, S. R., Shaw, G. M., McElhinney, D. B., Carmichael, S. L. 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

  • Prepregnancy body mass index and gestational diabetes mellitus across asian subpopulations Sperling, M., Leonard, S. A., Waldrop, A. R., Miller, S., Blumenfeld, Y. J., Carmichael, S., Chueh, J. MOSBY-ELSEVIER. 2021: S118–S119
  • Obstetric comorbidity scores and disparities in severe maternal morbidity across marginalized groups. American journal of obstetrics & gynecology MFM Leonard, S. A., Main, E. K., Lyell, D. J., Carmichael, S. L., Kennedy, C. J., Johnson, C., Mujahid, M. S. 2021: 100530

    Abstract

    A recently developed obstetric comorbidity scoring system enables comparisons of severe maternal morbidity rates independent of health status at the time of birth hospitalization. However, the scoring system has not been evaluated in racial-ethnic and socioeconomic groups or used to assess disparities in severe maternal morbidity.To evaluate the performance of applying an obstetric comorbidity scoring system across racial-ethnic and socioeconomic groups and to determine the effect of comorbidity score risk adjustment on disparities in severe maternal morbidity.We analyzed a population-based cohort of live births in California during 2011-2017 with linked birth certificate and birth hospitalization discharge data (n = 3,308,554). We updated a previously developed comorbidity scoring system to include ICD-9-CM and ICD-10-CM diagnosis codes, and applied the scoring system in subpopulations (groups) defined by race-ethnicity, nativity, payment method, and educational attainment. We then calculated risk-adjusted rates of severe maternal morbidity (including and excluding blood transfusion-only cases) in each group and estimated disparities for these outcomes before and after adjustment for the comorbidity score using logistic regression.The obstetric comorbidity scores performed consistently across groups (C-statistics ranged from 0.68-0.76; calibration curves demonstrated overall excellent prediction of absolute risk). All non-White groups had significantly elevated rates of severe maternal morbidity before and after risk adjustment for comorbidities compared to the White group (1.3% before, 1.3% after): American Indian-Alaska Native (2.1% before, 1.8% after), Asian (1.5% before, 1.7% after), Black (2.5% before, 2.0% after), Latinx (1.6% before, 1.7% after), Pacific Islander (2.2% before, 1.9% after), and Multi-race groups (1.7% before, 1.6% after). Risk adjustment also modestly increased disparities for the foreign-born group and non-commercial insurance groups. Increasing educational attainment was associated with decreasing severe maternal morbidity rates, which was largely unaffected by comorbidity risk adjustment. The pattern of results was the same whether or not transfusion-only cases were included as severe maternal morbidity.These results support the use of an updated comorbidity scoring system to assess disparities in severe maternal morbidity. Disparities in severe maternal morbidity decreased in magnitude for some racial-ethnic and socioeconomic groups and increased in magnitude for others after adjustment for the comorbidity score.

    View details for DOI 10.1016/j.ajogmf.2021.100530

    View details for PubMedID 34798329

  • 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 Zaganjor, I., Luben, T. J., Desrosiers, T. A., Keil, A. P., Engel, L. S., Michalski, A. M., Carmichael, S. L., Nembhard, W. N., Shaw, G. M., Reefhuis, J., Yazdy, M. M., Langlois, P. H., Feldkamp, M. L., Romitti, P. A., Olshan, A. F., The National Birth Defects Prevention Study 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

  • Factors associated with follow-up of infants with hypoxic-ischemic encephalopathy in a high-risk infant clinic in California. Journal of perinatology : official journal of the California Perinatal Association Pai, V. V., Kan, P., Lu, T., Gray, E. E., Bennett, M., Jocson, M. A., Lee, H. C., Carmichael, S. L., Hintz, S. R. 2020

    Abstract

    OBJECTIVE: To determine the rates of high-risk infant follow-up (HRIF) attendance and the characteristics associated with follow-up among infants with hypoxic-ischemic encephalopathy (HIE) in California.STUDY DESIGN: Using population-based datasets, 1314 infants with HIE born in 2010-2016 were evaluated. The characteristics associated with follow-up were identified through multivariable logistic regression.RESULTS: 73.9% of infants attended HRIF by age 1. Follow-up rates increased and variation in follow-up by clinic decreased over time. Female infants; those born to African-American, single, less than college-educated, or publicly insured caregivers; and those referred to high-volume or regional programs had lower follow-up rates. In multivariable analysis, Asian and Pacific Islander race/ethnicity had lower odds of follow-up; infants with college- or graduate school-educated caregivers or referred to mid-volume HRIF programs had greater odds.CONCLUSION: Sociodemographic and program-level characteristics were associated with lack of follow-up among HIE infants. Understanding these characteristics may improve the post-discharge care of HIE infants.

    View details for DOI 10.1038/s41372-020-00898-3

    View details for PubMedID 33311530

  • Trends in reproductive, maternal, newborn and child health and nutrition indicators during five years of piloting and scaling-up of Ananya interventions in Bihar, India. Journal of global health Abdalla, S., Weng, Y., Mehta, K. M., Mahapatra, T., Srikantiah, S., Shah, H., Ward, V. C., Pepper, K. T., Bentley, J., Carmichael, S. L., Creanga, A., Wilhelm, J., Tarigopula, U. K., Nanda, P., Bhattacharya, D., Atmavilas, Y., Darmstadt, G. L., Ananya Study Group, Atmavilas, Y., Bentley, J., Bhattacharya, D., Borkum, E., Carmichael, S. L., Chaudhuri, I., Creanga, A., Darmstadt, G. L., Dutt, P., Delhi, N., Irani, L., Delhi, N., Krishnan, S., Mahapatra, T., Mehta, K. M., Francisco, S., Mitra, R., Munar, W., Nanda, P., Pepper, K. T., Raheel, H., Rangarajan, A., Saggurti, N., Sastry, P., Schooley, J., Shah, H., Srikantiah, S., Tarigopula, U. K., Ward, V. C., Walker, D., Weng, Y., Wilhelm, J. 2020; 10 (2): 021003

    Abstract

    Background: The Ananya program in Bihar implemented household and community-level interventions to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) in two phases: a first phase of intensive ancillary support to governmental implementation and innovation testing by non-government organisation (NGO) partners in eight focus districts (2012-2014), followed by a second phase of state-wide government-led implementation with techno-managerial assistance from NGOs (2014 onwards). This paper examines trends in RMNCHN indicators in the program's implementation districts from 2012-2017.Methods: Eight consecutive rounds of cross-sectional Community-based Household Surveys conducted by CARE India in 2012-2017 provided comparable data on a large number of indicators of frontline worker (FLW) performance, mothers' behaviours, and facility-based care and outreach service delivery across the continuum of maternal and child care. Logistic regression, considering the complex survey design and sample weights generated by that design, was used to estimate trends using survey rounds 2-5 for the first phase in the eight focus districts and rounds 6-9 for the second phase in all 38 districts statewide, as well as the overall change from round 2-9 in focus districts. To aid in contextualising the results, indicators were also compared amongst the formerly focus and the non-focus districts at the beginning of the second phase.Results: In the first phase, the levels of 34 out of 52 indicators increased significantly in the focus districts, including almost all indicators of FLW performance in antenatal and postnatal care, along with mother's birth preparedness, some breastfeeding practices, and immunisations. Between the two phases, 33 of 52 indicators declined significantly. In the second phase, the formerly focus districts experienced a rise in the levels of 14 of 50 indicators and a decline in the levels of 14 other indicators. There was a rise in the levels of 22 out of 50 indicators in the non-focus districts in the second phase, with a decline in the levels of 13 other indicators.Conclusions: Improvements in indicators were conditional on implementation support to program activities at a level of intensity that was higher than what could be achieved at scale so far. Successes during the pilot phase of intensive support suggests that RMNCHN can be improved statewide in Bihar with sufficient investments in systems performance improvements.Study registration: ClinicalTrials.gov number NCT02726230.

    View details for DOI 10.7189/jogh.10.021003

    View details for PubMedID 33427818

  • Health layering of self-help groups: impacts on reproductive, maternal, newborn and child health and nutrition in Bihar, India. Journal of global health Mehta, K. M., Irani, L., Chaudhuri, I., Mahapatra, T., Schooley, J., Srikantiah, S., Abdalla, S., Ward, V., Carmichael, S. L., Bentley, J., Creanga, A., Wilhelm, J., Tarigopula, U. K., Bhattacharya, D., Atmavilas, Y., Nanda, P., Weng, Y., Pepper, K. T., Darmstadt, G. L., Ananya Study Group, Atmavilas, Y., Bhattacharya, D., Bentley, J., Borkum, E., Carmichael, S., Chaudhuri, I., Creanga, A., Darmstadt, G. L., Dutt, P., Irani, L., Mahapatra, T., Mehta, K. M., Mitra, R., Munar, W. A., Nanda, P., Pepper, K. T., Raheel, H., Rangarajan, A., Saggurti, N., Sastry, P., Shah, H., Srikantiah, S., Tarigopula, U. K., Ward, V., Weng, Y., Walker, D., Wilhelm, J. 2020; 10 (2): 021007

    Abstract

    Background: Self-help group (SHG) interventions have been widely studied in low and middle income countries. However, there is little data on specific impacts of health layering, or adding health education modules upon existing SHGs which were formed primarily for economic empowerment. We examined three SHG interventions from 2012-2017 in Bihar, India to test the hypothesis that health-layering of SHGs would lead to improved health-related behaviours of women in SHGs.Methods: A model for health layering of SHGs - Parivartan - was developed by the non-governmental organisation (NGO), Project Concern International, in 64 blocks of eight districts. Layering included health modules, community events and review mechanisms. The health layering model was adapted for use with government-led SHGs, called JEEViKA+HL, in 37 other blocks of Bihar. Scale-up of government-led SHGs without health layering (JEEViKA) occurred contemporaneously in 433 other blocks, providing a natural comparison group. Using Community-based Household Surveys (CHS, rounds 6-9) by CARE India, 62 reproductive, maternal, newborn and child health and nutrition (RMNCHN) and sanitation indicators were examined for SHGs with health layering (Pavivartan SHGs and JEEViKA+HL SHGs) compared to those without. We calculated mean, standard deviation and odds ratios of indicators using surveymeans and survey logistic regression.Results: In 2014, 64% of indicators were significantly higher in Parivartan members compared to non-members residing in the same blocks. During scale up, from 2015-17, half (50%) of indicators had significantly higher odds in health layered SHG members (Parivartan or JEEViKA+HL) in 101 blocks compared to SHG members without health layering (JEEViKA) in 433 blocks.Conclusions: Health layering of SHGs was demonstrated by an NGO-led model (Parivartan), adapted and scaled up by a government model (JEEViKA+HL), and associated with significant improvements in health compared to non-health-layered SHGs (JEEViKA). These results strengthen the evidence base for further layering of health onto the SHG platform for scale-level health change.Study registration: ClinicalTrials.gov number NCT02726230.

    View details for DOI 10.7189/jogh.10.021007

    View details for PubMedID 33425331

  • Health impact of self-help groups scaled-up statewide in Bihar, India. Journal of global health Mehta, K. M., Irani, L., Chaudhuri, I., Mahapatra, T., Schooley, J., Srikantiah, S., Abdalla, S., Ward, V. C., Carmichael, S. L., Bentley, J., Creanga, A., Wilhelm, J., Tarigopula, U. K., Bhattacharya, D., Atmavilas, Y., Nanda, P., Weng, Y., Pepper, K. T., Darmstadt, G. L., Ananya Study Group, Atmavilas, Y., Bhattacharya, D., Bentley, J., Borkum, E., Carmichael, S., Chaudhuri, I., Creanga, A., Darmstadt, G. L., Dutt, P., Irani, L., Mahapatra, T., Mehta, K. M., Mitra, R., Munar, W. A., Nanda, P., Pepper, K. T., Raheel, H., Rangarajan, A., Saggurti, N., Sastry, P., Shah, H., Srikantiah, S., Ward, V., Weng, Y., Walker, D., Wilhelm, J. 2020; 10 (2): 021006

    Abstract

    Background: The objective of this study was to assess the impact of self-help groups (SHGs) and subsequent scale-up on reproductive, maternal, newborn, child health, and nutrition (RMNCHN) and sanitation outcomes among marginalised women in Bihar, India from 2014-2017.Methods: We examined RMNCHN and sanitation behaviors in women who were members of any SHGs compared to non-members, without differentiating between types of SHGs. We analysed annual surveys across 38 districts of Bihar covering 62690 women who had a live birth in the past 12 months. All analyses utilised data from Community-based Household Surveys (CHS) rounds 6-9 collected in 2014-2017 by CARE India as part of the Bihar Technical Support Program funded by the Bill & Melinda Gates Foundation. We examined 66 RMNCHN and sanitation indicators using survey logistic regression; the comparison group in all cases was age-comparable women from the geographic contexts of the SHG members but who did not belong to SHGs. We also examined links between discussion topics in SHGs and changes in relevant behaviours, and stratification of effects by parity and mother's age.Results: SHG members had higher odds compared to non-SHG members for 60% of antenatal care indicators, 22% of delivery indicators, 70% of postnatal care indicators, 50% of nutrition indicators, 100% of family planning and sanitation indicators and no immunisation indicators measured. According to delivery platform, most FLW performance indicators (80%) had increased odds, followed by maternal behaviours (57%) and facility care and outreach service delivery (22%) compared to non-SHG members. Self-report of discussions within SHGs on specific topics was associated with increased related maternal behaviours. Younger SHG members (<25 years) had attenuated health indicators compared to older group members (≥25 years), and women with more children had more positive indicators compared to women with fewer children.Conclusions: SHG membership was associated with improved RMNCHN and sanitation indicators at scale in Bihar, India. Further work is needed to understand the specific impacts of health layering upon SHGs. Working through SHGs is a promising vehicle for improving primary health care.Study registration: ClinicalTrials.gov number NCT02726230.

    View details for DOI 10.7189/jogh.10.021006

    View details for PubMedID 33425330

  • Impact of mHealth interventions for reproductive, maternal, newborn and child health and nutrition at scale: BBC Media Action and the Ananya program in Bihar, India. Journal of global health Ward, V. C., Raheel, H., Weng, Y., Mehta, K. M., Dutt, P., Mitra, R., Sastry, P., Godfrey, A., Shannon, M., Chamberlain, S., Kaimal, R., Carmichael, S. L., Bentley, J., Abdalla, S., Pepper, K. T., Mahapatra, T., Srikantiah, S., Borkum, E., Rangarajan, A., Sridharan, S., Rotz, D., Nanda, P., Tarigopula, U. K., Atmavilas, Y., Bhattacharya, D., Darmstadt, G. L., Ananya Study Group, Atmavilas, Y., Bhattacharya, D., Bentley, J., Borkum, E., Carmichael, S., Chaudhuri, I., Creanga, A., Darmstadt, G. L., Dutt, P., Irani, L., Mahapatra, T., Mehta, K. M., Mitra, R., Munar, W. A., Nanda, P., Pepper, K. T., Raheel, H., Rangarajan, A., Saggurti, N., Sastry, P., Shah, H., Srikantiah, S., Tarigopula, U. K., Ward, V., Weng, Y., Walker, D., Wilhelm, J. 2020; 10 (2): 021005

    Abstract

    Background: Mobile health (mHealth) tools have potential for improving the reach and quality of health information and services through community health workers in low- and middle-income countries. This study evaluates the impact of an mHealth tool implemented at scale as part of the statewide reproductive,maternal, newborn and child health and nutrition (RMNCHN) program in Bihar, India.Methods: Three survey-based data sets were analysed to compare the health-related knowledge, attitudes and behaviours amongst childbearing women exposed to the Mobile Kunji and Dr. Anita mHealth tools during their visits with frontline workers compared with those who were unexposed.Results: An evaluation by Mathematica (2014) revealed that exposure to Mobile Kunji and Dr. Anita recordings were associated with significantly higher odds of consuming iron-folic acid tablets (odds ratio (OR)=2.3, 95% confidence interval (CI)=1.8-3.1) as well as taking a set of three measures for delivery preparedness (OR=2.8, 95% CI=1.9-4.2) and appropriate infant complementary feeding (OR=1.9, 95% CI=1.0-3.5). CARE India's Community-based Household Surveys (2012-2017) demonstrated significant improvements in early breastfeeding (OR=1.64, 95% CI=1.5-1.78) and exclusive breastfeeding (OR=1.46, 95% CI=1.33-1.62) in addition to birth preparedness practices. BBC Media Action's Usage & Engagement Survey (2014) demonstrated a positive association between exposure to Mobile Kunji and Dr. Anita and exclusive breastfeeding (58% exposed vs 43% unexposed, P<0.01) as well as maternal respondents' trust in their frontline worker.Conclusions: Significant improvements in RMNCHN-related knowledge and behaviours were observed for Bihari women who were exposed to Mobile Kunji and Dr. Anita. This analysis is unique in its rigorous evaluation across multiple data sets of mHealth interventions implemented at scale. These results can help inform global understanding of how best to use mHealth tools, for whom, and in what contexts.Study registration: ClinicalTrials.gov number NCT02726230.

    View details for DOI 10.7189/jogh.10.021005

    View details for PubMedID 33425329

  • Evaluation of a large-scale reproductive, maternal, newborn and child health and nutrition program in Bihar, India, through an equity lens. Journal of global health Ward, V. C., Weng, Y., Bentley, J., Carmichael, S. L., Mehta, K. M., Mahmood, W., Pepper, K. T., Abdalla, S., Atmavilas, Y., Mahapatra, T., Srikantiah, S., Borkum, E., Rangarajan, A., Sridharan, S., Rotz, D., Bhattacharya, D., Nanda, P., Tarigopula, U. K., Shah, H., Darmstadt, G. L., Ananya Study Group, Atmavilas, Y., Bhattacharya, D., Bentley, J., Borkum, E., Carmichael, S., Chaudhuri, I., Creanga, A., Darmstadt, G. L., Dutt, P., Irani, L., Mahapatra, T., Mehta, K. M., Mitra, R., Munar, W. A., Nanda, P., Pepper, K. T., Raheel, H., Rangarajan, A., Saggurti, N., Sastry, P., Shah, H., Srikantiah, S., Tarigopula, U. K., Ward, V., Weng, Y., Walker, D., Wilhelm, J. 2020; 10 (2): 021011

    Abstract

    Background: Despite increasing focus on health inequities in low- and middle income countries, significant disparities persist. We analysed impacts of a statewide maternal and child health program among the most compared to the least marginalised women in Bihar, India.Methods: Utilising survey-weighted logistic regression, we estimated programmatic impact using difference-in-difference estimators from Mathematica data collected at the beginning (2012, n=10174) and after two years of program implementation (2014, n=9611). We also examined changes in disparities over time using eight rounds of Community-based Household Surveys (CHS) (2012-2017, n=48349) collected by CARE India.Results: At baseline for the Mathematica data, least marginalised women generally performed desired health-related behaviours more frequently than the most marginalised. After two years, most disparities persisted. Disparities increased for skilled birth attendant identification [+16.2% (most marginalised) vs +32.6% (least marginalized), P<0.01) and skin-to-skin care (+14.8% vs +20.4%, P<0.05), and decreased for immediate breastfeeding (+10.4 vs -4.9, P<0.01). For the CHS data, odds ratios compared the most to the least marginalised women as referent. Results demonstrated that disparities were most significant for indicators reliant on access to care such as delivery in a facility (OR range: 0.15 to 0.48) or by a qualified doctor (OR range: 0.08 to 0.25), and seeking care for complications (OR range: 0.26 to 0.64).Conclusions: Disparities observed at baseline generally persisted throughout program implementation. The most significant disparities were observed amongst behaviours dependent upon access to care. Changes in disparities largely were due to improvements for the least marginalised women without improvements for the most marginalised. Equity-based assessments of programmatic impacts, including those of universal health approaches, must be undertaken to monitor disparities and to ensure equitable and sustainable benefits for all.Study registration: ClinicalTrials.gov number NCT02726230.

    View details for DOI 10.7189/jogh.10.021011

    View details for PubMedID 33425335

  • Impact of the Ananya program on reproductive, maternal, newborn and child health and nutrition in Bihar, India: early results from a quasi-experimental study. Journal of global health Darmstadt, G. L., Weng, Y., Pepper, K. T., Ward, V. C., Mehta, K. M., Borkum, E., Bentley, J., Raheel, H., Rangarajan, A., Bhattacharya, D., Tarigopula, U. K., Nanda, P., Sridharan, S., Rotz, D., Carmichael, S. L., Abdalla, S., Munar, W., Ananya Study Group, Atmavilas, Y., Bhattacharya, D., Bentley, J., Borkum, E., Carmichael, S., Chaudhuri, I., Creanga, A., Darmstadt, G. L., Dutt, P., Irani, L., Mahapatra, T., Mehta, K. M., Mitra, R., Munar, W. A., Nanda, P., Pepper, K. T., Raheel, H., Rangarajan, A., Saggurti, N., Sastry, P., Delhi, N., Shah, H., Srikantiah, S., Tarigopula, U. K., Ward, V., Weng, Y., Walker, D., Wilhelm, J. 2020; 10 (2): 021002

    Abstract

    Background: The Government of Bihar (GoB) in India, the Bill and Melinda Gates Foundation and several non-governmental organisations launched the Ananya program aimed to support the GoB to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) statewide. Here we summarise changes in indicators attained during the initial two-year pilot phase (2012-2013) of implementation in eight focus districts of approximately 28 million population, aimed to inform subsequent scale-up.Methods: The quasi-experimental impact evaluation included statewide household surveys at two time points during the pilot phase: January-April 2012 ("baseline") including an initial cohort of beneficiaries and January-April 2014 ("midline") with a new cohort. The two arms were: 1) eight intervention districts, and 2) a comparison arm comprised of the remaining 30 districts in Bihar where Ananya interventions were not implemented. We analysed changes in indicators across the RMNCHN continuum of care from baseline to midline in intervention and comparison districts using a difference-in-difference analysis.Results: Indicators in the two arms were similar at baseline. Overall, 40% of indicators (20 of 51) changed significantly from baseline to midline in the comparison districts unrelated to Ananya; two-thirds (n=13) of secular indicator changes were in a direction expected to promote health. Statistically significant impact attributable to the Ananya program was found for 10% (five of 51) of RMNCHN indicators. Positive impacts were most prominent for mother's behaviours in contraceptive utilisation.Conclusions: The Ananya program had limited impact in improving health-related outcomes during the first two-year period covered by this evaluation. The program's theories of change and action were not powered to observe statistically significant differences in RMNCHN indicators within two years, but rather aimed to help inform program improvements and scale-up. Evaluation of large-scale programs such as Ananya using theory-informed, equity-sensitive (including gender), mixed-methods approaches can help elucidate causality and better explain pathways through which supply- and demand-side interventions contribute to changes in behaviour among the actors involved in the production of population-level health outcomes. Evidence from Bihar indicates that deep structural constraints in health system organisation and delivery of interventions pose substantial limitations on behaviour change among health care providers and beneficiaries.Study registration: ClinicalTrials.gov number NCT02726230.

    View details for DOI 10.7189/jogh.10.021002

    View details for PubMedID 33427822

  • Postpartum health risks among women with hypertensive disorders of pregnancy, California 2008-2012. Journal of hypertension Murray Horwitz, M. E., Rodriguez, M. I., Dissanayake, M., Carmichael, S. L., Snowden, J. M. 2020

    Abstract

    OBJECTIVES: The aim of this study was to understand the associations between hypertensive disorders of pregnancy (HDP) and postpartum complications throughout the newly defined 12-week postpartum transition.STUDY DESIGN: We conducted a retrospective cohort study of the associations of HDP (any/subtype) with postpartum complications among 2.5 million California births, 2008-2012. We identified complications from discharge diagnoses from maternal hospital encounters (emergency department visits and readmissions) in the 12 weeks after giving birth. We compared rates of complications, overall and by diagnostic category, between groups defined by HDP. In survival analyses, we calculated the adjusted hazard ratios of postpartum complications associated with HDP. We adjusted for maternal age, race/ethnicity, prepregnancy obesity, chronic diabetes, gestational diabetes, insurance, delivery mode, gestational age and birth outcome (term and size).RESULTS: Among women with and without HDP, 12.8 and 7.7%, respectively, had a hospital encounter within 12 weeks of giving birth [adjusted hazard ratio 1.5, 95% confidence interval (95% CI): 1.5-1.5]. HDP was associated with increased risk across all major categories of complications: hypertension-related, adjusted hazard ratio 11.8 (95% CI: 11.2-12.3); childbirth-related, 1.4 (1.3-1.4); and other, 1.4 (1.4-1.4). Risk of any complication differed by hypertensive subtype: chronic hypertension with super-imposed preeclampsia, adjusted hazard ratio 1.8 (95% CI: 1.7-1.8); chronic hypertension, 1.6 (1.6-1.7); preeclampsia/eclampsia, 1.3 (1.3-1.4); and gestational hypertension, 1.2 (1.2-1.3). Over a quarter (28.9%) of maternal hospital encounters occurred more than 6 weeks after giving birth; this did not differ substantially by HDP status.CONCLUSION: Women with HDP are at an increased risk for virtually all postpartum complications, including those not related to hypertension, and may benefit from enhanced and comprehensive postpartum care.

    View details for DOI 10.1097/HJH.0000000000002711

    View details for PubMedID 33230021

  • Recurrence of severe maternal morbidity: A population-based cohort analysis of California women. Paediatric and perinatal epidemiology Bane, S., Wall-Wieler, E., Lyndon, A., Carmichael, S. L. 2020

    Abstract

    BACKGROUND: Severe maternal morbidity (SMM) has increased in the United States by 45% in the last decade. While the recurrence of several adverse pregnancy outcomes from one pregnancy to the next has been established, the recurrence risk of SMM is unknown.OBJECTIVE: To determine whether women who have SMM in a first pregnancy are at increased risk of SMM in their second pregnancy, compared to women who did not have SMM in their first pregnancy.METHODS: This is a population-based study using linked vital statistics and hospital discharge records from the Office of Statewide Health Planning and Development in California from 1997 to 2012. The study population had their first two singleton births (live births or stillbirths) in California between 1997 and 2012 (n=1180357). The primary exposure was SMM during the hospitalisation at first birth, and the primary outcome was SMM during the hospitalisation at second birth. Prevalence and risk ratios of SMM at second birth were computed for women who did and did not have SMM at first birth, as well as for certain specific indicators of SMM.RESULTS: Of the 1180357 women included in this analysis, 9088 (77 per 10000 births) experienced SMM at first birth. Among these women, the prevalence of SMM at second birth was 470 per 10000 births, compared to 68 per 10000 births among women without SMM at first birth. This corresponded to an unadjusted risk ratio of 6.87 (95%CI 6.23, 7.57), which did not differ substantially when adjusted for factors known to be associated with SMM (6.42, 95% CI 5.86, 7.13).CONCLUSION: Women experiencing SMM in their first pregnancy were at an approximately sixfold increased risk of experiencing SMM in their second pregnancy.

    View details for DOI 10.1111/ppe.12714

    View details for PubMedID 33155710

  • Birth Hospital and Racial/Ethnic Differences in Severe Maternal Morbidity in the State of California. American journal of obstetrics and gynecology Mujahid, M. S., Kan, P., Leonard, S. A., Hailu, E. M., Wall-Wieler, E., Abrams, B., Main, E., Profit, J., Carmichael, S. L. 2020

    Abstract

    BACKGROUND: Birth hospital has recently emerged as a potentially key contributor to disparities in severe maternal morbidity, but investigations remain limited.OBJECTIVES: We leveraged state-wide data from California to examine whether birth hospital explained racial/ethnic differences in severe maternal morbidity.METHODS: This cohort study used data on all births ≥20 weeks in California (2007-2012). Severe maternal morbidity during birth hospitalization was measured using the Centers for Disease Control and Prevention index of having at least one of 21 diagnoses and procedures (e.g. eclampsia, blood transfusion, hysterectomy). Mixed effects logistic regression models (i.e. women nested within hospitals) were used to compare racial/ethnic differences in severe maternal morbidity before and after adjustment for maternal sociodemographic and pregnancy-related factors, co-morbidities, and hospital characteristics. We also estimated risk-standardized severe maternal morbidity rates for each hospital (N=245) and the percent reduction in severe maternal morbidity if each group of racially/ethnically minoritized women gave birth at the same distribution of hospitals as non-Hispanic White women.RESULTS: Of the 3,020,525 women who gave birth, 39,192 (1.3%) had severe maternal morbidity (2.1% Black; 1.3% US-born Hispanic; 1.3% foreign-born Hispanic; 1.3% Asian/Pacific Islander; 1.1% White; 1.6% American Indian/Alaska Native and Mixed Race referred to as "Other"). Risk-standardized rates of severe maternal morbidity ranged from 0.3 to 4.0 per 100 births across hospitals. After adjusting for covariates, odds of severe maternal morbidity was greater among non-White women compared to Whites in a given hospital (Odds Ratios and 95% Confidence Intervals; Black =1.25 (1.19-1.31), US-born Hispanic=1.25 (1.20-1.29), Foreign-born Hispanic=1.17 (1.11-1.24), Asian/Pacific Islander=1.26 (1.21-1.32), "Other"=1.31 (1.15-1.50). Among the studied hospital factors, only teaching status was associated with severe maternal morbidity in fully adjusted models. Although 33% of White women delivered in hospitals with the highest tertile of severe maternal morbidity rates compared to 53% of Black women, birth hospital only accounted for 7.8% of the differences in severe maternal morbidity comparing Black and White women and accounted for 16.1-24.2% of the differences for all other racial/ethnic groups.CONCLUSION: In California, excess odds of severe maternal morbidity among racially/ethnically minoritized women was not fully explained by birth hospital. Structural causes of racial/ethnic disparities in severe maternal morbidity may vary by region, which warrants further examination to inform effective policies.

    View details for DOI 10.1016/j.ajog.2020.08.017

    View details for PubMedID 32798461

  • Opioid Prescription and Persistent Opioid Use After Ectopic Pregnancy. Obstetrics and gynecology Wall-Wieler, E., Shover, C. L., Hah, J. M., Carmichael, S. L., Butwick, A. J. 2020

    Abstract

    OBJECTIVE: To evaluate outpatient opioid dispensing and the incidence of persistent opioid use after ectopic pregnancy.METHODS: This cohort study used U.S. employer-based claims data to identify opioid-naive individuals experiencing ectopic pregnancy from November 1, 2008, to September 30, 2015. Treatment was categorized as surgical, medical (using methotrexate), or unknown. New opioid prescriptions were defined as prescriptions filled from 1 week before to 1 week after an ectopic pregnancy treatment. For those who filled a new opioid prescription, we calculated the incidence and risk factors for persistent opioid use, defined as having filled at least one opioid prescription both from 8 to 90 days after treatment and from 91 to 365 days after treatment.RESULTS: Of the 15,338 individuals in our study, 7,047 (45.9%, 95% CI 45.2-46.7%) filled an opioid prescription at the time of treatment, of whom 4.1% (95% CI 3.6-4.6%) developed persistent opioid use. The risk of persistent opioid use was lower among those who had surgical compared with medical treatment (3.7% and 6.8%, respectively; relative risk [RR] 0.54, 95% CI 0.38-0.77). Variables most strongly associated with persistent opioid use were a history of benzodiazepine use (RR 1.99; 95% CI 1.43-2.78; adjusted relative risk [aRR] 1.57, 95% CI 1.11-2.22), antidepressant use (RR 1.91, 95% CI 1.45-2.53; aRR 1.53, 95% CI 1.08-2.18), and a pre-existing pain disorder (RR 1.58, 95% CI 1.26-1.99; aRR 1.47, 95% CI 1.16-1.85) in the year before treatment.CONCLUSION: New opioid use is common after an ectopic pregnancy; approximately 4% of those with new opioid use develop persistent opioid use, with the rate higher in those treated medically. New pain-management guidelines need to be developed to prevent persistent opioid use after ectopic pregnancy.

    View details for DOI 10.1097/AOG.0000000000004015

    View details for PubMedID 32769649

  • An Expanded Obstetric Comorbidity Scoring System for Predicting Severe Maternal Morbidity. Obstetrics and gynecology Leonard, S. A., Kennedy, C. J., Carmichael, S. L., Lyell, D. J., Main, E. K. 2020

    Abstract

    OBJECTIVE: To develop and validate an expanded obstetric comorbidity score for predicting severe maternal morbidity that can be applied consistently across contemporary U.S. patient discharge data sets.METHODS: Discharge data from birth hospitalizations in California during 2016-2017 were used to develop the score. The outcomes were severe maternal morbidity, defined using the Centers for Disease Control and Prevention index, and nontransfusion severe maternal morbidity (excluding cases where transfusion was the only indicator of severe maternal morbidity). We selected 27 potential patient-level risk factors for severe maternal morbidity, identified using International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes. We used a targeted causal inference approach integrated with machine learning to rank the risk factors based on adjusted risk ratios (aRRs). We used these results to assign scores to each comorbidity, which sum to a single numeric score. We validated the score in California and national data sets and compared the performance to that of a previously developed obstetric comorbidity index.RESULTS: Among 919,546 births, the rates of severe maternal morbidity and nontransfusion severe maternal morbidity were 168 and 74 per 10,000 births, respectively. The highest risk comorbidity was placenta accreta spectrum (aRR of 30.5 for severe maternal morbidity and 54.7 for nontransfusion severe maternal morbidity) and the lowest was gestational diabetes mellitus (aRR of 1.06 for severe maternal morbidity and 1.12 for nontransfusion severe maternal morbidity). Normalized scores based on the aRR were developed for each comorbidity, which ranged from 1 to 59 points for severe maternal morbidity and from 1 to 36 points for nontransfusion severe maternal morbidity. The overall performance of the expanded comorbidity scores was good (C-statistics were 0.78 for severe maternal morbidity and 0.84 for nontransfusion severe maternal morbidity in California data and 0.82 and 0.87, respectively, in national data) and improved on prior comorbidity indices developed for obstetric populations. Calibration plots showed good concordance between predicted and actual risks of the outcomes.CONCLUSION: We developed and validated an expanded obstetric comorbidity score to improve comparisons of severe maternal morbidity rates across patient populations with different comorbidity case mixes.

    View details for DOI 10.1097/AOG.0000000000004022

    View details for PubMedID 32769656

  • Congenital diaphragmatic hernia and maternal dietary nutrient pathways and diet quality. Birth defects research Carmichael, S. L., Ma, C., Witte, J. S., Yang, W., Rasmussen, S. A., Brunelli, L., Nestoridi, E., Shaw, G. M., Feldkamp, M. L., National Birth Defects Prevention Study 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

  • Asthma Medication Use and Risk of Birth Defects: National Birth Defects Prevention Study, 1997-2011. The journal of allergy and clinical immunology. In practice Howley, M. M., Papadopoulos, E. A., Van Bennekom, C. M., Van Zutphen, A. R., Carmichael, S. L., Munsie, J. W., Herdt, M. L., Browne, M. L., National Birth Defects Prevention Study 2020

    Abstract

    BACKGROUND: Evidence regarding associations between maternal asthma medication use and birth defects is mixed.OBJECTIVE: Using National Birth Defects Prevention Study (NBDPS) data from 1997-2011, we estimated associations between asthma medication use and 52 specific birth defects.METHODS: We compared self-reported maternal asthma medication use for 28,481 birth defect cases and 10,894 non-malformed controls. We calculated adjusted odds ratios [95% confidence intervals] to estimate the risk of birth defects associated with early pregnancy asthma medication use (the month before through the third month of pregnancy), controlling for maternal age, race/ethnicity, body mass index, smoking, folic acid-containing supplement use, and parity. We calculated risks by medication groupings: bronchodilators, anti-inflammatories, and both.RESULTS: Overall, 1,304 (5%) case and 449 (4%) control women reported early pregnancy asthma medication use. We observed an association between asthma medication use and longitudinal limb deficiency (1.81 [1.27-2.58]). Early pregnancy bronchodilator only use was associated with cleft palate (1.50 [1.11-2.02]), cleft lip (1.58 [1.12-2.23]), longitudinal limb deficiency (2.35 [1.55-3.54]), and truncus arteriosus (2.48 [1.13-5.42]). While early pregnancy anti-inflammatory only use was not associated with the birth defects studied, use of both medications was associated with biliary atresia (3.60 [1.55-8.35]) and pulmonary atresia (2.50 [1.09-5.78]).CONCLUSION: Consistent with previous NBDPS analyses, asthma medication use was not associated with most birth defects examined, but we observed modest risks for bronchodilator use and several birth defects. Our findings support maintaining adequate asthma treatment during pregnancy, as early pregnancy asthma exacerbations have been associated with adverse birth outcomes, including birth defects.

    View details for DOI 10.1016/j.jaip.2020.07.033

    View details for PubMedID 32745701

  • Benzodiazepine use before conception and risk of ectopic pregnancy. Human reproduction (Oxford, England) Wall-Wieler, E., Robakis, T. K., Lyell, D. J., Masarwa, R., Platt, R. W., Carmichael, S. L. 2020

    Abstract

    STUDY QUESTION: Are women who fill a benzodiazepine prescription before conception at increased risk of ectopic pregnancy?SUMMARY ANSWER: Risk of ectopic pregnancy is 50% higher among women who fill a benzodiazepine prescription before conception.WHAT IS KNOWN ALREADY: Benzodiazepine use in pregnancy increases the risk of miscarriage, adverse birth outcomes and adverse child development outcomes.STUDY DESIGN, SIZE, DURATION: Using data from US commercial insurance claims, we performed a cohort study of 1691366 pregnancies between 1 November 2008 and 30 September 2015.PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified ectopic pregnancies using diagnosis and procedure codes and used unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models to calculate relative risks (RR) of ectopic pregnancy for pregnant women who did and did not fill any prescriptions for benzodiazepines in the 90days before conception. Two sub-groups of women with specific indications for benzodiazepine use were also examined-women who had a least one diagnosis for anxiety disorder and women who had at least one diagnosis of insomnia in the year before conception.MAIN RESULTS AND THE ROLE OF CHANCE: Of the 1691366 pregnancies, 1.06% filled at least two benzodiazepine prescriptions totaling at least 10days supply in the 90days before conception. Among women with a benzodiazepine prescription, there was an excess of 80 ectopic pregnancies per 10000 pregnancies, and their IPT-weighted risk of ectopic pregnancies was 1.47 (95% CI 1.32 to 1.63) times greater relative to women without benzodiazepine prescriptions before conception. The IPT-weighted RR between ectopic pregnancy and benzodiazepine use was 1.34 (95% CI 1.18 to 1.53) among women with anxiety disorder diagnoses and 1.28 (95% CI 0.99 to 1.68) among women with an insomnia diagnosis.LIMITATIONS, REASONS FOR CAUTION: We relied on outpatient prescription data to identify benzodiazepine use before conception, which could result in over- or under-estimation of actual benzodiazepine consumption. We relied on medical claim codes to identify pregnancies and conception date, which may result in misclassification of pregnancy outcomes and gestational length.WIDER IMPLICATIONS OF THE FINDINGS: This study found that women who have a benzodiazepine prescription before conception are at an increased risk of ectopic pregnancy. This information can help women, and their healthcare providers make more fully informed decisions about benzodiazepine use in their reproductive years.STUDY FUNDING/COMPETING INTEREST(S): Funding for this project was provided by a Banting Postdoctoral Fellowship and a Stanford Maternal and Child Health Research Institute Postdoctoral Award. Data access for this project was provided by the Stanford Center for Population Health Sciences Data Core. The PHS Data Core is supported by a National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085) and internal Stanford funding. The authors have no competing interest.TRIAL REGISTRATION NUMBER: N/A.

    View details for DOI 10.1093/humrep/deaa082

    View details for PubMedID 32485732

  • Antidepressant Use around Conception, Prepregnancy Depression, and Risk of Ectopic Pregnancy. Canadian journal of psychiatry. Revue canadienne de psychiatrie Wall-Wieler, E., Robakis, T. K., Cesta, C. E., Masarwa, R., Lyell, D. J., Liu, C., Platt, R. W., Carmichael, S. L. 2020: 706743720927829

    Abstract

    OBJECTIVE: To compare the risk of ectopic pregnancy among women with and women without antidepressant prescriptions around conception and examine whether this risk differs by prepregnancy depression status.METHODS: We conducted a cohort study of all pregnancies between November 1, 2008, and September 30, 2015, identified in the nationwide (American) IBM MarketScan Databases. At least one day's supply of antidepressants in the 3 weeks after a woman's last menstrual period defined active antidepressant use around conception. At least one depression diagnosis in the year before the last menstrual period defined prepregnancy depression. Relative risk (RR) of ectopic pregnancy was estimated using unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models.RESULTS: Of the 1,703,245 pregnancies, 106,788 (6.3%) women had a prepregnancy depression diagnosis. Among women with a depression diagnosis, 40,287 (37.7%) had an active antidepressant prescription around conception; the IPT-weighted risk of ectopic pregnancy was similar among women who did and did not fill an antidepressant prescription around conception (IPT-weighted RR = 1.01; 95% CI, 0.93 to 1.10). Overall, the risk of ectopic pregnancy was higher among women who had a prepregnancy depression diagnosis than women who did not have a prepregnancy depression diagnosis (IPT-weighted RR = 1.09; 95% CI, 1.04 to 1.15).CONCLUSIONS: This study's findings suggest that women who have a prepregnancy depression diagnosis are at a slightly increased risk of ectopic pregnancy, and among women who have a prepregnancy depression diagnosis, the use of antidepressants around conception does not increase the risk of ectopic pregnancy.

    View details for DOI 10.1177/0706743720927829

    View details for PubMedID 32436752

  • Treating Center Volume and Congenital Diaphragmatic Hernia Outcomes in California. The Journal of pediatrics Apfeld, J. C., Kastenberg, Z. J., Gibbons, A. T., Carmichael, S. L., Lee, H. C., Sylvester, K. G. 2020

    Abstract

    OBJECTIVE: To examined outcomes for infants born with congenital diaphragmatic hernias (CDH), according to specific treatment center volume indicators.STUDY DESIGN: A population-based retrospective cohort study was conducted involving neonatal intensive care units in California. Multivariable analysis was used to examine the outcomes of infants with CDH including mortality, total days on ventilation, and respiratory support at discharge. Significant covariables of interest included treatment center surgical and overall neonatal intensive care unit volumes.RESULTS: There were 728 infants in the overall CDH cohort, and 541 infants (74%) in the lower risk subcohort according to a severity-weighted congenital malformation score and never requiring extracorporeal membrane oxygenation. The overall cohort mortality was 28.3% (n=206), and 19.8% (n=107) for the subcohort. For the lower risk subcohort, the adjusted odds of mortality were significantly lower at treatment centers with higher CDH repair volume (OR, 0.41; 95% CI, 0.23-0.75; P=.003), ventilator days were significantly lower at centers with higher thoracic surgery volume (OR, 0.56; 9 5% CI, 0.33-0.95; P=.03), and respiratory support at discharge trended lower at centers with higher neonatal intensive care unit admission volumes (OR, 0.51; 9 5% CI, 0.26-1.02; P=.06).CONCLUSIONS: Overall and surgery-specific institutional experience significantly contribute to optimized outcomes for infants with CDH. These data and follow-on studies may help inform the ongoing debate over the optimal care setting and relevant quality indicators for newborn infants with major surgical anomalies.

    View details for DOI 10.1016/j.jpeds.2020.03.028

    View details for PubMedID 32418817

  • Defining maternal obesity in studies of birth outcomes: Comparing ICD-9 codes at delivery and measures on the birth certificate. Paediatric and perinatal epidemiology Wall-Wieler, E., Abrams, B., Snowden, J. M., Carmichael, S. L. 2020

    Abstract

    BACKGROUND: Using ICD-9 codes underestimates the prevalence of obesity in adults; however, the validity of these codes in studies of pregnancy-related outcomes is not known.OBJECTIVES: To compare classification of maternal obesity based on ICD-9 codes in hospital discharge records versus data from birth certificates in the same women, examine predictors of agreement, and assess how associations between obesity and two birth outcomes differ by source of weight data.METHODS: This population-based study included 2329145 California births between 2007 and 2012. We compared data on obesity from childbirth hospital discharge records (ICD-9 codes for obesity) and birth certificates (pre-pregnancy body mass index (BMI) calculated from weight and height) and identified predictors of agreement between the two sources. Logistic regression models assessed whether the two definitions of obesity resulted in different estimates of the associations of obesity with caesarean birth and large-for-gestational age.RESULTS: Overall, 464754 women (20.0%) had obesity based on their pre-pregnancy BMI while only 100002 (4.3%) had an obesity-related ICD-9 code. The sensitivity of ICD-9-based obesity was low at 16.2%; however, obesity codes were highly specific at 98.7%, with a negative predictive value of 82.5% and a positive predictive value of 75.2%. Among women with obesity identified by the birth certificate, those with pre-pregnancy and pregnancy-related complications (eg diabetes and hypertension) were more likely to have an obesity-related diagnosis in their delivery hospital discharge record. Using ICD-9 codes overestimated the association of obesity with caesarean birth and newborn large-for-gestational age.CONCLUSIONS: ICD-9 codes in childbirth discharge records captured only one in five women with pre-pregnancy obesity. Sensitivity varied by maternal characteristics and conditions. This misclassification resulted in bias when examining the association of obesity and pregnancy-related outcomes.

    View details for DOI 10.1111/ppe.12667

    View details for PubMedID 32180247

  • Multilevel social factors and NICU quality of care in California. Journal of perinatology : official journal of the California Perinatal Association Padula, A. M., Shariff-Marco, S., Yang, J., Jain, J., Liu, J., Conroy, S. M., Carmichael, S. L., Gomez, S. L., Phibbs, C., Oehlert, J., Gould, J. B., Profit, J. 2020

    Abstract

    OBJECTIVE: Our objective was to incorporate social and built environment factors into a compendium of multilevel factors among a cohort of very low birth weight infants to understand their contributions to inequities in NICU quality of care and support providers and NICUs in addressing these inequitiesvia development of a health equity dashboard.STUDY DESIGN: We examined bivariate associations between NICU patient pool and NICU catchment area characteristics and NICU quality of care with data from a cohort of 15,901 infants from 119 NICUs in California, born 2008-2011.RESULT: NICUs with higher proportion of minority racial/ethnic patients and lower SES patients had lower quality scores. NICUs with catchment areas of lower SES, higher composition of minority residents, and more household crowding had lower quality scores.CONCLUSION: Multilevel social factors impact quality of care in the NICU. Their incorporation into a health equity dashboard can inform providers of their patients' potential resource needs.

    View details for DOI 10.1038/s41372-020-0647-8

    View details for PubMedID 32157221

  • Maternal diet as a risk factor for primary congenital glaucoma and defects of the anterior segment of the eye in the National Birth Defects Prevention Study. Birth defects research Moore, K. J., Carmichael, S. L., Forestieri, N. E., Desrosiers, T. A., Meyer, R. E., Freedman, S. F., North, K. E., Olshan, A. F., National Birth Defects Prevention Study 2020

    Abstract

    Primary congenital glaucoma (PCG) and anterior segment defects (ASDs) are rare ocular malformations diagnosed early in life which can cause blindness. Pathogenic variants in several genes have been linked to these conditions, but little is known about nongenetic risk factors. We investigated the association between maternal nutrition and PCG and ASDs in the National Birth Defects Prevention Study, a large population-based, multicenter case-control study of major birth defects in the United States. Mothers of cases (n =152) and control infants without a birth defect (n =9,178) completed an interview which included a food frequency questionnaire capturing usual dietary intake in the year before pregnancy. Maternal nutrition was assessed through individual nutrient intake, calculating a Diet Quality Index for Pregnancy (DQI-P) score for each mother, and using latent class analysis to empirically derive four dietary patterns. We calculated adjusted odds ratios (aORs) and 95% confidence intervals (CI) using logistic regression. The results for individual nutrients varied, with some having an inverse or U-shaped pattern of association with increasing intake. The DQI-P was not associated with risk of PCG and ASDs (aOR 0.91; CI 0.49-1.66, highest vs. lowest quartile). The dietary pattern analysis suggested lower odds among women with a Prudent and Mexican dietary pattern (aOR 0.82, 95% CI 0.52-1.29; aOR 0.80, 95% CI 0.36-1.78, respectively) compared to those with a Western dietary pattern. We found that higher intake of some nutrients and certain dietary patterns may be inversely associated with PCG and ASDs, though caution is urged due to imprecision of estimates.

    View details for DOI 10.1002/bdr2.1664

    View details for PubMedID 32154673

  • Maternal dietary fat intake and the risk of congenital heart defects in offspring. Pediatric research Collins, R. T., Yang, W., Carmichael, S. L., Bolin, E. H., Nembhard, W. N., Shaw, G. M., National Birth Defects Prevention Study 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

  • Weight gain during pregnancy and the risk of severe maternal morbidity by prepregnancy BMI. The American journal of clinical nutrition Leonard, S. A., Abrams, B., Main, E. K., Lyell, D. J., Carmichael, S. L. 2020

    Abstract

    BACKGROUND: High and low prepregnancy BMI are risk factors for severe maternal morbidity (SMM), but the contribution of gestational weight gain (GWG) is not well understood.OBJECTIVES: We evaluated associations between GWG and SMM by prepregnancy BMI group.METHODS: We analyzed administrative records from 2,483,684 Californian births (2007-2012), utilizing z score charts to standardize GWG for gestational duration. We fit the z scores nonlinearly and categorized GWG as above, within, or below the Institute of Medicine (IOM) recommendations after predicting equivalent GWG at term from the z score charts. SMM was defined using a validated index. Associations were estimated using multivariable logistic regression models.RESULTS: We found generally shallow U-shaped relations between GWG z score and SMM in all BMI groups, except class 3 obesity (≥40kg/m2), for which risk was lowest with weight loss. The weight gain amount associated with the lowest risk of SMM was within the IOM recommendations for underweight and class 2 obesity, but above the IOM recommendations for normal weight, overweight, and class 1 obesity. The adjusted risk ratios (RRs) and 95% CIs for GWG below the IOM recommendations, compared with GWG within the recommendations, were the following for underweight, normal weight, overweight, class 1 obesity, class 2 obesity, and class 3 obesity: 1.13 (0.99, 1.29), 1.09 (1.04, 1.14), 1.10 (1.01, 1.19), 1.07 (0.95, 1.21), 1.03 (0.88, 1.22), and 0.89 (0.73, 1.08), respectively. For GWG above the recommendations, the corresponding RRs and 95% CIs were 0.99 (0.84, 1.15), 1.04 (0.99, 1.08), 0.98 (0.92, 1.04), 1.03 (0.95, 1.13), 1.07 (0.94, 1.23), and 1.08 (0.91, 1.30), respectively.CONCLUSIONS: High and low GWG may be modestly associated with increased risk of SMM across BMI groups, except in women with class 3 obesity, for whom low weight gain and weight loss may be associated with decreased risk of SMM.

    View details for DOI 10.1093/ajcn/nqaa033

    View details for PubMedID 32119734

  • Differences in pre-pregnancy diet quality by occupation among employed women. Public health nutrition Zaganjor, I., Carmichael, S. L., Agopian, A. J., Olshan, A. F., Desrosiers, T. A., National Birth Defects Prevention Study 2020: 1–8

    Abstract

    OBJECTIVE: Maternal risk factors for pregnancy outcomes are known to vary by employment status. We evaluated whether pre-pregnancy diet quality varies by occupation in a population-based sample.DESIGN: We analysed interview data from 7341 mothers in a national case-control study of pregnancy outcomes. Self-reported job(s) held during the 3 months before pregnancy were classified using Standard Occupational Classification (SOC) codes. Usual diet in the year before conception was assessed with a semi-quantitative FFQ and evaluated using the Diet Quality Index for Pregnancy (DQI-P). Using logistic regression, we calculated adjusted OR and 95 % CI to estimate associations between low diet quality (defined as the lowest quartile of DQI-P scores) and occupation types.SETTING: The National Birth Defects Prevention Study: Arkansas, California, Georgia, Iowa, Massachusetts, North Carolina, New Jersey, New York, Texas, Utah.PARTICIPANTS: Employed mothers of infants born between 1997 and 2011.RESULTS: No occupation was strongly associated with low diet quality. Moderate but relatively imprecise associations were observed for women employed in management (OR: 1·3; 95 % CI: 1·1, 1·7); arts, design, entertainment, sports and media (OR: 1·4; 95 % CI: 0·9, 2·1); protective service (OR 1·3; 95 % CI: 0·7, 2·5) and farming, fishing, and forestry occupations (OR: 0·5; 95 % CI: 0·2, 1·1).CONCLUSIONS: Our analyses suggest that women in certain occupations may have lower diet quality in the months before pregnancy. Further research is needed to determine whether certain occupations could benefit from interventions to improve diet quality in the workplace for women of reproductive age.

    View details for DOI 10.1017/S1368980019003926

    View details for PubMedID 32100672

  • Maternal genitourinary and wound infections: Early postpartum readmissions and emergency department visits Leonard, S. A., Girsen, A., Carmichael, S. L., Gibbs, R. S. MOSBY-ELSEVIER. 2020: S169
  • Severe maternal morbidity among migrants with insecure residency status in Sweden 2000-2014: a population-based cohort study. Journal of migration and health Liu, C., Wall-Wieler, E., Urquia, M., Carmichael, S. L., Stephansson, O. 2020; 1-2: 100006

    Abstract

    Background: Migrants with insecure residency status (i.e., undocumented migrants and asylum-seekers, who are denied or waiting for authorized residency) often experience social and psychosocial adversities and limited access to health care. Nonetheless, they have not been profiled on the risk of severe maternal morbidity (SMM), a sentinel measure of maternal health and maternity care.Methods: A cohort study on all births recorded in the Swedish Medical Birth Register from 2000-2014 (N=1,570,472). Lacking a maternal personal identification number was used as an indicator for insecure residency status (1.3% of all births). We used Poisson regression models to estimate risk ratios of SMM in migrant women with insecure residency status compared to the Swedish-born or migrant women with long-term residency, adjusting for the calendar year of birth, maternal age, and parity.Results: Overall SMM rate among migrant women with insecure residency status was 21.5/1000 and 14.7/1000 among Swedish-born women. Compared to Swedish-born, migrants with insecure residency status had 50% higher risk of overall SMM (adjusted risk ratio (aRR)=1.54 [1.37-1.74]) and over 80% higher risk of SMM excluding transfusion-only cases (aRR=1.88 [1.37-2.57]). When compared to migrant women with long-term residency, migrant women with insecure residency also had a higher risk of SMM (overall SMM aRR=1.42 [1.26,1.61]; SMM excluding transfusion only cases aRR=1.43 [1.04,1.97]), suggesting that insecure residency conferred additional risks of SMM beyond migration.Conclusion: Migrant women with insecure residency status had increased risk of severe maternal morbidity.

    View details for DOI 10.1016/j.jmh.2020.100006

    View details for PubMedID 34405161

  • Severe Maternal Morbidity among US- and Foreign-born Asian and Pacific Islander women in California. Annals of epidemiology Wall-Wieler, E. n., Bane, S. n., Lee, H. C., Carmichael, S. L. 2020

    Abstract

    To examine risk of severe maternal morbidity (SMM) - a composite of serious, potentially life-threatening conditions related to childbirth - among subgroups of nulliparous women with Asian and Pacific Islander race/ethnicity.This study used linked hospital discharge and vital record data California to identify nulliparous Asian and Pacific Islander women from 1997 to 2012 (n = 453,525). We examined risk of SMM for 15 Asian and Pacific Islander subgroups and compared risk between US- and foreign-born women.Risk of SMM was higher among Pacific Islander women than Asian women (148 and 127 cases per 10,000 births, respectively). Among Asian women, risk of SMM ranged from 94 (Korean) to 165 (Filipina) cases per 10,000 births, and among Pacific Islander women, risk ranged from 125 (Hawaiian) to 162 (Other). With the exception of Korean and Filipina women, relative risks of SMM for US- versus foreign-born Asian and Pacific Islander women were similar.Differences in risk of SMM exist between subgroups of the Asian and Pacific Islander community. These differences should be considered when conducting research on racial and ethnic differences of SMM and when counselling Asian and Pacific Islander women regarding their risk of SMM.

    View details for DOI 10.1016/j.annepidem.2020.07.016

    View details for PubMedID 32795600

  • Improving primary health care delivery in Bihar, India: Learning from piloting and statewide scale-up of Ananya. Journal of global health Darmstadt, G. L., Pepper, K. T., Ward, V. C., Srikantiah, S. n., Mahapatra, T. n., Tarigopula, U. K., Bhattacharya, D. n., Irani, L. n., Schooley, J. n., Chaudhuri, I. n., Dutt, P. n., Sastry, P. n., Mitra, R. n., Chamberlain, S. n., Monaghan, S. n., Nanda, P. n., Atmavilas, Y. n., Saggurti, N. n., Borkum, E. n., Rangarajan, A. n., Mehta, K. M., Abdalla, S. n., Wilhelm, J. n., Weng, Y. n., Carmichael, S. L., Raheel, H. n., Bentley, J. n., Munar, W. A., Creanga, A. n., Trehan, S. n., Walker, D. n., Shah, H. n. 2020; 10 (2): 021001

    Abstract

    In 2010, the Bill and Melinda Gates Foundation (BMGF) partnered with the Government of Bihar (GoB), India to launch the Ananya program to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) outcomes. The program sought to address supply- and demand-side barriers to the adoption, coverage, quality, equity and health impact of select RMNCHN interventions. Approaches included strengthening frontline worker service delivery; social and behavior change communications; layering of health, nutrition and sanitation into women's self-help groups (SHGs); and quality improvement in maternal and newborn care at primary health care facilities. Ananya program interventions were piloted in approximately 28 million population in eight innovation districts from 2011-2013, and then beginning in 2014, were scaled up by the GoB across the rest of the state's population of 104 million. A Bihar Technical Support Program provided techno-managerial support to governmental Health as well as Integrated Child Development Services, and the JEEViKA Technical Support Program supported health layering and scale-up of the GoB's SHG program. The level of support at the block level during statewide scale-up in 2014 onwards was approximately one-fourth that provided in the pilot phase of Ananya in 2011-2013. This paper - the first manuscript in an 11-manuscript and 2-viewpoint collection on Learning from Ananya: Lessons for primary health care performance improvement - seeks to provide a broad description of Ananya and subsequent statewide adaptation and scale-up, and capture the background and context, key objectives, interventions, delivery approaches and evaluation methods of this expansive program. Subsequent papers in this collection focus on specific intervention delivery platforms. For the analyses in this series, Stanford University held key informant interviews and worked with the technical support and evaluation grantees of the Ananya program, as well as leadership from the India Country Office of the BMGF, to analyse and synthesise data from multiple sources. Capturing lessons from the Ananya pilot program and statewide scale-up will assist program managers and policymakers to more effectively design and implement RMNCHN programs at scale through technical assistance to governments.

    View details for DOI 10.7189/jogh.10.021001

    View details for PubMedID 33414906

    View details for PubMedCentralID PMC7757841

  • Antepartum iron-deficiency anemia: An opportunity to reduce severe maternal morbidity Leonard, S. A., Main, E. K., Lyell, D. J., Butwick, A. J., Carmichael, S. L. MOSBY-ELSEVIER. 2020: S168–S169
  • Pregnancy outcomes of american indian and alaskan native women residing in rural versus urban areas Estes, J., Girsen, A., Sie, L., Leonard, S. A., Carmichael, S. L., El-Sayed, Y. Y. MOSBY-ELSEVIER. 2020: S97
  • Maternal Health after Stillbirth: Postpartum Hospital Readmission in California. American journal of perinatology Wall-Wieler, E. n., Butwick, A. J., Gibbs, R. S., Lyell, D. J., Girsen, A. I., El-Sayed, Y. Y., Carmichael, S. L. 2020

    Abstract

     The aim of this study is to assess whether the risk of postpartum readmission within 6 weeks of giving birth differs for women who had stillbirths compared with live births. Using data from the Office of Statewide Health Planning and Development in California, we performed a population-based cohort study of 7,398,640 births between 1999 and 2011. We identified diagnoses and procedures associated with the first postpartum hospital readmission that occurred within 6 weeks after giving birth. We used log-binomial models to estimate relative risk (RR) of postpartum readmission for women who had stillbirth compared with live birth deliveries, adjusting for maternal demographic, prepregnancy, pregnancy, and delivery characteristics. The rate of postpartum readmission was higher among women who had stillbirths compared with women who had live births (206 and 96 per 10,000 births, respectively). After adjusting for maternal demographic and medical characteristics, the risk of postpartum readmission for women who had stillbirths was nearly 1.5 times greater (adjusted RR = 1.47, 95% confidence interval: 1.35-1.60) compared with live births. Among women with stillbirths, the most common indications at readmission were uterine infection or pelvic inflammatory disease, psychiatric conditions, hypertensive disorder, and urinary tract infection. Based on our findings, women who have stillbirths are at higher risk of postpartum readmissions within 6 weeks of giving birth than women who have live births. Women who have stillbirths may benefit from additional monitoring and counseling after hospital discharge for potential postpartum medical and psychiatric complications.· Women who have stillbirths are at nearly 1.5 times greater risk of postpartum readmission than women who have live births.. · Uterine infections and pelvic inflammatory disease, and psychiatric conditions are the most common reasons for readmission among women who had a stillbirth.. · Women who have stillbirths may benefit from additional monitoring and counseling after hospital discharge for potential postpartum medical and psychiatric complications..

    View details for DOI 10.1055/s-0040-1708803

    View details for PubMedID 32365389

  • Pre-pregnancy Obesity and the Risk of Peripartum Cardiomyopathy. American journal of perinatology Cho, S. H., Leonard, S. A., Lyndon, A. n., Main, E. K., Abrams, B. n., Hameed, A. B., Carmichael, S. L. 2020

    Abstract

     The aim of this study is to evaluate the contribution of pre-pregnancy obesity and overweight to peripartum cardiomyopathy. This population-based study used linked birth record and maternal hospital discharge data from live births in California during 2007 to 2012 (n = 2,548,380). All women who had a diagnosis of peripartum cardiomyopathy during the childbirth hospitalization or who were diagnosed with peripartum cardiomyopathy during a postpartum hospital readmission within 5 months of birth were identified as cases. Pre-pregnancy body mass index (BMI, kg/m2) was classified as normal weight (18.5-24.9), overweight (25.0-29.9), obesity class 1 (30.0-34.9), obesity class 2 (35.0-39.9), and obesity class 3 (≥40). Because of small numbers, we excluded women with underweight BMI, and in some analyses, we combined obesity classes into one group. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) expressing associations between BMI and peripartum cardiomyopathy, adjusted for maternal age, race/ethnicity, education, health care payer, parity, plurality, and comorbidities. The overall prevalence of peripartum cardiomyopathy during hospital admissions was 1.3 per 10,000 live births (n = 320). Unadjusted ORs were 1.32 (95% CI: 1.01-1.74) for women with overweight BMI and 2.03 (95% CI: 1.57-2.62) for women with obesity, compared with women with normal pre-pregnancy BMI. Adjusted ORs were 1.26 (95% CI: 0.95-1.66) for overweight women and 1.38 (95% CI: 1.04-1.84) for women with obesity. The ORs suggested a dose-response relationship with increasing levels of obesity, but the 95% CIs for the specific classes of obesity included 1.00. Pre-pregnancy obesity was associated with an increased risk of peripartum cardiomyopathy. These findings underscore the importance of BMI during pregnancy. There is a need to recognize the increased risk of peripartum cardiomyopathy in women with high BMI, especially in the late postpartum period.· Pre-pregnancy obesity affects maternal health.. · Effects may extend to peripartum cardiomyopathy.. · The risk includes peripartum cardiomyopathy that emerges postpartum..

    View details for DOI 10.1055/s-0040-1712451

    View details for PubMedID 32512606

  • Periconceptional stressors and social support and risk for adverse birth outcomes. BMC pregnancy and childbirth Weber, K. A., Carmichael, S. L., Yang, W. n., Tinker, S. C., Shaw, G. M. 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

  • Mid-gestation serum lipidomic profile associations with spontaneous preterm birth are influenced by body mass index. PloS one Borkowski, K., Newman, J. W., Aghaeepour, N., Mayo, J. A., Blazenovic, I., Fiehn, O., Stevenson, D. K., Shaw, G. M., Carmichael, S. L. 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

  • Factors Associated with Early Neonatal and First-Year Mortality in Infants with Myelomeningocele in California from 2006 to 2011. American journal of perinatology Kancherla, V. n., Ma, C. n., Grant, G. n., Lee, H. C., Hintz, S. R., Carmichael, S. L. 2020

    Abstract

     The aim of this study is to examine factors associated with early neonatal (death within first 7 days of birth) and infant (death during the first year of life) mortality among infants born with myelomeningocele. We examined linked data from the California Perinatal Quality Care Collaborative, vital records, and hospital discharge records for infants born with myelomeningocele from 2006 to 2011. Survival probability was calculated using Kaplan-Meier Product Limit method and 95% confidence intervals (CI) using Greenwood's method; Cox proportional hazard models were used to estimate unadjusted and adjusted hazard ratios (HR) and 95% CI. Early neonatal and first-year survival probabilities among infants born with myelomeningocele were 96.0% (95% CI: 94.1-97.3%) and 94.5% (95% CI: 92.4-96.1%), respectively. Low birthweight and having multiple co-occurring birth defects were associated with increased HRs ranging between 5 and 20, while having congenital hydrocephalus and receiving hospital transfer from the birth hospital to another hospital for myelomeningocele surgery were associated with HRs indicating a protective association with early neonatal and infant mortality. Maternal race/ethnicity and social disadvantage did not predict early neonatal and infant mortality among infants with myelomeningocele; presence of congenital hydrocephalus and the role of hospital transfer for myelomeningocele repair should be further examined.· Mortality in myelomeningocele is a concern. · Social disadvantage was not associated with death. · Hospital-based factors should be further examined.

    View details for DOI 10.1055/s-0040-1712165

    View details for PubMedID 32473597

  • Early postpartum readmissions or emergency department visits: Identifying risk factors Girsen, A., Leonard, S. A., Carmichael, S. L., Gibbs, R. S. MOSBY-ELSEVIER. 2020: S351–S352
  • 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 Carmichael, S. L., Ma, C. n., Lee, H. C., Shaw, G. M., Sylvester, K. G., Hintz, S. R. 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

  • Improved Referral of Very Low Birthweight Infants to High-Risk Infant Follow-Up in California. The Journal of pediatrics Pai, V. V., Kan, P., Bennett, M., Carmichael, S. L., Lee, H. C., Hintz, S. R. 2019

    Abstract

    OBJECTIVE: To examine changes in referral rates of very low birthweight (birthweight <1500g) infants to high-risk infant follow-up in California and identify factors associated with referral before and after implementation of a statewide initiative in 2013 to address disparities in referral.STUDY DESIGN: We included very low birthweight infants born 2010-2016 in the population-based California Perinatal Quality Care Collaborative who survived to discharge home. We used multivariable logistic regression to examine factors associated with referral and derive risk-adjusted referral rates by neonatal intensive care unit (NICU) and region.RESULTS: Referral rate improved from 83.0% (preinitiative period) to 94.9% (postinitiative period); yielding an OR of 1.48 (95% CI, 1.26-1.72) for referral in the postinitiative period after adjustment for year. Referral rates improved the most (≥15%) for infants born at ≥33weeks of gestation, with a birthweight of 1251-1500g, and born in intermediate and lower volume NICUs. After the initiative, Hispanic ethnicity, small for gestational age status, congenital anomalies, and major morbidities were no longer associated with a decreased odds of referral. Lower birthweight, outborn status, and higher NICU volume were no longer associated with increased odds of referral. African American race was associated with lower odds of referral, and higher NICU level with a higher odds of referral during both time periods. Referral improved in many previously poor-performing NICUs and regions.CONCLUSIONS: High-risk infant follow-up referral of very low birthweight infants improved substantially across all sociodemographic, perinatal, and clinical variables after the statewide initiative, although disparities remain. Our results demonstrate the benefit of a targeted initiative in California, which may be applicable to other quality collaboratives.

    View details for DOI 10.1016/j.jpeds.2019.08.050

    View details for PubMedID 31587859

  • Risk Factors for Maternal Readmission with Sepsis. American journal of perinatology Foeller, M. E., Sie, L., Foeller, T. M., Girsen, A. I., Carmichael, S. L., Lyell, D. J., Lee, H. C., Gibbs, R. S. 2019

    Abstract

    OBJECTIVE: Our primary objective was to identify risk factors for maternal readmission with sepsis. Our secondary objectives were to (1) assess diagnoses and infecting organisms at readmission and (2) compare early (<6 weeks) and late (6 weeks to 9 months postpartum) maternal readmission with sepsis.STUDY DESIGN: We identified our cohort using linked hospital discharge data and birth certificates for California deliveries from 2008 to 2011. Consistent with the 2016 sepsis classification, we defined sepsis as septicemia plus acute organ dysfunction. We compared women with early or late readmission with sepsis to women without readmission with sepsis.RESULTS: Among 1,880,264 women, 494 (0.03%) were readmitted with sepsis, 61% after 6 weeks. Risk factors for readmission with sepsis included preterm birth, hemorrhage, obesity, government-provided insurance, and primary cesarean. For both early and late sepsis readmissions, the most common diagnoses were urinary tract infection and pyelonephritis, and the most frequently identified infecting organism was gram-negative bacteria. Women with early compared with late readmission with sepsis shared similar obstetric characteristics.CONCLUSION: Maternal risk factors for both early and late readmission with sepsis included demographic characteristics, cesarean, hemorrhage, and preterm birth. Risks for sepsis after delivery persist beyond the traditional postpartum period of 6 weeks.

    View details for DOI 10.1055/s-0039-1696721

    View details for PubMedID 31529451

  • Rate and causes of severe maternal morbidity at readmission: California births in 2008-2012. Journal of perinatology : official journal of the California Perinatal Association Girsen, A. I., Sie, L., Carmichael, S. L., Lee, H. C., Foeller, M. E., Druzin, M. L., Gibbs, R. S. 2019

    Abstract

    OBJECTIVE: To determine the rate, maternal characteristics, timing, and indicators of severe maternal morbidity (SMM) that occurs at postpartum readmission.STUDY DESIGN: Women with a birth in California during 2008-2012 were included in the analysis. Readmissions up to 42 days after delivery were investigated. SMM was defined as presence of any of the 21 indicators defined by ICD-9 codes.RESULTS: Among 2,413,943 women with a birth, SMM at readmission occurred in 4229 women. Of all SMM, 12.1% occurred at readmission. Over half (53.5%) of the readmissions with SMM occurred within the first week after delivery hospitalization. The most common indicators of SMM were blood transfusion, sepsis, and pulmonary edema/acute heart failure.CONCLUSION: Twelve percent of SMM was identified at readmission with the majority occurring within 1 week after discharge from delivery hospitalization. Because early readmission may reflect lack of discharge readiness, there may be opportunities to improve care.

    View details for DOI 10.1038/s41372-019-0481-z

    View details for PubMedID 31462721

  • Asthma medication use and risk of birth defects: National Birth Defects Prevention Study 1997-2011 Howley, M. M., Papadopoulos, E. A., Van Bennekom, C., Van Zutphen, A. R., Carmichael, S. L., Munsie, J. W., Herdt, M. L., Browne, M. L. WILEY. 2019: 365–66
  • Severe maternal morbidity and postpartum mental health-related outcomes in Sweden: a population-based matched-cohort study ARCHIVES OF WOMENS MENTAL HEALTH Wall-Wieler, E., Carmichael, S. L., Urquia, M. L., Liu, C., Hjern, A. 2019; 22 (4): 519–26
  • Factors Associated with Timeliness of Surgical Repair among Infants with Myelomeningocele: California Perinatal Quality Care Collaborative, 2006 to 2011. American journal of perinatology Kancherla, V., Ma, C., Grant, G., Lee, H. C., Shaw, G. M., Hintz, S. R., Carmichael, S. L. 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

  • Severe Maternal Morbidity Among Stillbirth and Live Birth Deliveries in California. Obstetrics and gynecology Wall-Wieler, E., Carmichael, S. L., Gibbs, R. S., Lyell, D. J., Girsen, A. I., El-Sayed, Y. Y., Butwick, A. J. 2019

    Abstract

    OBJECTIVE: To assess the prevalence and risk of severe maternal morbidity among delivery hospitalization for stillbirth compared with live birth deliveries.METHODS: Using data from the Office of Statewide Health Planning and Development in California, we performed a population-based cross-sectional study of 6,459,842 deliveries between 1999 and 2011. We identified severe maternal morbidity using an algorithm comprising diagnoses and procedures developed by the Centers for Disease Control and Prevention and used log-binomial regression models to examine the relative risk (RR) of severe maternal morbidity for stillbirth compared with live birth deliveries, adjusting for maternal demographic, medical, and obstetric characteristics. We also examined severe maternal morbidity prevalence by cause of fetal death among stillbirth deliveries.RESULTS: The prevalence of severe maternal morbidity for stillbirth and live birth was 578 and 99 cases per 10,000 deliveries, respectively. After adjusting for maternal demographic, medical, and obstetric characteristics, the risk of severe maternal morbidity among stillbirth deliveries was more than fourfold higher (adjusted RR 4.77; 95% CI 4.53-5.02) compared with live birth deliveries. The severe maternal morbidity prevalence was highest among stillbirths caused by hypertensive disorders and placental conditions (24 and 19 cases/100 deliveries, respectively), and lowest among stillbirths caused by fetal malformations or genetic abnormalities (1 case per 100 deliveries).CONCLUSION: Women who have stillbirths are at substantially higher risk for severe maternal morbidity than women who have live births, regardless of cause of fetal death. The prevalence of severe maternal morbidity varies by cause of fetal death.

    View details for DOI 10.1097/AOG.0000000000003370

    View details for PubMedID 31306335

  • The ARRIVE Trial: Interpretation from an Epidemiologic Perspective. Journal of midwifery & women's health Carmichael, S. L., Snowden, J. M. 2019

    Abstract

    The findings of the ARRIVE trial (A Randomized Trial of Induction Versus Expectant Management) were recently published. This multisite randomized trial was designed to provide evidence regarding whether labor induction or expectant management is associated with increased adverse perinatal outcomes and risk of cesarean birth among healthy nulliparous women at term. The trial reported that the primary outcome, a composite of adverse neonatal outcomes, was not significantly different between the 2 groups; the principal secondary outcome, cesarean birth, was significantly more common among women whose pregnancy was expectantly managed than among women whose labor was induced at 39weeks. These results have the potential to change existing practice. Several aspects of the study design may influence its potential internal and external validity and should be considered in order to make sound causal inferences from this trial, which will in turn affect how its findings are translated to practice. Although chance and confounding are of minimal concern, given the sample size and randomization used in the study, selection bias may be a concern. Studies are vulnerable to selection bias when the sample population differs from eligible nonparticipants, including in randomized controlled trials. External validity is defined as the extent to which the study population and setting are representative of the larger source population the study intends to represent. External validity may be limited given the characteristics of the women enrolled in the ARRIVE trial and the practice settings where the study was conducted. This brief report provides concrete suggestions for further analyses that could help solidify conclusions from the trial, and for further research questions that will continue advancement toward answering this complex question of how best to manage labor and birth decisions at full term among low-risk women.

    View details for DOI 10.1111/jmwh.12996

    View details for PubMedID 31264773

  • Sociodemographic, health behavioral, and clinical risk factors for anotia/microtia in a population-based case-control study INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY Ryan, M. A., Olshan, A. F., Canfield, M. A., Hoyt, A. T., Scheuerle, A. E., Carmichael, S. L., Shaw, G. M., Werler, M. M., Fisher, S. C., Desrosiers, T. A., Natl Birth Defects Prevention Stud 2019; 122: 18–26
  • Prenatal and postnatal inflammation-related risk factors for retinopathy of prematurity JOURNAL OF PERINATOLOGY Goldstein, G. P., Leonard, S. A., Kan, P., Koo, E. B., Lee, H. C., Carmichael, S. L. 2019; 39 (7): 964–73
  • The role of genetic variation in DGKK on moderate and severe hypospadias. Birth defects research Richard, M. A., Sok, P., Canon, S., Brown, A. L., Peckham-Gregory, E. C., Nembhard, W. N., Carmichael, S. L., Ehli, E. A., Kallsen, N. A., Peyton, S. A., Davies, G. E., Patel, A., Zamilpa, I., Wyatt, R. A., Hobbs, C. A., Scheurer, M. E., Lupo, P. J. 2019

    Abstract

    BACKGROUND: Recent genome-wide association studies of hypospadias have implicated the role of genetic variants in or near the diacylglycerol kinase kappa (DGKK) gene. However, these variants are largely identified among samples of mild and moderate hypospadias cases. Therefore, we evaluated previously identified DGKK variants among second- and third-degree hypospadias cases and controls recruited in Arkansas, a state characterized by a high birth prevalence of hypospadias.METHODS: Second- and third-degree hypospadias non-Hispanic white cases (n =36 and n = 9, respectively) and controls (n =45) were recruited at Arkansas Children's Hospital. Preputial tissue was collected on cases and controls between 2013 and 2017. Cases and controls were genotyped using the Illumina Infinium Global Screening Array. We used logistic regression models to assess the association of genotyped and imputed genetic variants mapped to the DGKK region with second- and third-degree hypospadias.RESULTS: All families self-reported as non-Hispanic white and genetic principal component analyses did not demonstrate evidence of population stratification. Five DGKK variants previously reported as associated with hypospadias were identified in the genotype data. None of the variants were associated with second- or third-degree hypospadias (range of odds ratios = 0.7-0.9, all p >.05).CONCLUSIONS: In our analyses, genetic variation in DGKK does not play a role in the development of moderate and severe hypospadias. Our findings provide support to the etiologic heterogeneity of hypospadias by all classifications of severity.

    View details for DOI 10.1002/bdr2.1522

    View details for PubMedID 31102501

  • Racial and ethnic disparities in severe maternal morbidity prevalence and trends ANNALS OF EPIDEMIOLOGY Leonard, S. A., Main, E. K., Scott, K. A., Profit, J., Carmichael, S. L. 2019; 33: 30–36
  • Stillbirth and Live Birth at Periviable Gestational Age: A Comparison of Prevalence and Risk Factors AMERICAN JOURNAL OF PERINATOLOGY Carmichael, S. L., Blumenfeld, Y. J., Mayo, J. A., Profit, J., Shaw, G. M., Hintz, S. R., Stevenson, D. K. 2019; 36 (5): 537–44
  • Sociodemographic, health behavioral, and clinical risk factors for anotia/microtia in a population-based case-control study. International journal of pediatric otorhinolaryngology Ryan, M. A., Olshan, A. F., Canfield, M. A., Hoyt, A. T., Scheuerle, A. E., Carmichael, S. L., Shaw, G. M., Werler, M. M., Fisher, S. C., Desrosiers, T. A., National Birth Defects Prevention Study 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

  • Comparing Usual Dietary Intakes Among Subgroups of Mothers in the Year Before Pregnancy PUBLIC HEALTH REPORTS Carmichael, S. L., Ma, C., Feldkamp, M. L., Shaw, G. M., Natl Birth Defects Prevention Stu 2019; 134 (2): 155–63
  • A machine learning approach to investigate potential risk factors for gastroschisis in California BIRTH DEFECTS RESEARCH Weber, K. A., Yang, W., Carmichael, S. L., Padula, A. M., Shaw, G. M. 2019; 111 (4): 212–21

    View details for DOI 10.1002/bdr2.1441

    View details for Web of Science ID 000461575000004

  • Fish consumption prior to pregnancy and pregnancy outcomes in the National Birth Defects Prevention Study, 1997-2011 PUBLIC HEALTH NUTRITION Benjamin, R. H., Mitchell, L. E., Canfield, M. A., Hoyt, A. T., Lai, D., Ramadhani, T. A., Carmichael, S. L., Case, A. P., Waller, D., Natl Birth Defects Prevention Stud 2019; 22 (2): 336–43
  • The contribution of maternal characteristics and cesarean delivery to an increasing trend of severe maternal morbidity. BMC pregnancy and childbirth Leonard, S. A., Main, E. K., Carmichael, S. L. 2019; 19 (1): 16

    Abstract

    Severe maternal morbidity - life-threatening childbirth complications - has more than doubled in the United States over the past 15 years, affecting more than 50,000 women (1.4% of deliveries) annually. During this time period, maternal age, obesity, comorbidities, and cesarean delivery also increased and may be related to the rise in severe maternal morbidity. We sought to evaluate: (1) the association of advanced maternal age, pre-pregnancy obesity, pre-pregnancy comorbidities, and cesarean delivery with severe maternal morbidity, and (2) whether changes in the prevalence of these risk factors affected the trend of severe maternal morbidity.This population-based cohort study used linked birth record and patient discharge data from live births in California during 2007-2014 (n = 3,556,206). We used multivariable logistic regression models to assess the association of advanced maternal age (≥35 years), pre-pregnancy obesity (body mass index ≥30 kg/m2), pre-pregnancy comorbidity (index of 12 conditions), and cesarean delivery with severe maternal morbidity prevalence and trends. Severe maternal morbidity was identified by an index of 18 diagnosis and procedure indicators. We estimated odds ratios, predicted prevalence, and population attributable risk percentages.The prevalence of severe maternal morbidity increased by 65% during 2007-2014. Advanced maternal age, pre-pregnancy obesity, and pre-pregnancy comorbidity also increased during this period, but cesarean delivery did not. None of these risk factors affected the increasing trend of severe maternal morbidity. However, the pre-pregnancy risk factors together were estimated to contribute to 13% (95% confidence interval: 12, 14%) of severe maternal morbidity cases in the study population overall, and cesarean delivery was estimated to contribute to 37% (95% confidence interval: 36, 38%) of cases.Pre-pregnancy health and cesarean delivery are important risk factors for severe maternal morbidity but do not explain an increasing trend of severe maternal morbidity in California during 2007-2014. Investigation of other potential contributors is needed in order to identify ways to reverse the trend of severe maternal morbidity.

    View details for DOI 10.1186/s12884-018-2169-3

    View details for PubMedID 30626349

    View details for PubMedCentralID PMC6327483

  • Use of mobile technology by frontline health workers to promote reproductive, maternal, newborn and child health and nutrition: a cluster randomized controlled Trial in Bihar, India. Journal of global health Carmichael, S. L., Mehta, K. n., Srikantiah, S. n., Mahapatra, T. n., Chaudhuri, I. n., Balakrishnan, R. n., Chaturvedi, S. n., Raheel, H. n., Borkum, E. n., Trehan, S. n., Weng, Y. n., Kaimal, R. n., Sivasankaran, A. n., Sridharan, S. n., Rotz, D. n., Tarigopula, U. K., Bhattacharya, D. n., Atmavilas, Y. n., Pepper, K. T., Rangarajan, A. n., Darmstadt, G. L. 2019; 9 (2): 0204249

    Abstract

    mHealth technology holds promise for improving the effectiveness of frontline health workers (FLWs), who provide most health-related primary care services, especially reproductive, maternal, newborn, child health and nutrition services (RMNCHN), in low-resource - especially hard-to-reach - settings. Data are lacking, however, from rigorous evaluations of mHealth interventions on delivery of health services or on health-related behaviors and outcomes.The Information Communication Technology-Continuum of Care Service (ICT-CCS) tool was designed for use by community-based FLWs to increase the coverage, quality and coordination of services they provide in Bihar, India. It consisted of numerous mobile phone-based job aids aimed to improve key RMNCHN-related behaviors and outcomes. ICT-CCS was implemented in Saharsa district, with cluster randomization at the health sub-center level. In total, evaluation surveys were conducted with approximately 1100 FLWs and 3000 beneficiaries who had delivered an infant in the previous year in the catchment areas of intervention and control health sub-centers, about half before implementation (mid-2012) and half two years afterward (mid-2014). Analyses included bivariate and difference-in-difference analyses across study groups.The ICT-CCS intervention was associated with more frequent coordination of AWWs with ASHAs on home visits and greater job confidence among ASHAs. The intervention resulted in an 11 percentage point increase in FLW antenatal home visits during the third trimester (P = 0.04). In the post-implementation period, postnatal home visits during the first week were increased in the intervention (72%) vs the control (60%) group (P < 0.01). The intervention also resulted in 13, 12, and 21 percentage point increases in skin-to-skin care (P < 0.01), breastfeeding immediately after delivery (P < 0.01), and age-appropriate complementary feeding (P < 0.01). FLW supervision and other RMNCHN behaviors were not significantly impacted.Important improvements in FLW home visits and RMNCHN behaviors were achieved. The ICT-CCS tool shows promise for facilitating FLW effectiveness in improving RMNCHN behaviors.

    View details for DOI 10.7189/jogh.09.020424

    View details for PubMedID 31788233

    View details for PubMedCentralID PMC6875677

  • Re: Unexpected term NICU admissions: a marker of obstetrical care quality? American journal of obstetrics and gynecology Snowden, J. M., Carmichael, S. L., Klebanoff, M. A. 2019

    View details for DOI 10.1016/j.ajog.2019.08.031

    View details for PubMedID 31469988

  • Risk of Stillbirth for Fetuses With Specific Birth Defects. Obstetrics and gynecology Heinke, D. n., Nestoridi, E. n., Hernandez-Diaz, S. n., Williams, P. L., Rich-Edwards, J. W., Lin, A. E., Van Bennekom, C. M., Mitchell, A. A., Nembhard, W. N., Fretts, R. C., Roberts, D. J., Duke, C. W., Carmichael, S. L., Yazdy, M. M. 2019

    Abstract

    To estimate the risk of stillbirth (fetal death at 20 weeks of gestation or more) associated with specific birth defects.We identified a population-based retrospective cohort of neonates and fetuses with selected major birth defects and without known or strongly suspected chromosomal or single-gene disorders from active birth defects surveillance programs in nine states. Abstracted medical records were reviewed by clinical geneticists to confirm and classify all birth defects and birth defect patterns. We estimated risks of stillbirth specific to birth defects among pregnancies overall and among those with isolated birth defects; potential bias owing to elective termination was quantified.Of 19,170 eligible neonates and fetuses with birth defects, 17,224 were liveborn, 852 stillborn, and 672 electively terminated. Overall, stillbirth risks ranged from 11 per 1,000 fetuses with bladder exstrophy (95% CI 0-57) to 490 per 1,000 fetuses with limb-body-wall complex (95% CI 368-623). Among those with isolated birth defects not affecting major vital organs, elevated risks (per 1,000 fetuses) were observed for cleft lip with cleft palate (10; 95% CI 7-15), transverse limb deficiencies (26; 95% CI 16-39), longitudinal limb deficiencies (11; 95% CI 3-28), and limb defects due to amniotic bands (110; 95% CI 68-171). Quantified bias analysis suggests that failure to account for terminations may lead to up to fourfold underestimation of the observed risks of stillbirth for sacral agenesis (13/1,000; 95% CI 2-47), isolated spina bifida (24/1,000; 95% CI 17-34), and holoprosencephaly (30/1,000; 95% CI 10-68).Birth defect-specific stillbirth risk was high compared with the U.S. stillbirth risk (6/1,000 fetuses), even for isolated cases of oral clefts and limb defects; elective termination may appreciably bias some estimates. These data can inform clinical care and counseling after prenatal diagnosis.

    View details for DOI 10.1097/AOG.0000000000003614

    View details for PubMedID 31809437

  • Effects of team-based goals and non-monetary incentives on front-line health worker performance and maternal health behaviours: a cluster randomised controlled trial in Bihar, India. BMJ global health Carmichael, S. L., Mehta, K., Raheel, H., Srikantiah, S., Chaudhuri, I., Trehan, S., Mohanty, S., Borkum, E., Mahapatra, T., Weng, Y., Kaimal, R., Sivasankaran, A., Sridharan, S., Rotz, D., Tarigopula, U. K., Bhattacharya, D., Atmavilas, Y., Munar, W., Rangarajan, A., Darmstadt, G. L., Ananya Study Group, Atmavilas, Y., Bhattacharya, D., Borkum, E., Carmichael, S. L., Chaudhuri, I., Creanga, A., Darmstadt, G. L., Dutt, P., Irani, L., Kaimal, R., Mahapatra, T., Mehta, K. M., Mitra, R., Munar, W., Pepper, K., Raheel, H., Rangarajan, A., Saggurti, N., Sastry, P., Schooley, J., Shah, H., Srikantiah, S., Kiran Tarigopula, U., Ward, V., Weng, Y., Wahid, S., Wilhelm, J. 2019; 4 (4): e001146

    Abstract

    Introduction: We evaluated the impact of a 'Team-Based Goals and Incentives' (TBGI) intervention in Bihar, India, designed to improve front-line (community health) worker (FLW) performance and health-promoting behaviours related to reproductive, maternal, newborn and child health and nutrition.Methods: This study used a cluster randomised controlled trial design and difference-in-difference analyses of improvements in maternal health-related behaviours related to the intervention's team-based goals (primary), and interactions of FLWs with each other and with maternal beneficiaries (secondary). Evaluation participants included approximately 1300 FLWs and 3600 mothers at baseline (May to June 2012) and after 2.5 years of implementation (November to December 2014) who had delivered an infant in the previous year.Results: The TBGI intervention resulted in significant increases in the frequency of antenatal home visits (15 absolute percentage points (PP), p=0.03) and receipt of iron-folic acid (IFA) tablets (7 PP, p=0.02), but non-significant changes in other health behaviours related to the trial's goals. Improvements were seen in selected attitudes related to coordination and teamwork among FLWs, and in the provision of advice to beneficiaries (ranging from 8 to 14 PP) related to IFA, cord care, breast feeding, complementary feeding and family planning.Conclusion: Results suggest that combining an integrated set of team-based coverage goals and targets, small non-cash incentives for teams who meet targets and team building to motivate FLWs resulted in improvements in FLW coordination and teamwork, and in the quality and quantity of FLW-beneficiary interactions. These improvements represent programmatically meaningful steps towards improving health behaviours and outcomes.Trial registration number: NCT03406221.

    View details for DOI 10.1136/bmjgh-2018-001146

    View details for PubMedID 31543982

  • Risk of severe maternal morbidity in relation to prepregnancy body mass index: Roles of maternal co-morbidities and caesarean birth. Paediatric and perinatal epidemiology Leonard, S. A., Carmichael, S. L., Main, E. K., Lyell, D. J., Abrams, B. n. 2019

    Abstract

    An association between prepregnancy body mass index (BMI) and severe maternal morbidity (SMM) has been reported, but evidence has been mixed and potential explanations have not been examined.To evaluate the association between prepregnancy BMI and SMM in a large, diverse birth cohort and assess potential mediation by obesity-related co-morbidities and caesarean birth.This cohort study used linked birth certificate and hospitalisation discharge records from Californian births during 2007-2012. We assessed associations between prepregnancy BMI and SMM, and used inverse probability weighting for multiple mediators to estimate relative and absolute natural direct and indirect effects accounting for mediation by co-morbidities (hypertensive conditions, diabetes, asthma) and caesarean birth.Among 2 650 182 births, the prevalence of SMM was 1.42%. Adjusted risk ratios for the total association between prepregnancy BMI category and SMM were 1.12 (95% confidence interval [CI] 1.07, 1.18) for underweight, 1.02 (95% CI 0.99, 1.04) for overweight, 1.04 (95% CI 1.00, 1.07) for obesity class 1, 1.14 (95% CI 1.09, 1.20) for obesity class 2, and 1.28 (95% CI 1.22, 1.36) for obesity class 3 compared to women with normal weight. After accounting for mediation by co-morbidity and caesarean birth, the risk ratios were 1.19 (95% CI 1.14, 1.26) for underweight, 0.91 (95% CI 0.89, 0.94) for overweight, 0.86 (95% CI 0.84, 0.89) for obesity class 1, 0.88 (95% CI 0.84, 0.92) for obesity class 2, and 0.89 (95% CI 0.83, 0.95) for obesity class 3.Co-morbidities and caesarean birth explained an association between high prepregnancy BMI and SMM. These findings suggest that promotion of healthy prepregnancy weight, along with management of co-morbidities and support of vaginal birth in pregnant women with high BMI, could reduce the risk of SMM. However, these mediators did not reduce the elevated risk of SMM observed in women with low BMI.

    View details for DOI 10.1111/ppe.12555

    View details for PubMedID 31106879

  • Gestational Weight Gain and Severe Maternal Morbidity at Delivery Hospitalization. Obstetrics and gynecology Leonard, S. A., Carmichael, S. L., Abrams, B. n. 2019; 134 (2): 420

    View details for DOI 10.1097/AOG.0000000000003389

    View details for PubMedID 31348212

  • Survival of infants with spina bifida and the role of maternal prepregnancy body mass index. Birth defects research Pace, N. D., Siega-Riz, A. M., Olshan, A. F., Chescheir, N. C., Cole, S. R., Desrosiers, T. A., Tinker, S. C., Hoyt, A. T., Canfield, M. A., Carmichael, S. L., Meyer, R. E. 2019

    Abstract

    To investigate first-year survival of infants born with spina bifida, and examine the association of maternal prepregnancy body mass index (BMI) with infant mortality.This is a retrospective cohort study of 1,533 liveborn infants with nonsyndromic spina bifida with estimated dates of delivery from 1998 to 2011 whose mothers were eligible for the National Birth Defects Prevention Study (NBDPS). NBDPS data were linked to death records to conduct survival analyses. Kaplan-Meier survival functions estimated mortality risk over the first year of life. Cox proportional hazards models estimated hazard ratios (HRs) for maternal prepregnancy BMI categorized as underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), and obese (≥30).Infant mortality risk among infants with spina bifida was (4.4% [3.52, 5.60%]). Infants with multiple co-occurring defects, very preterm delivery, multiple gestation, high-level spina bifida lesions, or non-Hispanic Black mothers had an elevated risk of infant mortality. Maternal prepregnancy underweight and obesity were associated with higher infant mortality (15.7% [7.20, 32.30%] and 5.82% [3.60, 9.35%], respectively). Adjusted HR estimates showed underweight and obese mothers had greater hazard of infant mortality compared to normal weight mothers (HR: 4.5 [1.08, 16.72] and 2.6 [1.36, 8.02], respectively).The overall risk of infant mortality for infants born with spina bifida was lower than most previously reported estimates. Infants born with spina bifida to mothers who were underweight or obese prepregnancy were at higher risk of infant mortality. This study provides additional evidence of the importance of healthy maternal weight prior to pregnancy.

    View details for DOI 10.1002/bdr2.1552

    View details for PubMedID 31322328

  • Teratology society position statement on surveillance and prevalence estimation of neural tube defects BIRTH DEFECTS RESEARCH Kancherla, V., Carmichael, S. L., Feldkamp, M. L., Berry, R. J. 2019; 111 (1): 5-8

    View details for DOI 10.1002/bdr2.1434

    View details for Web of Science ID 000455540100001

  • Prenatal and postnatal inflammation-related risk factors for retinopathy of prematurity. Journal of perinatology : official journal of the California Perinatal Association Goldstein, G. P., Leonard, S. A., Kan, P. n., Koo, E. B., Lee, H. C., Carmichael, S. L. 2019

    Abstract

    To evaluate the relationship between prenatal and postnatal inflammation-related risk factors and severe retinopathy of prematurity (ROP).The study included infants born <30 weeks in California from 2007 to 2011. Multivariable log-binomial regression was used to assess the association between prenatal and postnatal inflammation-related exposures and severe ROP, defined as stage 3-5 or surgery for ROP.Of 14,816 infants, 10.8% developed severe ROP. Though prenatal inflammation-related risk factors were initially associated with severe ROP, after accounting for the effect of these risk factors on gestational age at birth through mediation analysis, the association was non-significant (P = 0.6). Postnatal factors associated with severe ROP included prolonged oxygen exposure, sepsis, intraventricular hemorrhage, and necrotizing enterocolitis.Postnatal inflammation-related factors were associated with severe ROP more strongly than prenatal factors. The association between prenatal inflammation-related factors and ROP was explained by earlier gestational age in infants exposed to prenatal inflammation.

    View details for PubMedID 30932029

  • The contribution of maternal characteristics and cesarean delivery to an increasing trend of severe maternal morbidity BMC Pregnancy and Childbirth Leonard, S. A., Main, E. K., Carmichael, S. L. 2019; 19 (16)
  • Racial and ethnic disparities in severe maternal morbidity prevalence and trends. Annals of epidemiology Leonard, S. A., Main, E. K., Scott, K. A., Profit, J. n., Carmichael, S. L. 2019

    Abstract

    Racial/ethnic disparities in severe maternal morbidity (SMM) are substantial, but little is known about whether these disparities are changing over time or the role of maternal and obstetric factors.We examined disparities in SMM prevalence and trends using linked birth certificate and delivery discharge records from Californian births during 1997-2014 (n = 8,252,025).The prevalence of SMM was highest in non-Hispanic (NH) Black women (1.63%), lowest in NH White women (0.84%), and increased from 1997 to 2014 by approximately 170% in each racial/ethnic group. The magnitude of SMM disparities remained consistent over time. Compared with NH White women, the adjusted risk of SMM was higher in women who identified as Hispanic (RR 1.14; 95% CI 1.12, 1.16), Asian/Pacific Islander (RR 1.23; 95% CI 1.20, 1.26), NH Black (RR 1.27; 95% CI 1.23, 1.31), and American Indian/Alaska Native (RR 1.29; 95% CI 1.15, 1.44), accounting for comorbidities, anemia, cesarean birth, and other maternal characteristics.The prevalence of SMM varied considerably by race/ethnicity but increased at similarly high rates among all racial/ethnic groups. Comorbidities, cesarean birth, and other factors did not fully explain the disparities in SMM, which remained persistent over time.

    View details for PubMedID 30928320

  • Comparing Usual Dietary Intakes Among Subgroups of Mothers in the Year Before Pregnancy. Public health reports (Washington, D.C. : 1974) Carmichael, S. L., Ma, C., Feldkamp, M. L., Shaw, G. M. 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

  • A machine learning approach to investigate potential risk factors for gastroschisis in California. Birth defects research Weber, K. A., Yang, W., Carmichael, S. L., Padula, A. M., Shaw, G. M. 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

  • Teratology society position statement on surveillance and prevalence estimation of neural tube defects. Birth defects research Kancherla, V., Carmichael, S. L., Feldkamp, M. L., Berry, R. J. 2018

    View details for PubMedID 30569547

  • Prepregnancy maternal body mass index and venous thromboembolism: A population based cohort study. BJOG : an international journal of obstetrics and gynaecology Butwick, A. J., Bentley, J., Leonard, S. A., Carmichael, S. L., El-Sayed, Y. Y., Stephansson, O., Guo, N. 2018

    Abstract

    OBJECTIVE: To assess the relationship between maternal body mass index (BMI) and pregnancy-related venous thromboembolism (VTE).DESIGN: Cross-sectional study.SETTING & POPULATION: 2,449,133 women with singleton pregnancies who underwent delivery hospitalization in California between 2008 and 2012.METHODS: Association of prepregnancy BMI and the risk of an antepartum and postpartum VTE was examined using logistic regression, with normal BMI as reference.MAIN OUTCOME MEASURES: Antepartum and postpartum VTE related hospitalization.RESULTS: The prevalences of antepartum and postpartum VTE increased with increasing BMI (antepartum: 2.3, 3.0, 3.8, 4.2, 4.7, and 10.6 per 10 000 women for underweight, normal BMI, overweight, obesity class I, II, and III, P<0.001. postpartum: 2.0, 3.1, 3.9, 5.6, 9.0, and 13.2 per 10 000 women, P<0.01). The adjusted odds of antepartum and postpartum VTE increased progressively with increasing BMI, and obese class III women being at highest risk of pregnancy-related VTE compared with normal BMI women: adjusted odds ratio (OR) for antepartum VTE: 2.9; 95% CI 2.2-3.8 and adjusted OR for postpartum VTE: 3.6; 95% CI 2.9-4.6.CONCLUSIONS: Our findings clearly demonstrate an increasing risk of pregnancy-related VTE with increasing BMI. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30500109

  • 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 La Frano, M. R., Carmichael, S. L., Ma, C., Hardley, M., Shen, T., Wong, R., Rosales, L., Borkowski, K., Pedersen, T. L., Shaw, G. M., Stevenson, D. K., Fiehn, O., Newman, J. W. 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

  • Impact of post-collection freezing delay on the reliability of serum metabolomics in samples reflecting the California mid-term pregnancy biobank METABOLOMICS La Frano, M. R., Carmichael, S. L., Ma, C., Hardley, M., Shen, T., Wong, R., Rosales, L., Borkowski, K., Pedersen, T. L., Shaw, G. M., Stevenson, D. K., Fiehn, O., Newman, J. W. 2018; 14 (11)
  • An application of data mining to identify potential risk factors for anophthalmia and microphthalmia PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Weber, K. A., Yang, W., Carmichael, S. L., Lupo, P. J., Dukhovny, S., Yazdy, M. M., Lin, A. E., Van Bennekom, C. M., Mitchell, A. A., Shaw, G. M., Natl Birth Defects Prevention 2018; 32 (6): 545–55

    View details for DOI 10.1111/ppe.12509

    View details for Web of Science ID 000451452900007

  • Application of machine-learning to predict early spontaneous preterm birth among nulliparous non-Hispanic black and white women ANNALS OF EPIDEMIOLOGY Weber, A., Darmstadt, G. L., Gruber, S., Foeller, M. E., Carmichael, S. L., Stevenson, D. K., Shaw, G. M. 2018; 28 (11): 783–89
  • Fish consumption prior to pregnancy and pregnancy outcomes in the National Birth Defects Prevention Study, 1997-2011. Public health nutrition Benjamin, R. H., Mitchell, L. E., Canfield, M. A., Hoyt, A. T., Lai, D., Ramadhani, T. A., Carmichael, S. L., Case, A. P., Waller, D. K., National Birth Defects Prevention Study 2018: 1–8

    Abstract

    OBJECTIVE: To evaluate the relationships between maternal fish consumption and pregnancy outcomes in a large, population-based sample of women in the USA.DESIGN: We collected average fish consumption prior to pregnancy using a modified version of the semi-quantitative Willett FFQ. We estimated adjusted OR (aOR) and 95 % CI for associations between different levels of fish consumption and preterm birth (<37 weeks), early preterm birth (<32 and <35 weeks) and small-for-gestational-age infants (SGA; <10th percentile).SETTING: The National Birth Defects Prevention Study (NBDPS).SUBJECTS: Control mother-infant pairs with estimated delivery dates between 1997 and 2011 (n 10 919).RESULTS: No significant associations were observed between fish consumption and preterm birth or early preterm birth (aOR = 0·7-1·0 and 0·7-0·9, respectively). The odds of having an SGA infant were elevated (aOR = 2·1; 95 % CI 1·2, 3·4) among women with daily fish consumption compared with women consuming fish less than once per month. No associations were observed between other levels of fish consumption and SGA (aOR = 0·8-1·0).CONCLUSIONS: High intake of fish was associated with twofold higher odds of having an SGA infant, while moderate fish consumption prior to pregnancy was not associated with preterm or SGA. Our study, like many other studies in this area, lacked information regarding preparation methods and the specific types of fish consumed. Future studies should incorporate information on nutrient and contaminant contents, preparation methods and biomarkers to assess these relationships.

    View details for PubMedID 30326983

  • Severe maternal morbidity and postpartum mental health-related outcomes in Sweden: a population-based matched-cohort study. Archives of women's mental health Wall-Wieler, E., Carmichael, S. L., Urquia, M. L., Liu, C., Hjern, A. 2018

    Abstract

    We examined whether women experiencing severe maternal morbidity (SMM) are more likely to be treated for a psychiatric illness or be prescribed psychotropic medications in the postpartum year than mothers who did not experience SMM. We also examine the relationship between SMM and specific mental health-related outcomes, and the relationship between specific SMM diagnoses/procedures and postpartum mental-health-related outcomes. The national registers in Sweden were used to create a population-based matched cohort. Every delivery with SMM between July 1, 2006, and December 31, 2012 (n=8558), was matched with two deliveries without SMM (n=17,116). Conditional logistic regression models assessed the relationship between SMM and postpartum mental health-related outcomes. Women who experienced SMM had significantly greater odds of being treated for a psychiatric disorder (aOR 1.22; 95% CI 1.03-1.45) and being prescribed psychotropic medications (aOR 1.40; 95% CI 1.24-1.58) in the postpartum year. Specifically, they had significantly greater odds of being treated for neuroses (aOR 1.35; 95% CI 1.09-1.69) and having a prescription for anxiolytics/hypnotics (aOR 1.36; 95% CI 1.18-1.58) or antidepressants (aOR 1.35; 95% CI 1.17-1.55). Women who were diagnosed with shock or uterine rupture/obstetric laparotomy during delivery had the greatest odds of postpartum mental health-related outcomes. This study identified mothers with SMM as a group at high risk for postpartum mental illness. Postpartum mental health services should be provided to ensure the well-being of these high-risk mothers.

    View details for PubMedID 30334101

  • Congenital heart disease complexity and childhood cancer risk BIRTH DEFECTS RESEARCH Collins, R., Von Behren, J., Yang, W., Carmichael, S. L., Reynolds, P., Fisher, P. G., Shaw, G. M. 2018; 110 (17): 1314–21

    View details for DOI 10.1002/bdr2.1390

    View details for Web of Science ID 000448368300002

  • An application of data mining to identify potential risk factors for anophthalmia and microphthalmia. Paediatric and perinatal epidemiology Weber, K. A., Yang, W., Carmichael, S. L., Lupo, P. J., Dukhovny, S., Yazdy, M. M., Lin, A. E., Van Bennekom, C. M., Mitchell, A. A., Shaw, G. M., National Birth Defects Prevention Study 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

  • Stillbirth and Live Birth at Periviable Gestational Age: A Comparison of Prevalence and Risk Factors. American journal of perinatology Carmichael, S. L., Blumenfeld, Y. J., Mayo, J. A., Profit, J., Shaw, G. M., Hintz, S. R., Stevenson, D. K. 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

  • Application of machine-learning to predict early spontaneous preterm birth among nulliparous non-Hispanic black and white women. Annals of epidemiology Weber, A., Darmstadt, G. L., Gruber, S., Foeller, M. E., Carmichael, S. L., Stevenson, D. K., Shaw, G. M. 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

  • Women's periconceptional diet and risk of biliary atresia in offspring BIRTH DEFECTS RESEARCH Carmichael, S. L., Ma, C., Van Zutphen, A. R., Moore, C. A., Shaw, G. M., Natl Birth Defects Prevention Stud 2018; 110 (12): 994-1000

    View details for DOI 10.1002/bdr2.1340

    View details for Web of Science ID 000445630800004

  • Residential agricultural pesticide exposures and risks of preeclampsia. Environmental research Shaw, G. M., Yang, W., Roberts, E. M., Aghaeepour, N., Mayo, J. A., Weber, K. A., Maric, I., Carmichael, S. L., Winn, V. D., Stevenson, D. K., English, P. B. 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

  • Dietary factors and pediatric multiple sclerosis: A case-control study MULTIPLE SCLEROSIS JOURNAL Pakpoor, J., Seminatore, B., Graves, J. S., Schreiner, T., Waldman, A. T., Lotze, T. E., Belman, A., Greenberg, B. M., Weinstock-Guttman, B., Aaen, G., Tillema, J., McDonald, J. C., Hart, J., Ness, J. M., Harris, Y., Rubin, J., Candee, M., Krupp, L., Gorman, M., Benson, L., Rodriguez, M., Chitnis, T., Mar, S., Kahn, I., Rose, J., Carmichael, S. L., Roalstad, S., Waltz, M., Casper, T., Waubant, E., US Network Pediat Multiple Scleros 2018; 24 (8): 1067–76

    Abstract

    The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease.To determine the association between dietary factors and MS in children.Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011-2016. Chi-squared test compared categorical variables, Kruskal-Wallis test compared continuous variables, and multivariable logistic regression analysis was performed.In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01).Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.

    View details for PubMedID 28608728

    View details for PubMedCentralID PMC5711616

  • Residential agricultural pesticide exposures and risks of preeclampsia ENVIRONMENTAL RESEARCH Shaw, G. M., Yang, W., Roberts, E. M., Aghaeepour, N., Mayo, J. A., Weber, K. A., Maric, I., Carmichael, S. L., Winn, V. D., Stevenson, D. K., English, P. B. 2018; 164: 546–55
  • Nutrient intake in women before conception and risks of anophthalmia and microphthalmia in their offspring. Birth defects research Weber, K. A., Yang, W., Carmichael, S. L., Shaw, G. M., National Birth Defects Prevention Study 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

  • Maternal body mass index and risk of intraventricular hemorrhage in preterm infants PEDIATRIC RESEARCH Pai, V. V., Carmichae, S. L., Kan, P., Leonard, S. A., Lee, H. C. 2018; 83 (6): 1146-1151

    View details for DOI 10.1038/pr.2018.47

    View details for Web of Science ID 000436345400011

  • Nutrient intake in women before conception and risks of anophthalmia and microphthalmia in their offspring BIRTH DEFECTS RESEARCH Weber, K. A., Yang, W., Carmichael, S. L., Shaw, G. M., Natl Birth Defects Prevention 2018; 110 (10): 863–70

    View details for DOI 10.1002/bdr2.1201

    View details for Web of Science ID 000434062300004

  • Women's periconceptional diet and risk of biliary atresia in offspring. Birth defects research Carmichael, S. L., Ma, C., Van Zutphen, A. R., Moore, C. A., Shaw, G. M., National Birth Defects Prevention Study 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

  • Chemical Contaminants in Raw and Pasteurized Human Milk JOURNAL OF HUMAN LACTATION Hartle, J. C., Cohen, R. S., Sakamoto, P., Barr, D., Carmichael, S. L. 2018; 34 (2): 340–49

    Abstract

    Environmental contaminants ranging from legacy chemicals like p,p'-dichlorodiphenyltrichloroethane (DDT) to emerging chemicals like phthalates are ubiquitous. Research aims/questions: This research aims to examine the presence and co-occurrence of contaminants in human milk and effects of pasteurization on human milk chemical contaminants.We analyzed human milk donated by 21 women to a milk bank for 23 chemicals, including the persistent organic pollutants (POPs) polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) isomers that are known to sequester in adipose tissue, along with the current-use and nonpersistent pesticides chlorpyrifos and permethrin, phthalates, and bisphenol A (BPA). Human milk was analyzed raw and pasteurized for these chemicals using gas chromatography-tandem mass spectrometry for the POPs and high-performance liquid chromatography-tandem mass spectrometry for non-POPs.Within the different chemical classes, PBDE47, PCB153, ppDDE, and MEHHP (phthalate metabolite) had the highest median concentrations and were observed in all samples. We also observed chlorpyrifos and BPA in all samples and permethrin in 90% of the samples tested. Only two chemicals, chlorpyrifos and permethrin, were susceptible to substantial degradation from pasteurization, a standard method for processing donated human milk.We detected 19 of 23 chemicals in all of our prepasteurized milk and 18 of 23 chemicals in all of our pasteurized milk. Pasteurization did not affect the presence of most of the chemicals. Future research should continue to explore human milk for potential chemical contamination and as a means to surveil exposures among women and children.

    View details for PubMedID 29601252

  • Maternal Body Mass Index and Risk of Intraventricular Hemorrhage in Preterm Neonates Pai, V. V., Carmichael, S. L., Kan, P., Lee, H. C. AMER ACAD PEDIATRICS. 2018
  • Maternal body mass index and risk of intraventricular hemorrhage in preterm infants. Pediatric research Pai, V. V., Carmichael, S. L., Kan, P., Leonard, S. A., Lee, H. C. 2018

    Abstract

    BACKGROUND: Intraventricular hemorrhage (IVH) and pre-pregnancy obesity and underweight have been linked to inflammatory states. We hypothesize that IVH in preterm infants is associated with pre-pregnancy obesity and underweight due to an inflammatory intrauterine environment.METHODS: Population-based study of infants born between 22 and 32 weeks' gestation from 2007 to 2011. Data were extracted from vital statistics and the California Perinatal Quality Care Collaborative. Results were examined for all cases (any IVH) and for severe IVH.RESULTS: Among 20,927 infants, 4,818 (23%) had IVH and 1,514 (7%) had severe IVH. After adjustment for confounders, there was an increased risk of IVH associated with pre-pregnancy obesity, relative risk 1.14 (95% CI 1.06, 1.32) for any IVH, and 1.25 (85% CI 1.10, 1.42) for severe IVH. The direct effect of pre-pregnancy obesity on any IVH was significant (P<0.001) after controlling for antenatal inflammation-related conditions, but was not significant after controlling for gestational age (P=0.56).CONCLUSION: Pre-pregnancy obesity was found to be a risk factor for IVH in preterm infants; however, this relationship appeared to be largely mediated through the effect of BMI on gestational age at delivery. The etiology of IVH is complex and it is important to understand contributing maternal factors.Pediatric Research accepted article preview online, 06 April 2018. doi:10.1038/pr.2018.47.

    View details for PubMedID 29624572

  • Occurrence of Selected Structural Birth Defects Among Women With Preeclampsia and Other Hypertensive Disorders AMERICAN JOURNAL OF EPIDEMIOLOGY Weber, K. A., Mayo, J. A., Carmichael, S. L., Stevenson, D. K., Winn, V. D., Shaw, G. M. 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

  • Residential Agricultural Pesticide Exposures and Risks of Spontaneous Preterm Birth EPIDEMIOLOGY Shaw, G. M., Yang, W., Roberts, E. M., Kegley, S. E., Stevenson, D. K., Carmichael, S. L., English, P. B. 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

  • Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Azary, S., Schreiner, T., Graves, J., Waldman, A., Belman, A., Guttman, B., Aaen, G., Tillema, J., Mar, S., Hart, J., Ness, J., Harris, Y., Krupp, L., Gorman, M., Benson, L., Rodriguez, M., Chitnis, T., Rose, J., Barcellos, L. F., Lotze, T., Carmichael, S. L., Roalstad, S., Casper, C. T., Waubant, E. 2018; 89 (1): 28–33

    Abstract

    The role of diet in multiple sclerosis (MS) course remains largely unknown. Children with MS have a higher relapse rate compared with MS in adults. Thus, studying the effect of diet on relapse rate in this age group is likely to provide more robust answers.This is a multicentre study done at 11 paediatric MS centres in the USA. Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) with disease onset before 18 years of age and duration of less than 4 years were included in this study. Dietary intake during the week before enrolment was assessed with the validated Block Kids Food Screener. The outcome of the study was time from enrolment to the next relapse. 219 patients with paediatric RRMS or CIS were enrolled. Each 10% increase in energy intake from fat increased the hazard of relapse by 56% (adjusted HR 1.56, 95% CI 1.05 to 2.31, p=0.027), and in particular each 10% increase in saturated fat tripled this hazard (adjusted HR: 3.37, 95% CI 1.34 to 8.43, p=0.009). In contrast, each additional one cup equivalent of vegetable decreased the hazard of relapse by 50% (adjusted HR: 0.50, 95% CI 0.27 to 0.91, p=0.024). These associations remained with mutual adjustment and persisted when adjusting for baseline 25(OH) vitamin D serum level. Other studied nutrients were not associated with relapse.This study suggests that in children with MS, high energy intake from fat, especially saturated fat, may increase the hazard to relapse, while vegetable intake may be independently protective.

    View details for PubMedID 28993476

    View details for PubMedCentralID PMC5732893

  • Congenital heart disease complexity and childhood cancer risk. Birth defects research Collins, R. T., Von Behren, J. n., Yang, W. n., Carmichael, S. L., Reynolds, P. n., Fisher, P. G., Shaw, G. M. 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

  • Antioxidant Consumption is Associated with Decreased Odds of Congenital Limb Deficiencies PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Pace, N. D., Desrosiers, T. A., Carmichael, S. L., Shaw, G. M., Olshan, A. F., Siega-Riz, A., Natl Birth Defects Prevention Stud 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

  • Characteristics of women with multiple postpartum hospital admissions Girsen, A. I., Sie, L., Carmichael, S., Foeller, M. E., Druzin, M. L., Lee, H. C., Gibbs, R. S. MOSBY-ELSEVIER. 2018: S461–S462
  • Thyroid Medication Use and Birth Defects in the National Birth Defects Prevention Study BIRTH DEFECTS RESEARCH Howley, M. M., Fisher, S. C., Van Zutphen, A. R., Waller, D. K., Carmichael, S. L., Browne, M. L., Natl Birth Defects Prevention 2017; 109 (18): 1471–81

    Abstract

    Thyroid disorders are common among reproductive-aged women, with hypothyroidism affecting 2 to 3% of pregnancies, and hyperthyroidism affecting an additional 0.1 to 1%. We examined associations between thyroid medications and individual birth defects using data from the National Birth Defects Prevention Study (NBDPS).The NBDPS is a multisite, population-based, case-control study that included pregnancies with estimated delivery dates from 1997 to 2011. We analyzed self-reported thyroid medication use from mothers of 31,409 birth defect cases and 11,536 unaffected controls. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for birth defects with five or more exposed cases, controlling for maternal age, race/ethnicity, and study center. Crude ORs and exact 95% CIs were estimated for defects with 3 to 4 exposed cases.Thyroid hormone was used by 738 (2.3%) case and 237 (2.1%) control mothers, and was associated with anencephaly (OR = 1.68; 95% CI, 1.03-2.73), holoprosencephaly (OR = 2.48; 95% CI, 1.13-5.44), hydrocephaly (1.77; 95% CI, 1.07-2.95) and small intestinal atresia (OR = 1.81; 95% CI, 1.04-3.15). Anti-thyroid medication was used by 34 (0.1%) case and 10 (<0.1%) control mothers, and was associated with aortic valve stenosis (OR = 6.91; 95% CI, 1.21-27.0).While new associations were identified, our findings are relatively consistent with previous NBDPS analyses. Our findings suggest thyroid medication use is not associated with most birth defects studied in the NBDPS, but may be associated with some specific birth defects. These results should not be interpreted to suggest that medications used to treat thyroid disease are teratogens, as the observed associations may reflect effects of the underlying thyroid disease. Birth Defects Research 109:1471-1481, 2017.© 2017 Wiley Periodicals, Inc.

    View details for PubMedID 28758357

  • Maternal Exposure to Nitrogen Dioxide, Intake of Methyl Nutrients, and Congenital Heart Defects in Offspring AMERICAN JOURNAL OF EPIDEMIOLOGY Stingone, J. A., Luben, T. J., Carmichael, S. L., Aylsworth, A. S., Botto, L. D., Correa, A., Gilboa, S. M., Langlois, P. H., Nembhard, W. N., Richmond-Bryant, J., Shaw, G. M., Olshan, A. F., Natl Birth Defects Prevention 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

  • Social disadvantage and the black-white disparity in spontaneous preterm delivery among California births PLOS ONE Carmichael, S. L., Kan, P., Padula, A. M., Rehkopf, D. H., Oehlert, J. W., Mayo, J. A., Weber, A. M., Wise, P. H., Shaw, G. M., Stevenson, D. K. 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

  • Maternal prepregnancy body mass index and risk of bronchopulmonary dysplasia. Pediatric research Carmichael, S. L., Kan, P., Gould, J. B., Stevenson, D. K., Shaw, G. M., Lee, H. C. 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

  • Air pollution, neighborhood acculturation factors, and neural tube defects among Hispanic women in California BIRTH DEFECTS RESEARCH Padula, A. M., Yang, W., Carmichael, S. L., Lurmann, F., Balmes, J., Hammond, S. K., Shaw, G. M. 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

  • What factors are related to recurrent preterm birth among underweight women? journal of maternal-fetal & neonatal medicine Girsen, A. I., Mayo, J. A., Wallenstein, M. B., Gould, J. B., Carmichael, S. L., Stevenson, D. K., Lyell, D. J., Shaw, G. M. 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

  • Maternal underweight and obesity and risk of orofacial clefts in a large international consortium of population-based studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Kutbi, H., Wehby, G. L., Uribe, L., Romitti, P. A., Carmichael, S., Shaw, G. M., Olshan, A. F., DeRoo, L., Rasmussen, S. A., Murray, J. C., Wilcox, A., Lie, R. T., Munger, R. G. 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

  • Postpartum readmission and severe maternal morbidity in California Girsen, A., Lee, L. C., Carmichael, S. L., Foeller, M., Druzin, M. L., Gibbs, R. MOSBY-ELSEVIER. 2017: S112
  • An Investigation of Connections between Birth Defects and Cancers Arising in Adolescence and Very Young Adulthood. The Journal of pediatrics Von Behren, J. n., Fisher, P. G., Carmichael, S. L., Shaw, G. M., Reynolds, P. n. 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

  • Maternal Stressors and Social Support and Risks of Delivering Babies With Gastroschisis or Hypospadias. American journal of epidemiology Carmichael, S. L., Ma, C. n., Tinker, S. n., Shaw, G. M. 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

  • Maternal Smoking, Alcohol, and Caffeine Exposures and Risk of Hypospadias. Birth defects research Carmichael, S. L., Ma, C. n., Shaw, G. M. 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

  • Temporal Relationship of Onset of Necrotizing Enterocolitis and Introduction of Enteric Feedings and Powdered Milk Fortifier. American journal of perinatology Vaks, Y. n., Birnie, K. L., Carmichael, S. L., Hernandez-Boussard, T. n., Benitz, W. E. 2017

    View details for PubMedID 29190848

  • 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 Yang, W., Carmichael, S. L., Shaw, G. M. 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

  • Women's prepregnancy underweight as a risk factor for preterm birth: a retrospective study. bjog-an international journal of obstetrics and gynaecology Girsen, A. I., Mayo, J. A., Carmichael, S. L., Phibbs, C. S., Shachar, B. Z., Stevenson, D. K., Lyell, D. J., Shaw, G. M., Gould, J. B. 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

  • Maternal Autoimmune Disease and Birth Defects in the National Birth Defects Prevention Study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Howley, M. M., Browne, M. L., Van Zutphen, A. R., Richardson, S. D., Blossom, S. J., Broussard, C. S., Carmichael, S. L., Druschel, C. M. 2016; 106 (11): 950-962

    Abstract

    Little is known about the association between maternal autoimmune disease or its treatment and the risk of birth defects. We examined these associations using data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study.Analyses included 25,116 case and 9897 unaffected control infants with estimated delivery dates between 1997 and 2009. Information on autoimmune disease, medication use, and other pregnancy exposures was collected by means of telephone interview. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for birth defects with five or more exposed cases; crude ORs and exact 95% CIs were estimated for birth defects with three to four exposed cases.Autoimmune disease was reported by 373 mothers (279 case and 94 control mothers). The majority of birth defects evaluated were not associated with autoimmune disease; however, a statistically significant association between maternal autoimmune disease and encephalocele was observed (OR, 4.64; 95% CI, 1.95-11.04). Eighty-two mothers with autoimmune disease used an immune modifying/suppressing medication during pregnancy; this was associated with encephalocele (OR, 7.26; 95% CI, 1.37-24.61) and atrial septal defects (OR, 3.01; 95% CI, 1.16-7.80).Our findings suggest maternal autoimmune disease and treatment are not associated with the majority of birth defects, but may be associated with some defects, particularly encephalocele. Given the low prevalence of individual autoimmune diseases and the rare use of specific medications, we were unable to examine associations of specific autoimmune diseases and medications with birth defects. Other studies are needed to confirm these findings. Birth Defects Research (Part A) 106:950-962, 2016. © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/bdra.23527

    View details for Web of Science ID 000392817500012

    View details for PubMedID 27891777

    View details for PubMedCentralID PMC5305117

  • Gene variants as risk factors for gastroschisis. American journal of medical genetics. Part A Padula, A. M., Yang, W., Schultz, K., Tom, L., Lin, B., Carmichael, S. L., Lammer, E. J., Shaw, G. M. 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

  • Inflammatory biomarkers and spontaneous preterm birth among obese women. journal of maternal-fetal & neonatal medicine Wallenstein, M. B., Jelliffe-Pawlowski, L. L., Yang, W., Carmichael, S. L., Stevenson, D. K., Ryckman, K. K., Shaw, G. M. 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

  • Maternal diet quality before pregnancy and risk of childhood leukaemia BRITISH JOURNAL OF NUTRITION Singer, A. W., Carmichael, S. L., Selvin, S., Fu, C., Block, G., Metayer, C. 2016; 116 (8): 1469-1478

    Abstract

    Previous studies on maternal nutrition and childhood leukaemia risk have focused on the role of specific nutrients such as folate and have not considered broader measures of diet quality, which may better capture intake of diverse nutrients known to impact fetal development. We examined the relationship between maternal diet quality before pregnancy, as summarised by a diet quality index, and risk of childhood acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in a case-control study in California. Dietary intake in the year before pregnancy was assessed using FFQ in 681 ALL cases, 103 AML cases and 1076 matched controls. Conditional logistic regression was used to estimate OR and 95 % CI for diet quality continuous score and quartiles (Q1-Q4). Higher maternal diet quality score was associated with reduced risk of ALL (OR 0·66; 95 % CI 0·47, 0·93 for Q4 v. Q1) and possibly AML (OR 0·42; 95 % CI 0·15, 1·15 for Q4 v. Q1). No single index component appeared to account for the association. The association of maternal diet quality with risk of ALL was stronger in children diagnosed under the age of 5 years and in children of women who did not report using vitamin supplements before pregnancy. These findings suggest that the joint effects of many dietary components may be important in influencing childhood leukaemia risk.

    View details for DOI 10.1017/S0007114516003469

    View details for Web of Science ID 000386912200016

    View details for PubMedID 27725005

  • Gastroschisis and maternal intake of phytoestrogens AMERICAN JOURNAL OF MEDICAL GENETICS PART A Wadhwa, E. L., Ma, C., Shaw, G. M., Carmichael, S. L. 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

  • Joint effects of genetic variants and residential proximity to pesticide applications on hypospadias risk. Birth defects research. Part A, Clinical and molecular teratology Carmichael, S. L., Yang, W., Ma, C., Roberts, E., Kegley, S., English, P., Lammer, E. J., Witte, J. S., Shaw, G. M. 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

  • Body Mass Index Change between Pregnancies and Risk of Spontaneous Preterm Birth. American journal of perinatology Riley, K. L., Carmichael, S. L., Mayo, J. A., Shachar, B. Z., Girsen, A. I., Wallenstein, M. B., Gould, J. B., Stevenson, D. K., Shaw, G. M. 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

  • Maternal prenatal intake of one-carbon metabolism nutrients and risk of childhood leukemia CANCER CAUSES & CONTROL Singer, A. W., Selvin, S., Block, G., Golden, C., Carmichael, S. L., Metayer, C. 2016; 27 (7): 929-940

    Abstract

    Folate, vitamins B12 and B6, riboflavin, and methionine are critical nutrients for the one-carbon metabolism cycle involved in DNA synthesis and epigenetic processes. We examined the association between maternal intake of these nutrients before pregnancy and risk of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in a matched case-control study.Maternal dietary intake and vitamin supplement use in the year before pregnancy was assessed by food frequency questionnaire for 681 ALL cases, 103 AML cases, and 1076 controls. Principal component analysis was used to construct a variable representing combined nutrient intake, and conditional logistic regression estimated the odds ratio (OR) and 95% confidence interval (CI) for the association of ALL and AML with the principal component and each nutrient.Higher maternal intake of one-carbon metabolism nutrients from food and supplements combined was associated with reduced risk of ALL (OR for one-unit change in the principal component = 0.91, CI 0.84-0.99) and possibly AML (OR for the principal component = 0.83, CI 0.66-1.04). When analyzed separately, intake of supplements high in these nutrients was associated with a reduced risk of ALL in children of Hispanic women only.In conclusion, these data suggest that higher maternal intake of one-carbon metabolism nutrients may reduce risk of childhood leukemia.

    View details for DOI 10.1007/s10552-016-0773-y

    View details for Web of Science ID 000381121400010

    View details for PubMedID 27294727

    View details for PubMedCentralID PMC4939072

  • 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 Carmichael, S. L., Yang, W., Gilboa, S., Ailes, E., Correa, A., Botto, L. D., Feldkamp, M. L., Shaw, G. M. 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

  • 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 Carmichael, S. L., Yang, W., Gilboa, S., Ailes, E., Correa, A., Botto, L. D., Feldkamp, M. L., Shaw, G. M. 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

  • 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 Carmichael, S. L., Yang, W., Roberts, E., Kegley, S. E., Brown, T. J., English, P. B., Lammer, E. J., Shaw, G. M. 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

  • 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 Botto, L. D., Krikov, S., Carmichael, S. L., Munger, R. G., Shaw, G. M., Feldkamp, M. L. 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

  • Effects of race/ethnicity and BMI on the association between height and risk for spontaneous preterm birth AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Shachar, B. Z., Mayo, J. A., Lee, H. C., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Gould, J. B. 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

  • Air Pollution, Neighbourhood Socioeconomic Factors, and Neural Tube Defects in the San Joaquin Valley of California PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Padula, A. M., Yang, W., Carmichael, S. L., Tager, I. B., Lurmann, F., Hammond, S. K., Shaw, G. M. 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

  • Effects of race/ethnicity and BMI on the association between height and risk for spontaneous preterm birth. American journal of obstetrics and gynecology Shachar, B. Z., Mayo, J. A., Lee, H. C., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Gould, J. B. 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

  • Prepregnancy Obesity and Risks of Stillbirth PLOS ONE Carmichael, S. L., Blumenfeld, Y. J., Mayo, J., Wei, E., Gould, J. B., Stevenson, D. K., Shaw, G. M. 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

  • Heightened risk of preterm birth and growth restriction after a first-born son ANNALS OF EPIDEMIOLOGY Bruckner, T. A., Mayo, J. A., Gould, J. B., Stevenson, D. K., Lewis, D. B., Shaw, G. M., Carmichael, S. L. 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

  • Periconceptional changes in weight and risk of delivering offspring with conotruncal heart defects. Birth defects research. Part A, Clinical and molecular teratology Carter, E. H., Carmichael, S. L., Birnie, K., Yang, W., Lammer, E. J., Shaw, G. M. 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

  • Society for Paediatric and Perinatal Epidemiology 2015 Annual Meeting: Present and Future. Paediatric and perinatal epidemiology Hernandez-Diaz, S., Carmichael, S. L. 2015; 29 (5): 373-5

    View details for DOI 10.1111/ppe.12217

    View details for PubMedID 26264567

  • Next steps for birth defects research and prevention: The birth defects study to evaluate pregnancy exposures (BD-STEPS) BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Tinker, S. C., Carmichael, S. L., Anderka, M., Browne, M. L., Conway, K. M., Meyer, R. E., Nembhard, W. N., Olney, R. S., Reefhuis, J. 2015; 103 (8): 733-740

    Abstract

    The Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) is a population-based, multi-Center case-control study of modifiable risk factors for selected birth defects in the United States. BD-STEPS is the second major research effort of the Centers for Birth Defects Research and Prevention, which extends and expands the initial research effort, the National Birth Defects Prevention Study (NBDPS).BD-STEPS focuses on 17 categories of structural birth defects selected based on severity, prevalence, consistent ascertainment, and previous findings that warrant additional research. Cases are identified through existing birth defects surveillance programs; controls are from vital records or birth hospital logs from the same catchment area. BD-STEPS uses a standardized computer-assisted telephone interview to collect information from case and control mothers on topics including demographics, health conditions, and medication use. Following the maternal interview, selected Centers request permission to sample residual newborn screening blood spots from state repositories for genetic analyses. New components planned for BD-STEPS include linkages with external datasets and use of online questionnaires to collect in-depth information on selected exposures.BD-STEPS extends NBDPS by continuing to collect data on many exposures that were assessed in NBDPS, allowing data from both studies to be combined and providing an unprecedented sample size to analyze rare exposures. BD-STEPS expands upon NBDPS by collecting more detailed information on existing exposures as well as new exposures.The goal of BD-STEPS is to provide women and healthcare providers with information they need to make decisions to promote the healthiest pregnancy possible. Birth Defects Research (Part A) 103:733-740, 2015. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/bdra.23373

    View details for Web of Science ID 000359740800012

    View details for PubMedCentralID PMC4537667

  • Next steps for birth defects research and prevention: The birth defects study to evaluate pregnancy exposures (BD-STEPS). Birth defects research. Part A, Clinical and molecular teratology Tinker, S. C., Carmichael, S. L., Anderka, M., Browne, M. L., Caspers Conway, K. M., Meyer, R. E., Nembhard, W. N., Olney, R. S., Reefhuis, J. 2015; 103 (8): 733-740

    Abstract

    The Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) is a population-based, multi-Center case-control study of modifiable risk factors for selected birth defects in the United States. BD-STEPS is the second major research effort of the Centers for Birth Defects Research and Prevention, which extends and expands the initial research effort, the National Birth Defects Prevention Study (NBDPS).BD-STEPS focuses on 17 categories of structural birth defects selected based on severity, prevalence, consistent ascertainment, and previous findings that warrant additional research. Cases are identified through existing birth defects surveillance programs; controls are from vital records or birth hospital logs from the same catchment area. BD-STEPS uses a standardized computer-assisted telephone interview to collect information from case and control mothers on topics including demographics, health conditions, and medication use. Following the maternal interview, selected Centers request permission to sample residual newborn screening blood spots from state repositories for genetic analyses. New components planned for BD-STEPS include linkages with external datasets and use of online questionnaires to collect in-depth information on selected exposures.BD-STEPS extends NBDPS by continuing to collect data on many exposures that were assessed in NBDPS, allowing data from both studies to be combined and providing an unprecedented sample size to analyze rare exposures. BD-STEPS expands upon NBDPS by collecting more detailed information on existing exposures as well as new exposures.The goal of BD-STEPS is to provide women and healthcare providers with information they need to make decisions to promote the healthiest pregnancy possible. Birth Defects Research (Part A) 103:733-740, 2015. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/bdra.23373

    View details for PubMedID 25846741

  • Spatial and temporal patterns in preterm birth in the United States PEDIATRIC RESEARCH Byrnes, J., Mahoney, R., Quaintance, C., Gould, J. B., Carmichael, S., Shaw, G. M., Showen, A., Phibbs, C., Stevenson, D. K., Wise, P. H. 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

  • Genetic Polymorphisms in ESR1 and ESR2 Genes, and Risk of Hypospadias in a Multiethnic Study Population JOURNAL OF UROLOGY Choudhry, S., Baskin, L. S., Lammer, E. J., Witte, J. S., Dasgupta, S., Ma, C., Surampalli, A., Shen, J., Shaw, G. M., Carmichael, S. L. 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

  • Sex Ratios Among Infants with Birth Defects, National Birth Defects Prevention Study, 1997-2009 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Michalski, A. M., Richardson, S. D., Browne, M. L., Carmichael, S. L., Canfield, M. A., VanZutphen, A. R., Anderka, M. T., Marshall, E. G., Druschel, C. M. 2015; 167A (5): 1071-1081

    Abstract

    A small number of population-based studies have examined sex differences among infants with birth defects. This study presents estimates of sex ratio for both isolated cases and those with multiple congenital anomalies, as well as by race/ethnicity. Male-female sex ratios and their 95% confidence intervals were calculated for 25,952 clinically reviewed case infants included in the National Birth Defects Prevention Study (1997-2009), a large population-based case-control study of birth defects. The highest elevations in sex ratios (i.e., male preponderance) among isolated non-cardiac defects were for craniosynostosis (2.12), cleft lip with cleft palate (2.01), and cleft lip without cleft palate (1.78); the lowest sex ratios (female preponderance) were for choanal atresia (0.45), cloacal exstrophy (0.46), and holoprosencephaly (0.64). Among isolated cardiac defects, the highest sex ratios were for aortic stenosis (2.88), coarctation of the aorta (2.51), and d-transposition of the great arteries (2.34); the lowest were multiple ventricular septal defects (0.52), truncus arteriosus (0.63), and heterotaxia with congenital heart defect (0.64). Differences were observed by race/ethnicity for some but not for most types of birth defects. The sex differences we observed for specific defects, between those with isolated versus multiple defects, as well as by race/ethnicity, demonstrate patterns that may suggest etiology and improve classification.

    View details for DOI 10.1002/ajmg.a.36865

    View details for Web of Science ID 000353171900015

    View details for PubMedID 25711982

  • Craniosynostosis and Risk Factors Related to Thyroid Dysfunction AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Ma, C., Rasmussen, S. A., Cunningham, M. L., Browne, M. L., Dosiou, C., Lammer, E. J., Shaw, G. M. 2015; 167A (4): 701-707
  • Factors Associated With Recurrent Preterm Birth Among Underweight Women Girsen, A. I., Mayo, J., Matthew, W. B., Gould, J. B., Carmichael, S. L., Lyell, D. J., Shaw, G. M. SAGE PUBLICATIONS INC. 2015: 150A
  • 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 Botto, L. D., Krikov, S., Carmichael, S. L., Munger, R. G., Shaw, G. M., Feldkamp, M. L. 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

  • Residential agricultural pesticide exposures and risk of selected congenital heart defects among offspring in the San Joaquin Valley of California. Environmental research Carmichael, S. L., Yang, W., Roberts, E., Kegley, S. E., Padula, A. M., English, P. B., Lammer, E. J., Shaw, G. M. 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

  • Better Diet Quality before Pregnancy Is Associated with Reduced Risk of Gastroschisis in Hispanic Women JOURNAL OF NUTRITION Feldkamp, M. L., Krikov, S., Botto, L. D., Shaw, G. M., Carmichael, S. L. 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

  • Corticosteroid Use and Risk for Orofacial Clefts EDITORIAL COMMENT OBSTETRICAL & GYNECOLOGICAL SURVEY Skuladottir, H., Wilcox, A. J., Ma, C., Lammer, E. J., Rasmussen, S. A., Werler, M. M., Shaw, G. M., Carmichael, S. L. 2014; 69 (10): 573-575
  • Birth Defects, Causal Attributions, and Ethnicity in the National Birth Defects Prevention Study JOURNAL OF GENETIC COUNSELING Case, A. P., Royle, M., Scheuerle, A. E., Carmichael, S. L., Moffitt, K., Ramadhani, T. 2014; 23 (5): 860-873

    Abstract

    In order to translate research findings into effective prevention strategies, it is important to understand people's beliefs about the causes of poor health outcomes. However, with the exception of knowledge and beliefs about folic acid supplementation, little is known regarding women's causal attributions women regarding birth defects. We employed Attribution Theory constructs to analyze open-text interview responses from 2,672 control mothers in the National Birth Defects Prevention Study who gave birth in 1997-2005. Common themes included use of alcohol, tobacco, illicit drugs, and medications during pregnancy. Stress and emotional upset were also suggested as possible causes of birth defects. Genetic- and heredity-related responses were more likely to be mentioned by Asian/Pacific Islander women compared to non-Hispanic Whites. Hispanic women were less likely to suggest several specific possible teratogens, such as paint, pesticides, or other chemicals, but were more likely to suggest events occurring during childbirth. Differences also emerged among ethnic groups for theoretical constructs, although most responses were categorized as controllable, changeable over time, and with an internal locus of causality.

    View details for DOI 10.1007/s10897-014-9708-5

    View details for Web of Science ID 000341840500018

    View details for PubMedID 24682893

  • Medications and Other Risk Factors for 2nd and 3rd Degree Hypospadias in the National Birth Defects Prevention Study, 1997-2009 Reefhuis, J., in 't Woud, S., van Rooij, I., van Gelder, M., Olney, R., Carmichael, S., Roeleveld, N. WILEY-BLACKWELL. 2014: 23
  • 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 Shaw, G. M., Yang, W., Roberts, E., Kegley, S. E., Padula, A., English, P. B., Carmichael, S. L. 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

  • Differences in Risk Factors for Second and Third Degree Hypospadias in the National Birth Defects Prevention Study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY in 't Woud, S. G., van Rooij, I. A., van Gelder, M. M., Olney, R. S., Carmichael, S. L., Roeleveld, N., Reefhuis, J. 2014; 100 (9): 703-711

    Abstract

    Hypospadias is a frequent birth defect with three phenotypic subtypes. With data from the National Birth Defects Prevention Study, a large, multi-state, population-based, case-control study, we compared risk factors for second and third degree hypospadias.A wide variety of data on maternal and pregnancy-related risk factors for isolated second and third degree hypospadias was collected by means of computer-assisted telephone interviews to identify potential etiological differences between the two phenotypes. Logistic regression was used to calculate odds ratios including a random effect by study center.In total, 1547 second degree cases, 389 third degree cases, and 5183 male controls were included in our study. Third degree cases were more likely to have a non-Hispanic black or Asian/Pacific Islander mother, be delivered preterm, have a low birth weight, be small for gestational age, and be conceived with fertility treatments than second degree cases and controls. Associations with both second and third degree hypospadias were observed for maternal age, family history, parity, plurality, and hypertension during pregnancy. Risk estimates were generally higher for third degree hypospadias except for family history.Most risk factors were associated with both or neither phenotype. Therefore, it is likely that the underlying mechanism is at least partly similar for both phenotypes. However, some associations were different between second and third degree hypospadias, and went in opposite directions for second and third degree hypospadias for Asian/Pacific Islander mothers. Effect estimates for subtypes of hypospadias may be over- or underestimated in studies without stratification by phenotype.

    View details for DOI 10.1002/bdra.23296

    View details for Web of Science ID 000342625200008

    View details for PubMedCentralID PMC4591539

  • 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 Shaw, G. M., Yang, W., Roberts, E., Kegley, S. E., Padula, A., English, P. B., Carmichael, S. L. 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

  • Birth defects epidemiology EUROPEAN JOURNAL OF MEDICAL GENETICS Carmichael, S. L. 2014; 57 (8): 355-358

    Abstract

    This article provides background information about epidemiologic methods and how they can be used to further our understanding of what causes birth defects. It briefly describes basic study designs and advantages and disadvantages of each, provides examples of how epidemiologic studies contribute to our current understanding of the etiologies of birth defects, and makes recommendations for future research.

    View details for DOI 10.1016/j.ejmg.2014.03.002

    View details for Web of Science ID 000341362400002

    View details for PubMedID 24657225

  • Maternal stressors and social support as risks for delivering babies with structural birth defects. Paediatric and perinatal epidemiology Carmichael, S. L., Ma, C., Tinker, S., Rasmussen, S. A., Shaw, G. M. 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

  • Maternal prepregnancy body mass index and risk of spontaneous preterm birth. Paediatric and perinatal epidemiology Shaw, G. M., Wise, P. H., Mayo, J., Carmichael, S. L., Ley, C., Lyell, D. J., Shachar, B. Z., Melsop, K., Phibbs, C. S., Stevenson, D. K., Parsonnet, J., Gould, J. B. 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

  • Corticosteroid Use and Risk of Orofacial Clefts BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Skuladottir, H., Wilcox, A. J., Ma, C., Lammer, E. J., Rasmussen, S. A., Werler, M. M., Shaw, G. M., Carmichael, S. L. 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

  • Preconceptional Folic Acid-Containing Supplement Use in the National Birth Defects Prevention Study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Khodr, Z. G., Lupo, P. J., Agopian, A. J., Canfield, M. A., Case, A. P., Carmichael, S. L., Mitchell, L. E. 2014; 100 (6): 472-482

    Abstract

    Despite public health campaigns encouraging women to take a daily folic acid supplement, the proportion of reproductive age women, in the United States, who comply with this recommendation is less than optimal. The objective of this analysis was to identify predictors of preconceptional folic acid-containing supplement use to define subgroups of women who may benefit from targeted folic acid campaigns.This study included 6570 mothers of live born infants from the control population of National Birth Defects Prevention Study (1997-2005). Logistic regression analyses were used to identify predictors of preconceptional folic acid supplementation. A classification and regression tree (CART) analysis was used to define subgroups of women with different patterns of preconceptional folic acid supplementation.Race/ethnicity, education, age at delivery, nativity, employment, income, number of dependents, smoking, and birth control use were significantly associated with preconceptional folic acid-containing supplement use. Based on a CART analysis, education, race/ethnicity, and age were the most distinguishing factors between women with different preconceptional supplementation patterns. Non-white women with <4 years of a college education were the least likely to use folic acid-containing supplements (11%). However, even in the most compliant subgroup (women with ≥4 years of college), only 60% of women supplemented with folic acid.These results demonstrate the need for continued efforts to increase folic acid supplementation among all reproductive aged women. However, the success of such efforts may be improved if maternal characteristics such as education, race/ethnicity, and age, are considered in the development of future interventions.

    View details for DOI 10.1002/bdra.23238

    View details for Web of Science ID 000338036300003

  • Late Detection of Critical Congenital Heart Disease Among US Infants: Estimation of the Potential Impact of Proposed Universal Screening Using Pulse Oximetry. JAMA pediatrics Peterson, C., Ailes, E., Riehle-Colarusso, T., Oster, M. E., Olney, R. S., Cassell, C. H., Fixler, D. E., Carmichael, S. L., Shaw, G. M., Gilboa, S. M. 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

  • 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 Yang, W., Carmichael, S. L., Roberts, E. M., Kegley, S. E., Padula, A. M., English, P. B., Shaw, G. M. 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

  • Maternal Body Mass and Risk for Premature Birth among 1.2 Million California Births Shaw, G. M., Wise, P. H., Mayo, J., Carmichael, S. L., Ley, C., Lyell, D. J., Shachar, B., Melsop, K., Phibbs, C. S., Stevenson, D. K., Parsonnet, J., Gould, J. B. SAGE PUBLICATIONS INC. 2014: 340A
  • One-carbon metabolite levels in mid-pregnancy and risks of conotruncal heart defects. Birth defects research. Part A, Clinical and molecular teratology Shaw, G. M., Yang, W., Carmichael, S. L., Vollset, S. E., Hobbs, C. A., Lammer, E. J., Ueland, P. M. 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

  • Hypospadias and variants in genes related to sex hormone biosynthesis and metabolism ANDROLOGY Carmichael, S. L., Witte, J. S., Ma, C., Lammer, E. J., Shaw, G. M. 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

  • Population-Level Correlates of Preterm Delivery among Black and White Women in the U.S. PloS one Carmichael, S. L., Cullen, M. R., Mayo, J. A., Gould, J. B., Loftus, P., Stevenson, D. K., Wise, P. H., Shaw, G. M. 2014; 9 (4)

    View details for DOI 10.1371/journal.pone.0094153

    View details for PubMedID 24740117

  • Population-level correlates of preterm delivery among black and white women in the U.S. PloS one Carmichael, S. L., Cullen, M. R., Mayo, J. A., Gould, J. B., Loftus, P., Stevenson, D. K., Wise, P. H., Shaw, G. M. 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

  • Could genetic polymorphisms related to oxidative stress modulate effects of heavy metals for risk of human preterm birth? Reproductive toxicology Shachar, B. Z., Carmichael, S. L., Stevenson, D. K., Shaw, G. M. 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

  • Hypospadias and Genes Related to Genital Tubercle and Early Urethral Development JOURNAL OF UROLOGY Carmichael, S. L., Ma, C., Choudhry, S., Lammer, E. J., Witte, J. S., Shaw, G. M. 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

  • Hypospadias and residential proximity to pesticide applications. Pediatrics Carmichael, S. L., Yang, W., Roberts, E. M., Kegley, S. E., Wolff, C., Guo, L., Lammer, E. J., English, P., Shaw, G. M. 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

  • Hypospadias and residential proximity to pesticide applications. Pediatrics Carmichael, S. L., Yang, W., Roberts, E. M., Kegley, S. E., Wolff, C., Guo, L., Lammer, E. J., English, P., Shaw, G. M. 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

  • Traffic-related air pollution and selected birth defects in the San Joaquin Valley of California. Birth defects research. Part A, Clinical and molecular teratology Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Yang, W., Lurmann, F. W., Shaw, G. M. 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

  • Periconceptional nutrient intakes and risks of orofacial clefts in California. Pediatric research Wallenstein, M. B., Shaw, G. M., Yang, W., Carmichael, S. L. 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

  • Maternal Dietary Nutrient Intake and Risk of Preterm Delivery AMERICAN JOURNAL OF PERINATOLOGY Carmichael, S. L., Yang, W., Shaw, G. M. 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

  • Hypospadias and Maternal Intake of Phytoestrogens AMERICAN JOURNAL OF EPIDEMIOLOGY Carmichael, S. L., Cogswell, M. E., Ma, C., Gonzalez-Feliciano, A., Olney, R. S., Correa, A., Shaw, G. M. 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

  • Ambient air pollution and traffic exposures and congenital heart defects in the san joaquin valley of california. Paediatric and perinatal epidemiology Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Yang, W., Lurmann, F., Shaw, G. M. 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

  • Maternal medication and herbal use and risk for hypospadias: data from the National Birth Defects Prevention Study, 1997-2007 PHARMACOEPIDEMIOLOGY AND DRUG SAFETY Lind, J. N., Tinker, S. C., Broussard, C. S., Reefhuis, J., Carmichael, S. L., Honein, M. A., Olney, R. S., Parker, S. E., Werler, M. M. 2013; 22 (7): 783-793

    Abstract

    To investigate associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants.We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1537 infants with second-degree or third-degree isolated hypospadias and 4314 live-born male control infants without major birth defects, with estimated dates of delivery from 1997 to 2007. Exposure was reported use of prescription or over-the-counter medications or herbal products, from 1 month before to 4 months after conception. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, previous live births, maternal subfertility, study site, and year.We assessed 64 medication and 24 herbal components. Maternal uses of most components were not associated with an increased risk of hypospadias. A new associations was observed for venlafaxine (aOR 2.4; 95%CI 1.0, 6.0) [Correction made here after initial online publication.]. The previously reported association for clomiphene citrate was confirmed (aOR 1.9; 95%CI 1.2, 3.0). Numbers were relatively small for exposure to other specific patterns of fertility agents, but elevated aORs were observed for the most common of them.Overall, findings were reassuring that hypospadias is not associated with most medication components examined in this analysis. New associations will need to be confirmed in other studies. Increased risks for hypospadias associated with various fertility agents raise the possibility of confounding by underlying subfertility.

    View details for DOI 10.1002/pds.3448

    View details for Web of Science ID 000325867800013

    View details for PubMedID 23620412

  • Maternal Dietary Patterns are Associated With Risk of Neural Tube and Congenital Heart Defects AMERICAN JOURNAL OF EPIDEMIOLOGY Sotres-Alvarez, D., Siega-Riz, A. M., Herring, A. H., Carmichael, S. L., Feldkamp, M. L., Hobbs, C. A., Olshan, A. F. 2013; 177 (11): 1279-1288

    Abstract

    Studying empirically derived dietary patterns is useful in understanding dietary practice. We classified women by their dietary patterns using latent class analysis of 66 foods and studied the association of these patterns with neural tube defects (NTDs) and congenital heart defects (CHDs) in the U.S. National Birth Defects Prevention Study (1997-2005). Logistic regression models used data from 1,047 with an NTD, 6,641 with a CHD, and 6,123 controls that were adjusted for maternal characteristics and tested the effect modification of multivitamin supplement use. Four latent dietary patterns were identified: prudent, Western, low-calorie Western, and Mexican. Among participants who did not use supplements, those in the Mexican, Western, and low-calorie Western classes were significantly more likely (odds ratios of 1.6, 1.5, and 1.4, respectively) to have offspring born with NTDs than were those in the prudent class after adjustment of for dietary folic acid intake. In contrast, among supplement users, there was no difference in the incidence of NTDs between classes. Associations between dietary class and CHD subgroups were not modified by supplement use except for tetralogy of Fallot; among supplement users, those in the Western class were twice as likely (95% confidence interval: 1.4, 2.8) as the prudent class to have offspring with tetralogy of Fallot. Women who adhered to a Western diet were 1.2 (95% confidence interval: 1.03, 1.35) times more likely to have an infant with septal heart defect than were women who adhered to a prudent diet. A prudent dietary pattern, even with folate fortification, may decrease the risk of NTDs and some heart defects.

    View details for DOI 10.1093/aje/kws349

    View details for Web of Science ID 000319752400014

    View details for PubMedID 23639938

    View details for PubMedCentralID PMC3664332

  • The Association of Ambient Air Pollution and Traffic Exposures With Selected Congenital Anomalies in the San Joaquin Valley of California AMERICAN JOURNAL OF EPIDEMIOLOGY Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Lurmann, F., Shaw, G. M. 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

  • 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 Gupta, T., Yang, W., Iovannisci, D. M., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Lammer, E. J. 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

  • Fever Literacy and Fever Phobia CLINICAL PEDIATRICS Wallenstein, M. B., Schroeder, A. R., Hole, M. K., Ryan, C., Fijalkowski, N., Alvarez, E., Carmichael, S. L. 2013; 52 (3): 254-259

    Abstract

    To identify the percentage of parents who define the threshold for fever between 38.0°C and 38.3°C, which has not been reported previously, and to describe parental attitudes toward fever and antipyretic use.Thirteen-question survey study of caregivers.Overall, 81% of participants defined the threshold for fever as <38.0°C, 0% correctly defined fever between 38.0°C and 38.3°C, and 19% defined fever as >38.3°C. Twenty percent of children brought to clinic for a chief complaint of fever were never truly febrile. Ninety-three percent of participants believed that high fever can cause brain damage. For a comfortable-appearing child with fever, 89% of caregivers reported that they would give antipyretics and 86% would schedule a clinic visit.Our finding that 0% of parents correctly defined fever is both surprising and unsettling, and it should inform future discussions of fever between parents and clinicians.

    View details for DOI 10.1177/0009922812472252

    View details for Web of Science ID 000317849900007

    View details for PubMedID 23349363

  • Thymidylate synthase polymorphisms and risks of human orofacial clefts BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Yang, W., Perloff, S., Shaw, N. M., Carmichael, S. L., Zhu, H., Lammer, E. J. 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

  • Diacylglycerol Kinase K Variants Impact Hypospadias in a California Study Population JOURNAL OF UROLOGY Carmichael, S. L., Mohammed, N., Ma, C., Iovannisci, D., Choudhry, S., Baskin, L. S., Witte, J. S., Shaw, G. M., Lammer, E. J. 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

  • Association between weight gain during pregnancy and neural tube defects and gastroschisis in offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, W., Carmichael, S. L., Tinker, S. C., Shaw, G. M. 2012; 94 (12): 1019-1025

    Abstract

    Limited information is available about the association of maternal weight gain during pregnancy and birth defects. The objective of this study was to investigate the association of maternal weight gain with neural tube defects (NTDs) and gastroschisis among offspring.We used data from the National Birth Defects Prevention Study, an ongoing multicenter, population-based, case-control study. Mothers of cases and controls were interviewed by telephone. Analyses included 255 anencephaly, 577 spina bifida, 648 gastroschisis cases, and 5587 controls with deliveries from 1999 to 2005. After subtracting birth weight, the associations of total and average weekly weight gain (kg) with each phenotype were estimated, stratified by gestational age (<37 vs. ≥37 weeks) and adjusted for relevant covariates.Among deliveries <37 weeks gestation, mothers of infants with anencephaly and spina bifida had lower weight gains compared to control mothers; no association between weight gains and gastroschisis was observed. Among deliveries ≥37 weeks, mothers of infants with anencephaly had lower weight gains during pregnancy; a similar association was not observed for spina bifida; mothers of infants with gastroschisis were twice as likely to have weight gains in the highest quartile. Stratification by maternal age (gastroschisis) or body mass index (BMI) or race/ethnicity (all phenotypes) did not alter odds ratio estimates.Altered weight gain during pregnancy may be a consequence of carrying an NTD/gastroschisis affected fetus or a marker for underlying factors common to the etiology of these birth defects. It is possible that whatever mechanisms influence weight gain may also influence the development of NTDs and gastroschisis, but in opposite directions.

    View details for DOI 10.1002/bdra.23057

    View details for Web of Science ID 000312527100009

    View details for PubMedID 22847944

    View details for PubMedCentralID PMC3522774

  • Association of microtia with maternal nutrition BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Ma, C., Shaw, G. M., Scheuerle, A. E., Canfield, M. A., Carmichael, S. L. 2012; 94 (12): 1026-1032

    Abstract

    Few studies have investigated the potential association of maternal dietary intake and risk of microtia among offspring.The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic cases of microtia were compared to nonmalformed, population-based, live-born control infants by estimating adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race or ethnicity, education, folic acid-containing supplement intake, fertility treatment, study site, and total energy intake.Comparing intake in the lowest 10th percentile versus the 10th to 90th percentiles, lower maternal intakes of carbohydrate (OR, 1.59; 95% CI, 1.07-2.38) and dietary folate (OR, 1.57; 95% CI, 1.09-2.25) were associated with elevated risk of microtia. In addition, results suggested that higher diet quality (as measured by the Diet Quality Index, and comparing the highest with the lowest quartile) was protective, but the CI did not exclude one (OR, 0.73; 95% CI, 0.50-1.07). Results were similar among obese and nonobese women.These data contribute to the limited body of evidence regarding the potential contribution of maternal nutrition to the etiology of microtia.

    View details for DOI 10.1002/bdra.23053

    View details for Web of Science ID 000312527100010

    View details for PubMedID 22821770

  • Maternal and Infant Gene-Folate Interactions and the Risk of Neural Tube Defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Etheredge, A. J., Finnell, R. H., Carmichael, S. L., Lammer, E. J., Zhu, H., Mitchell, L. E., Shaw, G. M. 2012; 158A (10): 2439-2446

    Abstract

    Neural tube defects (NTDs) are common, serious malformations with a complex etiology that suggests involvement of both genetic and environmental factors. The authors evaluated maternal or offspring folate-related gene variants and interactions between the gene variants and maternal intake of folates on the risk of NTDs in their offspring. A case-control study was conducted on mothers and/or their fetuses and infants who were born in California from 1999 to 2003 with an NTD (cases n = 222, including 24 mother-infant pairs) or without a major malformation (controls n = 454, including 186 mother-infant pairs). Maternal intake of folates was assessed by food frequency questionnaire and genotyping was performed on samples from mothers and infants. For mothers in the lowest folate-intake group, risk of NTDs in offspring was significantly decreased for maternal MTHFR SNPs rs1476413, rs1801131, and rs1801133 (odds ratio [OR] = 0.55, 80% confidence interval [CI]: 0.20, 1.48; OR = 0.58, 80% CI: 0.24, 1.43; OR = 0.69, 80% CI: 0.41, 1.17, respectively), and TYMS SNPs rs502396 and rs699517 (OR = 0.91, 80% CI: 0.53, 1.56; OR = 0.70, 80% CI: 0.38, 1.29). A gene-only effect was observed for maternal SHMT1 SNP rs669340 (OR = 0.69, 95% CI: 0.49, 0.96). When there was low maternal folate intake, risk of NTDs was significantly increased for infant MTHFD1 SNPs rs2236224, rs2236225, and rs11627387 (OR = 1.58, 80% CI: 0.99, 2.51; OR = 1.53, 80% CI: 0.95, 2.47; OR = 4.25, 80% CI: 2.33, 7.75, respectively) and SHMT1 SNP rs12939757 (OR = 2.01, 80% CI: 1.20, 3.37), but decreased for TYMS SNP rs2847153 (OR = 0.73, 80% CI: 0.37, 1.45). Although power to detect interaction effects was low for this birth defects association study, the gene-folate interactions observed in this study represent preliminary findings that will be useful for informing future studies on the complex etiology of NTDs.

    View details for DOI 10.1002/ajmg.a.35552

    View details for Web of Science ID 000310070700011

    View details for PubMedID 22903727

    View details for PubMedCentralID PMC3448841

  • Thymidylate Synthase Polymorphisms and Risk of Conotruncal Heart Defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zhu, H., Yang, W., Shaw, N., Perloff, S., Carmichael, S. L., Finnell, R. H., Shaw, G. M., Lammer, E. J. 2012; 158A (9): 2194-2203

    Abstract

    In this study, we investigated whether the two TYMS functional variants (28 bp VNTR and 1494del6) (275 cases and 653 controls) and six selected SNPs (265 case infants, 535 control infants; 169 case mothers and 276 control mothers) were associated with risks of conotruncal heart defects. Further, we evaluated interaction effects between these gene variants and maternal folate intake for risk of CTD. Cases with diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. DNA samples were collected using buccal brushes or drawn from the repository of newborn screening blood specimens when available. Genetic variants were treated as categorical variables (homozygous referent, heterozygote, homozygous variant). Odds ratios and 95% confidence intervals (CI) were computed to estimate risks among all subjects, Hispanic and non-Hispanic whites, respectively, using logistic regression. Gene-folate interactions were assessed for these variants by adding an interaction term to the logistic model. A dichotomized composite variable, "combined folate intake," was created by combining maternal peri-conceptional use of folic acid-containing vitamin supplements with daily dietary intake of folate. In general, the results do not show strong gene-only effects on risk of CTD. We did, however, observe a 3.6-fold increase in CTD risk (95% CI: 1.1-11.9) among infants who were homozygotes for the 6 bp deletion in the 3'-untranslated region (UTR) (1694del6) and whose mothers had low folate intake during the peri-conceptional period.

    View details for DOI 10.1002/ajmg.a.35310

    View details for Web of Science ID 000310068700015

    View details for PubMedID 22887475

    View details for PubMedCentralID PMC3429723

  • Maternal Medication and Herbal Use and Risk of Hypospadias: Data from the National Birth Defects Prevention Study, 1997-2007 Lind, J. N., Broussard, C. S., Reefhuis, J., Carmichael, S. L., Honein, M. A., Olney, R. S., Werler, M. M., Tinker, S. C. WILEY PERIODICALS, INC. 2012: 386
  • Nutritional Factors and Hypospadias Risks PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Ma, C., Feldkamp, M. L., Munger, R. G., Olney, R. S., Botto, L. D., Shaw, G. M., Correa, A. 2012; 26 (4): 353-360

    Abstract

    We examined whether hypospadias was associated with several aspects of the diet, including intake of animal products, intake of several nutrients and food groups related to a vegetarian diet and oestrogen metabolism, and diet quality.The study included deliveries from 1997 to 2005 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews, and two diet quality indices were developed based on existing indices. Analyses included 1250 cases with second- or third-degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 3118 male, liveborn, non-malformed controls. All odds ratios (OR) and 95% confidence intervals [CI] were estimated from logistic regression models that included several potential confounders, including energy intake.Intake of animal products was not associated with hypospadias; for example, the adjusted OR for any vs. no intake of meat was 1.0 [95% CI 0.6, 1.6]. Frequency of intake of meat or other animal products was also not associated with hypospadias, nor was intake of iron or several nutrients that are potentially related to oestrogen metabolism. Diet quality was also not associated with hypospadias; the OR for diet quality in the highest vs. lowest quartile for the two diet quality indices were 1.0 [95% CI 0.6, 1.6] and 0.9 [95% CI 0.7, 1.1].This large study does not support an association of a vegetarian diet or worse diet quality with hypospadias.

    View details for DOI 10.1111/j.1365-3016.2012.01272.x

    View details for Web of Science ID 000305121500013

    View details for PubMedID 22686387

    View details for PubMedCentralID PMC3376012

  • Environmental and genetic contributors to hypospadias: A review of the epidemiologic evidence BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Lammer, E. J. 2012; 94 (7): 499-510

    Abstract

    This review evaluates current knowledge related to trends in the prevalence of hypospadias, the association of hypospadias with endocrine-disrupting exposures, and the potential contribution of genetic susceptibility to its etiology. The review focuses on epidemiologic evidence. Increasing prevalence of hypospadias has been observed, but such increases tend to be localized to specific regions or time periods. Thus, generalized statements that hypospadias is increasing are unsupported. Owing to the limitations of study designs and inconsistent results, firm conclusions cannot be made regarding the association of endocrine-disrupting exposures with hypospadias. Studies with more rigorous study designs (e.g., larger and more detailed phenotypes) and exposure assessment that encompasses more breadth and depth (e.g., specific endocrine-related chemicals) will be critical to make better inferences about these important environmental exposures. Many candidate genes for hypospadias have been identified, but few of them have been examined to an extent that enables solid conclusions. Further study is needed that includes larger sample sizes, comparison groups that are more representative of the populations from which the cases were derived, phenotype-specific analyses, and more extensive exploration of variants. In conclusion, examining the associations of environmental and genetic factors with hypospadias remain important areas of inquiry, although our actual understanding of their contribution to hypospadias risk in humans is currently limited.

    View details for DOI 10.1002/bdra.23021

    View details for Web of Science ID 000306186100001

    View details for PubMedID 22678668

    View details for PubMedCentralID PMC3393839

  • Cancer in Children with Nonchromosomal Birth Defects JOURNAL OF PEDIATRICS Fisher, P. G., Reynolds, P., Von Behren, J., Carmichael, S. L., Rasmussen, S. A., Shaw, G. M. 2012; 160 (6): 978-983

    Abstract

    To examine whether the incidence of childhood cancer is elevated in children with birth defects but no chromosomal anomalies.We examined cancer risk in a population-based cohort of children with and without major birth defects born between 1988 and 2004, by linking data from the California Birth Defects Monitoring Program, the California Cancer Registry, and birth certificates. Cox proportional hazards models generated hazard ratios (HRs) and 95% CIs based on person-years at risk. We compared the risk of childhood cancer in infants born with and without specific types of birth defects, excluding infants with chromosomal anomalies.Of the 4869 children in the birth cohort with cancer, 222 had a major birth defect. Although the expected elevation in cancer risk was observed in children with chromosomal birth defects (HR, 12.44; 95% CI, 10.10-15.32), especially for the leukemias (HR, 28.99; 95% CI, 23.07-36.42), children with nonchromosomal birth defects also had an increased risk of cancer (HR, 1.58; 95% CI, 1.33-1.87), but instead for brain tumors, lymphomas, neuroblastoma, and germ cell tumors.Children with nonchromosomal birth defects are at increased risk for solid tumors, but not leukemias. Dysregulation of early human development likely plays an important role in the etiology of childhood cancer.

    View details for DOI 10.1016/j.jpeds.2011.12.006

    View details for Web of Science ID 000304377300019

    View details for PubMedID 22244463

  • Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zhu, H., Yang, W., Lu, W., Etheredge, A. J., Lammer, E. J., Finnell, R. H., Carmichael, S. L., Shaw, G. M. 2012; 158A (5): 1124-1134

    Abstract

    We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring.

    View details for DOI 10.1002/ajmg.a.35313

    View details for Web of Science ID 000303000200022

    View details for PubMedID 22495907

    View details for PubMedCentralID PMC3331895

  • Is Maternal Parity an Independent Risk Factor for Birth Defects? BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Duong, H. T., Hoyt, A. T., Carmichael, S. L., Gilboa, S. M., Canfield, M. A., Case, A., McNeese, M. L., Waller, D. K. 2012; 94 (4): 230-236

    Abstract

    Although associations between maternal parity and birth defects have been observed previously, few studies have focused on the possibility that parity is an independent risk factor for birth defects. We investigated the relation between levels of parity and a range of birth defects, adjusting each defect group for the same covariates.We included infants who had an estimated delivery date between 1997 and 2007 and participated in the National Birth Defects Prevention Study, a multisite case-control study. Cases included infants or fetuses belonging to 38 phenotypes of birth defects (n = 17,908), and controls included infants who were unaffected by a major birth defect (n = 7173). Odds ratios (ORs) were adjusted for 12 covariates using logistic regression.Compared with primiparous mothers, nulliparous mothers were more likely to have infants with amniotic band sequence, hydrocephaly, esophageal atresia, hypospadias, limb reduction deficiencies, diaphragmatic hernia, omphalocele, gastroschisis, tetralogy of Fallot, and septal cardiac defects, with significant ORs (1.2 to 2.3). Compared with primiparous mothers, multiparous mothers had a significantly increased risk of omphalocele, with an OR of 1.5, but had significantly decreased risk of hypospadias and limb reduction deficiencies, with ORs of 0.77 and 0.77.Nulliparity was associated with an increased risk of specific phenotypes of birth defects. Most of the phenotypes associated with nulliparity in this study were consistent with those identified by previous studies. Research into biologic or environmental factors that are associated with nulliparity may be helpful in explaining some or all of these associations.

    View details for DOI 10.1002/bdra.22889

    View details for Web of Science ID 000302606600005

    View details for PubMedID 22371332

  • Reduced Risks of Neural Tube Defects and Orofacial Clefts With Higher Diet Quality ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Carmichael, S. L., Yang, W., Feldkamp, M. L., Munger, R. G., Siega-Riz, A. M., Botto, L. D., Shaw, G. 2012; 166 (2): 121-126

    Abstract

    To examine whether better maternal diet quality was associated with reduced risk for selected birth defects.A multicenter, population-based case-control study, the National Birth Defects Prevention Study.Ten participating centers in the United States.Eligible subjects' estimated due dates were from October 1997 through December 2005. Telephone interviews were conducted with 72% of case and 67% of control mothers. Analyses included 936 cases with neural tube defects (NTDs), 2475 with orofacial clefts, and 6147 nonmalformed controls.Food-frequency data were used to calculate the Mediterranean Diet Score (MDS) and Diet Quality Index (DQI), modeled after existing indices.Adjusted odds ratios (ORs).After covariate adjustment, increasing diet quality based on either index was associated with reduced risks for the birth defects studied. The strongest association was between anencephaly and DQI; the OR for highest vs lowest quartile was 0.49 (95% CI, 0.31-0.75). The ORs for cleft lip with or without cleft palate and cleft palate and DQI were also notable (0.66 [95% CI, 0.54-0.81] and 0.74 [95%CI, 0.56-0.96], respectively).Healthier maternal dietary patterns, as measured by diet quality scores, were associated with reduced risks of NTDs and clefts. These results suggest that dietary approaches could lead to further reduction in risks of major birth defects and complement existing efforts to fortify foods and encourage periconceptional multivitamin use.

    View details for DOI 10.1001/archpediatrics.2011.185

    View details for Web of Science ID 000301211000002

    View details for PubMedID 21969361

  • Paternal Age and Congenital Malformations in Offspring in California, 1989-2002 MATERNAL AND CHILD HEALTH JOURNAL Grewal, J., Carmichael, S. L., Yang, W., Shaw, G. M. 2012; 16 (2): 385-392

    Abstract

    This study examined the association between paternal age and a wide range of structural birth defects. Data were drawn from The California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with defects born between 1989 and 2002. The analysis included 46,114 cases with defects, plus a random sample of 36,838 non-malformed births. After adjustment for maternal age, risks of anomalies of the nervous system for 38 and 42 year-old fathers, as compared to 29 year-old fathers, were 1.05-fold [1.00, 1.11] and 1.10-fold [1.02, 1.18] higher, respectively. Similar results were observed for anomalies of the limbs, where 38 and 42 year-old fathers had a 1.06-fold [1.02, 1.11] and 1.11-fold [1.05, 1.18] higher risk, respectively. Risks of anomalies of the integument were 1.05-fold [1.00, 1.09] and 1.10-fold [1.03, 1.16] higher for 38 and 42 year olds, respectively. Young paternal age, i.e., less than 29 years, was associated with an increased risk of amniotic bands (OR: 0.87 [0.78, 0.97]), pyloric stenosis (OR: 0.93 [0.90, 0.96]) and anomalies of the great veins (OR: 0.93 [0.87, 1.00]). In sum, both advanced and young paternal age was associated with select birth defects in California between 1989 and 2002.

    View details for DOI 10.1007/s10995-011-0759-z

    View details for Web of Science ID 000299370400013

    View details for PubMedID 21344170

  • A Genetic Signature of Spina Bifida Risk from Pathway-Informed Comprehensive Gene-Variant Analysis PLOS ONE Marini, N. J., Hoffmann, T. J., Lammer, E. J., Hardin, J., Lazaruk, K., Stein, J. B., Gilbert, D. A., Wright, C., Lipzen, A., Pennacchio, L. A., Carmichael, S. L., Witte, J. S., Shaw, G. M., Rine, J. 2011; 6 (11)

    Abstract

    Despite compelling epidemiological evidence that folic acid supplements reduce the frequency of neural tube defects (NTDs) in newborns, common variant association studies with folate metabolism genes have failed to explain the majority of NTD risk. The contribution of rare alleles as well as genetic interactions within the folate pathway have not been extensively studied in the context of NTDs. Thus, we sequenced the exons in 31 folate-related genes in a 480-member NTD case-control population to identify the full spectrum of allelic variation and determine whether rare alleles or obvious genetic interactions within this pathway affect NTD risk. We constructed a pathway model, predetermined independent of the data, which grouped genes into coherent sets reflecting the distinct metabolic compartments in the folate/one-carbon pathway (purine synthesis, pyrimidine synthesis, and homocysteine recycling to methionine). By integrating multiple variants based on these groupings, we uncovered two provocative, complex genetic risk signatures. Interestingly, these signatures differed by race/ethnicity: a Hispanic risk profile pointed to alterations in purine biosynthesis, whereas that in non-Hispanic whites implicated homocysteine metabolism. In contrast, parallel analyses that focused on individual alleles, or individual genes, as the units by which to assign risk revealed no compelling associations. These results suggest that the ability to layer pathway relationships onto clinical variant data can be uniquely informative for identifying genetic risk as well as for generating mechanistic hypotheses. Furthermore, the identification of ethnic-specific risk signatures for spina bifida resonated with epidemiological data suggesting that the underlying pathogenesis may differ between Hispanic and non-Hispanic groups.

    View details for DOI 10.1371/journal.pone.0028408

    View details for Web of Science ID 000298168100069

    View details for PubMedID 22140583

    View details for PubMedCentralID PMC3227667

  • Periconceptional Intake of Folic Acid and Food Folate and Risks of Preterm Delivery AMERICAN JOURNAL OF PERINATOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Siega-Riz, A. M. 2011; 28 (10): 747-751

    Abstract

    We investigated multiple sources of folate and folic acid to determine whether their periconceptional intakes were associated with preterm delivery. Studied were controls from the National Birth Defects Prevention Study delivered September 1998 to December 2005. Telephone interviews were conducted with 5952 (68% of eligible) mothers. Women were queried about intake of vitamin supplements in the 12 weeks before conception through delivery. A version of the Nurse's Health Study food frequency questionnaire was used to assess food sources. Eight percent of infants ( N = 487) were preterm (<37 weeks). Compared with women who began intake of supplements with folic acid before pregnancy, those who began any time during pregnancy had an ~20% lowered risk of preterm delivery. Lower dietary intakes showed a modest increased risk of preterm delivery: odds ratios were 1.44 (1.01 to 2.04) for lowest quartile intake of folate and 1.27 (0.95 to 1.69) for lowest quartile intake of folic acid compared with the highest. Findings suggest some evidence that folates influenced risks; however, an interpretation of results was also consistent with no association between intake of folates and preterm delivery.

    View details for DOI 10.1055/s-0031-1280855

    View details for Web of Science ID 000298200500002

    View details for PubMedID 21681695

  • Estimated dietary phytoestrogen intake and major food sources among women during the year before pregnancy NUTRITION JOURNAL Carmichael, S. L., Gonzalez-Feliciano, A. G., Ma, C., Shaw, G. M., Cogswell, M. E. 2011; 10

    Abstract

    Phytoestrogens may be associated with a variety of different health outcomes, including outcomes related to reproductive health. Recently published data on phytoestrogen content of a wide range of foods provide an opportunity to improve estimation of dietary phytoestrogen intake.Using the recently published data, we estimated intake among a representative sample of 6,584 women of reproductive age from a multi-site, population-based case-control study, the National Birth Defects Prevention Study (NBDPS). The NBDPS uses a shortened version of the Willett food frequency questionnaire to estimate dietary intake during the year before pregnancy. We estimated intake among NBDPS control mothers.Lignans contributed 65% of total phytoestrogen intake; isoflavones, 29%; and coumestrol, 5%. Top contributors to total phytoestrogen intake were vegetables (31%) and fruit (29%); for isoflavones, dairy (33%) and fruit (21%); for lignans, vegetables (40%) and fruit (29%); and for coumestans, fruit (55%) and dairy (18%). Hispanic women had higher phytoestrogen intake than non-Hispanic white or black women. Associations with maternal age and folic acid-containing supplements were more modest but indicated that older mothers and mothers taking supplements had higher intake.The advantage of the approach used for the current analysis lies in its utilization of phytoestrogen values derived from a single laboratory that used state-of-the-art measurement techniques. The database we developed can be applied directly to other studies using food frequency questionnaires, especially the Willett questionnaire. The database, combined with consistent dietary intake assessment, provides an opportunity to improve our ability to understand potential associations of phytoestrogen intake with health outcomes.

    View details for DOI 10.1186/1475-2891-10-105

    View details for Web of Science ID 000295960300001

    View details for PubMedID 21978267

    View details for PubMedCentralID PMC3196693

  • Maternal nutrition and gastroschisis: findings from the National Birth Defects Prevention Study AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Feldkamp, M. L., Carmichael, S. L., Shaw, G. M., Panichello, J. D., Moore, C. A., Botto, L. D. 2011; 204 (5)

    Abstract

    Gastroschisis is increasing in many countries, especially among young women. Because young women may have inadequate nutrition, we assessed the relationship between individual nutrients and the risk for gastroschisis.We analyzed data from the National Birth Defects Prevention Study, a population-based case-control study. Cases were ascertained from 10 birth defect surveillance systems. Controls were randomly selected from birth certificates or hospital records. Nutrient intake was estimated for the year prior to conception from maternal interviews based on a 58-item food frequency questionnaire and cereal consumption reported. A total of 694 cases and 6157 controls were available for analysis.Reported intake of individual nutrients did not substantially affect the risk for gastroschisis. Stratification by maternal age, preconception body mass index, folic acid-containing supplements, or energy intake (kilocalories) did not alter risk estimates.This study does not support an increased risk for gastroschisis with decreasing tertiles of individual nutrients.

    View details for DOI 10.1016/j.ajog.2010.12.053

    View details for Web of Science ID 000290206200025

    View details for PubMedID 21396620

  • Craniosynostosis and Nutrient Intake during Pregnancy BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Rasmussen, S. A., Lammer, E. J., Ma, C., Shaw, G. M. 2010; 88 (12): 1032-1039

    Abstract

    To examine the association of craniosynostosis with maternal intake of folic acid-containing supplements and dietary nutrients.The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic infants with craniosynostosis (n = 815) were compared to nonmalformed, population-based liveborn control infants (n = 6789), by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included mother's age, parity, race-ethnicity, education, body mass index, smoking, alcohol, fertility treatments, plurality, and study center. We compared quartiles of intake and specified nutrients as continuous.Intake of folic acid-containing supplements was not associated with craniosynostosis (AORs were close to 1). Analyses of dietary nutrients were restricted to mothers who took supplements during the first trimester (i.e., most women). Based on continuous specifications of nutrients, sagittal synostosis risk was significantly lower among women with higher intake of riboflavin and vitamins B₆, E, and C; metopic synostosis risk was significantly higher among women with higher intakes of choline and vitamin B₁₂; and coronal synostosis risk was significantly lower among women with higher intake of methionine and vitamin C. As examples, AORs for sagittal synostosis among women with intakes of vitamin B₆ and riboflavin in the highest versus lowest quartiles were 0.4 (95% CI, 0.2-0.6) and 0.5 (95% CI, 0.3-0.7), respectively.This analysis suggests that dietary intake of certain nutrients may be associated with craniosynostosis, and results may vary by suture type.

    View details for DOI 10.1002/bdra.20717

    View details for Web of Science ID 000285396200006

    View details for PubMedID 20842649

    View details for PubMedCentralID PMC3136510

  • Association of Microtia With Maternal Obesity and Periconceptional Folic Acid Use AMERICAN JOURNAL OF MEDICAL GENETICS PART A Ma, C., Carmichael, S. L., Scheuerle, A. E., Canfield, M. A., Shaw, G. M. 2010; 152A (11): 2756-2761

    Abstract

    The study objective was to examine the association of microtia with maternal intake of folic-acid-containing supplements and obesity. The study data included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Non-syndromic cases of microtia were compared to non-malformed, population-based liveborn control infants, by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race/ethnicity, education, and study site. Maternal obesity was only weakly associated with microtia. Maternal periconceptional intake of folic-acid-containing vitamin supplements reduced the risk for microtia, but only among non-obese women (OR: 0.63; 95% CI: 0.44-0.91). The reduced risk was stronger when analyses were restricted to isolated cases (OR: 0.51; 95% CI: 0.34-0.77), and it was independent of the level of maternal dietary folate intake. Adjusting for maternal race/ethnicity did not reveal alternative interpretations of this association. This analysis suggests that maternal periconceptional intake of folic-acid-containing supplements may provide protection from microtia for non-obese women.

    View details for DOI 10.1002/ajmg.a.33694

    View details for Web of Science ID 000284005700013

    View details for PubMedID 20949601

  • Prepregnancy Obesity: A Complex Risk Factor for Selected Birth Defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Rasmussen, S. A., Shaw, G. M. 2010; 88 (10): 804-810

    Abstract

    Obesity is associated with increased risk of many adverse health conditions. During pregnancy, obesity presents particularly important challenges for both mother and baby. Over the last 20 years, studies have emerged indicating an association between prepregnancy weight and risks of birth defects. However, few studies have examined the mechanisms through which this association occurs. Understanding the underlying mechanisms may provide clues to public health strategies for the prevention of birth defects associated with maternal obesity. This article briefly reviews existing literature on the association between maternal obesity and birth defects, discusses potential underlying mechanisms, and suggests research needed to improve our understanding of this important association.

    View details for DOI 10.1002/bdra.20679

    View details for Web of Science ID 000283638500006

    View details for PubMedID 20973050

  • Periconceptional Nutrient Intakes and Risks of Neural Tube Defects in California 6th International Conference on Neural Tube Defects Carmichael, S. L., Yang, W., Shaw, G. M. WILEY-LISS. 2010: 670–78

    Abstract

    This study investigated the association of neural tube defects (NTDs) with maternal periconceptional intake of folic acid-containing supplements and dietary nutrients, including folate, among deliveries that occurred after folic acid fortification in selected California counties.The population-based case-control study included fetuses and live born infants with spina bifida (189) or anencephaly (141) and 625 nonmalformed, live born controls delivered from 1999 to 2003. Mothers reported supplement use during telephone interviews, which included a 107-item food frequency questionnaire. For dietary nutrients, intakes <25th, 25th to <75th (reference), and > or =75th percentile were compared, based on control distributions.After adjustment for potential confounders, any versus no supplement intake resulted in ORs of 0.8 (95% CI, 0.5-1.3) for anencephaly and 0.8 (95% CI, 0.6-1.2) for spina bifida. After stratification by maternal intake of vitamin supplements, most factors in the glycemic pathway were not associated with either NTD, with the exception of low levels of fructose and glucose that were significantly associated with anencephaly. Some nutrients that contribute to one-carbon metabolism showed lowered risks (folate, riboflavin, vitamins B(6) and B(12)); others did not (choline, methionine, zinc). Antioxidant nutrients tended to be associated with lowered risks (vitamins C, E, A, beta-carotene, lutein).Mothers' intake of vitamin supplements was modestly if at all associated with a lowered risk of NTDs. Dietary intake of several nutrients contributing to one-carbon metabolism and oxidative stress were associated with reduced NTD risk.

    View details for DOI 10.1002/bdra.20675

    View details for Web of Science ID 000281529700009

    View details for PubMedID 20740594

    View details for PubMedCentralID PMC2929981

  • Hypospadias and halogenated organic pollutant levels in maternal mid-pregnancy serum samples CHEMOSPHERE Carmichael, S. L., Herring, A. H., Sjoedin, A., Jones, R., Needham, L., Ma, C., Ding, K., Shaw, G. M. 2010; 80 (6): 641-646

    Abstract

    Environmental contaminants that disrupt endocrine function may contribute to hypospadias etiology.To compare levels of selected halogenated organic pollutants in women delivering infants with and without hypospadias.This study examined levels of nine polybrominated flame retardants (PBDEs), 30 polychlorinated biphenyls (PCBs) and nine persistent pesticides in mid-pregnancy serum samples from 20 women who delivered infants with hypospadias and 28 women who delivered unaffected infants, in California. Analytes were measured using isotope dilution high-resolution mass spectrometry. Values below individual limits of detection (LOD) for each analyte were imputed based on a truncated multivariate normal distribution. Levels of 17 analytes for which at least 50% of cases and controls had values above the LOD were compared using t-tests and by generating odds ratios from logistic regression analyses.Means were greater for cases than controls for 11 of the 17 reported analytes (4 of 5 PBDEs, 7 of 9 PCBs, and 0 of 3 other persistent pesticides), but none of the differences were statistically significant. Eleven of the 17 odds ratios exceeded one (the same analytes that had greater means), but none of the confidence intervals excluded one. After adjustment for sample processing time and foreign-born Hispanic race-ethnicity, only four of the odds ratios exceeded one.Levels of the PBDEs and PCBs were not statistically significantly different, but the sample size was small. The current study adds to a relatively limited knowledge base regarding the potential association of specific contaminants with hypospadias or other birth defects.

    View details for DOI 10.1016/j.chemosphere.2010.04.055

    View details for Web of Science ID 000280749500005

    View details for PubMedID 20494400

    View details for PubMedCentralID PMC2944405

  • Patterns of tobacco exposure before and during pregnancy ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA Anderka, M., Romitti, P. A., Sun, L., Druschel, C., Carmichael, S., Shaw, G. 2010; 89 (4): 505-514

    Abstract

    To describe maternal exposure to tobacco in the three months before conception and throughout pregnancy, examine risk factors associated with tobacco exposure in pregnancy and smoking cessation, assess use of pharmacotherapy for smoking cessation and evaluate birth outcomes by smoking status.A cohort of women from a multi-site United States study were asked retrospectively about their exposure to tobacco.The study population was comprised of 4,667 mothers of non-malformed control infants who participated in the National Birth Defects Prevention Study from 1997 to 2003.Using computer-assisted telephone interview responses from this population-based sample, we assessed patterns of maternal smoking and exposure to environmental tobacco smoke (ETS) as well as use of pharmacotherapy for quitting smoking during pregnancy.Overall, 961 (20.6%) mothers reported any smoking and 1,401 (30.0%) reported any exposure to ETS at home or work during the three months before conception through pregnancy. Of the 961 smokers, 512 (53.3%) reportedly quit smoking before or during pregnancy, including 379 (74% of quitters) in the first trimester, and 420 (43.7%) continued to smoke throughout the pregnancy. Only 2.1% of smokers reportedly used pharmacotherapy to quit smoking anytime from three months before conception through pregnancy. Low birthweight and preterm delivery rates were lowest among offspring of non-smokers and highest in offspring of those who continued to smoke throughout pregnancy.About one-half of mothers who reported preconceptional smoking quit before or during pregnancy. Use of pharmacotherapy to quit smoking during pregnancy was not common.

    View details for DOI 10.3109/00016341003692261

    View details for Web of Science ID 000277094700011

    View details for PubMedID 20367429

  • Fetal Constraint as a Potential Risk Factor for Craniosynostosis AMERICAN JOURNAL OF MEDICAL GENETICS PART A Sanchez-Lara, P. A., Carmichael, S. L., Graham, J. M., Lammer, E. J., Shaw, G. M., Ma, C., Rasmussen, S. A. 2010; 152A (2): 394-400

    Abstract

    Non-syndromic craniosynostosis is multifactorial, and fetal head constraint has been hypothesized as one factor thought to play a role. Data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, were used to evaluate associations between four selected factors related to fetal constraint and craniosynostosis: plurality (twins or higher), macrosomia (birth weight >4,000 g), post-term gestational age (> or =42 weeks), and nulliparity (no previous live births). Case infants (n = 675) had craniosynostosis documented either by radiographic evidence or by surgical intervention. Infants with a recognized or strongly suspected single-gene conditions or chromosomal abnormalities were excluded. Control infants (n = 5,958) had no major birth defects and were randomly selected from the same population as case infants. Logistic regression was used to estimate odds ratios for the association between these four factors and craniosynostosis, while adjusting for several covariates. We found that plurality and nulliparity were associated with a twofold increased risk for metopic craniosynostosis, and macrosomia had almost twice the risk of developing coronal craniosynostosis. Contrary to our hypothesis, prematurity and low birth weight were also associated with craniosynostosis. In conclusion, these four constraint-related factors were not found to be associated with craniosynostosis when all suture types were combined, though some types of craniosynostosis were associated with individual constraint-related factors.

    View details for DOI 10.1002/ajmg.a.33246

    View details for Web of Science ID 000274508300019

    View details for PubMedID 20101684

    View details for PubMedCentralID PMC2815148

  • Socioeconomic Measures, Orofacial Clefts, and Conotruncal Heart Defects in California BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Ma, C., Shaw, G. M. 2009; 85 (10): 850-857

    Abstract

    To examine the association of multiple measures of socioeconomic status (SES) with risks of orofacial clefts and conotruncal heart defects.Data were from a recent population-based case-control study conducted in California that included 608 patients with orofacial clefts, 277 patients with conotruncal heart defects, and 617 nonmalformed controls.The odds ratio for the worst versus best score on a household-level SES index was strongest for cleft lip with or without palate, at 1.7 (95% confidence interval, 0.9-3.4); the odds ratios for this comparison were closer to 1 and less precise for the other defect groups. An index based on neighborhood-level SES was also not associated with increased risk of the studied defects.This detailed analysis of SES and selected birth defects did not suggest worse SES was associated with increased risk of the studied defects, with the possible exception of cleft lip with or without cleft palate.

    View details for DOI 10.1002/bdra.20614

    View details for Web of Science ID 000271348700006

    View details for PubMedID 19645048

    View details for PubMedCentralID PMC2865188

  • Maternal Nutrient Intake and Risks for Transverse and Longitudinal Limb Deficiencies: Data from the National Birth Defects Prevention Study, 1997-2003 48th Annual Meeting of the Teratology-Society Robitaille, J., Carmichael, S. L., Shaw, G. M., Olney, R. S. WILEY-BLACKWELL. 2009: 773–79

    Abstract

    The association between periconceptional intake of supplements containing folic acid with specific subtypes of limb deficiencies has been inconsistent. The objective was to investigate whether intake of nutrients involved in one-carbon metabolism (folate, vitamin B(6), vitamin B(12), riboflavin, choline, betaine, zinc, and methionine) through diet alone or in combination with a supplement containing folic acid influenced the risk for transverse limb deficiency (TLD) and longitudinal limb deficiency (LLD).We analyzed 1997-2003 data from the National Birth Defects Prevention Study and included 324 case infants with TLD, 158 case infants with LLD, and 4982 nonmalformed control infants. A food frequency questionnaire was used to estimate nutrient intakes. Use of supplements containing folic acid 1 month before through 2 months after conception was recorded.Use of a supplement containing folic acid was not associated with LLD or TLD. For nonsupplement users, within (1) the lowest quartile of dietary folate intake or vitamin B(6) intake, adjusted odds ratios (aORs) for LLD were, respectively, 3.86 (95% confidence interval [CI]: 1.08-13.78) and 4.36 (95% CI: 0.93-20.48); and (2) the lowest quartile for riboflavin intake, the aOR for TLD was 2.94 (95% CI: 1.04-8.32). For supplement users within the lowest quartile of folate intake or riboflavin intake, the aORs for TLD were, respectively, 1.52 (95% CI: 0.91-2.54) and 1.54 (95% CI: 1.00-2.37).TLD and LLD were not associated with supplement use, but TLD was associated with low intakes of riboflavin from diet.

    View details for DOI 10.1002/bdra.20587

    View details for Web of Science ID 000270586400004

    View details for PubMedID 19350655

  • Anencephaly and Spina Bifida among Hispanics: Maternal, Sociodemographic, and Acculturation Factors in the National Birth Defects Prevention Study 21st Annual Meeting of the Society-for-Pediatric-Epidemiology-Research Canfield, M. A., Ramadhani, T. A., Shaw, G. M., Carmichael, S. L., Waller, D. K., Mosley, B. S., Royle, M. H., Olney, R. S. WILEY-BLACKWELL. 2009: 637–46

    Abstract

    We used data from the multisite National Birth Defects Prevention Study for expected delivery dates from October 1997 through 2003, to determine whether the increased risk in anencephaly and spina bifida (neural tube defects (NTDs)) in Hispanics was explained by selected sociodemographic, acculturation, and other maternal characteristics.For each type of defect, we examined the association with selected maternal characteristics stratified by race/ethnicity and the association with Hispanic parents' acculturation level, relative to non-Hispanic whites. We used logistic regression and calculated crude odds ratios (ORs) and their 95% confidence intervals (CIs).Hispanic mothers who reported the highest level of income were 80% less likely to deliver babies with spina bifida. In addition, highly educated Hispanic and white mothers had 76 and 35% lower risk, respectively. Other factors showing differing effects for spina bifida in Hispanics included maternal age, parity, and gestational diabetes. For spina bifida there was no significant elevated risk for U.S.-born Hispanics, relative to whites, but for anencephaly, corresponding ORs ranged from 1.9 to 2.3. The highest risk for spina bifida was observed for recent Hispanic immigrant parents from Mexico or Central America residing in the United States <5 years (OR = 3.28, 95% CI = 1.46-7.37).Less acculturated Hispanic parents seemed to be at highest risk of NTDs. For anencephaly, U.S.-born and English-speaking Hispanic parents were also at increased risk. Finally, from an etiologic standpoint, spina bifida and anencephaly appeared to be etiologically heterogeneous from these analyses.

    View details for DOI 10.1002/bdra.20582

    View details for Web of Science ID 000268426000007

    View details for PubMedID 19334286

  • Maternal Thyroid Disease, Thyroid Medication Use, and Selected Birth Defects in the National Birth Defects Prevention Study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Browne, M. L., Rasmussen, S. A., Hoyt, A. T., Waller, D. K., Druschel, C. M., Caton, A. R., Canfield, M. A., Lin, A. E., Carmichael, S. L., Romitti, P. A. 2009; 85 (7): 621-628

    Abstract

    Although thyroid disorders are present in approximately 3% of pregnant women, little is known about the association between maternal thyroid disease and birth defects.We assessed the association between maternal thyroid disease, thyroid medication use, and 38 types of birth defects among 14,067 cases and 5875 controls in the National Birth Defects Prevention Study, a multisite, population-based, case-control study. Infants in this study were born between October 1997 and December 2004. Information on exposures including maternal diseases and use of medications was collected by telephone interview.We found statistically significant associations between maternal thyroid disease and left ventricular outflow tract obstruction heart defects (1.5; 95% CI, 1.0-2.3), hydrocephaly (2.9; 95% CI, 1.6-5.2), hypospadias (1.6; 95% CI, 1.0-2.5), and isolated anorectal atresia (2.4; 95% CI, 1.2-4.6). Estimates for the association between periconceptional use of thyroxine and specific types of birth defects were similar to estimates for any thyroid disease. Given that antithyroid medication use was rare, we could not adequately assess risks for their use for most case groups.Our results are consistent with the positive associations between maternal thyroid disease or thyroid medication use and both hydrocephaly and hypospadias observed in some previous studies. New associations with left ventricular outflow tract obstruction heart defects and anorectal atresia may be chance findings.

    View details for DOI 10.1002/bdra.20573

    View details for Web of Science ID 000268426000005

    View details for PubMedID 19215015

  • Maternal Corticosteroid Use and Hypospadias JOURNAL OF PEDIATRICS Carmichael, S. L., Ma, C., Werler, M. M., Olney, R. S., Shaw, G. M. 2009; 155 (1): 39-44

    Abstract

    To explore whether women who reported corticosteroid use during pregnancy were more likely to deliver an infant with hypospadias than women who did not.The analysis encompassed data on deliveries with an estimated due date between 1997 and 2004 from the National Birth Defects Prevention Study, a large population-based, case-control study conducted in the United States. Included were 1165 cases of moderate to severe hypospadias and 3000 nonmalformed male controls.The mothers of 39 cases (3.3%) and 62 controls (2.1%) reported using a corticosteroid medication during the period extending from 4 weeks before conception to 14 weeks after conception. The odds ratio (OR) for any corticosteroid exposure versus no corticosteroid exposure was 1.6 (95% confidence interval [CI] = 1.1 to 2.5); after adjustment for maternal race/ethnicity, education, age, and study site, it was 1.3 (95% CI = 0.8 to 2.0). Analyses by route of administration and specific component suggest that elevated ORs occurred only for nasal spray/inhaled corticosteroids (OR = 1.5; 95% CI = 0.9 to 2.6).Maternal use of corticosteroid medications was weakly associated with risk of hypospadias, but the association was negligible after adjustment for potential confounders.

    View details for DOI 10.1016/j.jpeds.2009.01.039

    View details for Web of Science ID 000267672600013

    View details for PubMedID 19394038

  • Increased Prevalence of Cardiovascular Defects Among 56,709 California Twin Pairs AMERICAN JOURNAL OF MEDICAL GENETICS PART A Hardin, J., Carmichael, S. L., Selvin, S., Lammer, E. J., Shaw, G. M. 2009; 149A (5): 877-886

    Abstract

    This study compared the prevalence of cardiovascular defects in twin and singleton births and explored the influences of zygosity (monozygotic and dizygotic) and maternal age (<35 and >or=35 years of age) on concordance. Data on twin and singleton infants with (n = 628 twin pairs and n = 14,078 singletons) and without (n = 53,974 twin pairs and n = 4,858,255 singletons) cardiovascular defects were obtained from the California Birth Defects Monitoring Program and the California vital statistics birth and fetal death records during the period 1983-2003. Prevalence ratios (PR) (prevalence of twin/singleton) and approximate 95% confidence intervals were calculated for 16 congenital cardiovascular categories. Poisson regression techniques using log-linear models were employed to assess whether the probability of concordance of defects within each cardiovascular category varied by zygosity or maternal age. An increased prevalence was observed in twins compared to singletons in all 16 cardiovascular categories. Seven of the cardiovascular categories had at least double the prevalence in twins compared to singletons. Like-sex twins, as a proxy of monozygosity, had an increased prevalence of cardiovascular defects compared to unlike sex twins. Probabilities of concordance for flow lesions were higher among monozygotic than dizygotic twins. Our study provides evidence that twinning is associated with more cardiovascular defects than singletons. Increased concordance for flow lesions in monozygotic twins was observed, an observation that is in agreement with findings from familial recurrence studies of cardiovascular defects.

    View details for DOI 10.1002/ajmg.a.32745

    View details for Web of Science ID 000265805900010

    View details for PubMedID 19353581

  • Neural tube defects: an analysis of neighbourhood- and individual-level socio-economic characteristics PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Grewal, J., Carmichael, S. L., Song, J., Shaw, G. M. 2009; 23 (2): 116-124

    Abstract

    Several studies have reported that neural tube defects (NTD) occur more frequently among children born to women of lower socio-economic status (SES). This study investigated the relationship between individual- and neighbourhood-level SES and the risk of an NTD-affected pregnancy. Data were drawn from a population-based case-control study of fetuses and infants among a cohort of California births between July 1999 and June 2003. Information on individual SES was obtained via telephone interviews with mothers of 337 (76% of eligible) cases and 626 (79% of eligible) non-malformed liveborn controls. Respondents' addresses were linked to the 2000 US Census to characterise six measures of neighbourhood SES (education, poverty, unemployment, occupation, crowding and rental occupancy). The analyses indicated that relative to women with a high school education, those with less than a high school education had a 1.7-fold increased risk of delivering infants with NTDs [95% CI 1.2, 2.6]. Twofold elevated risks for NTDs were observed for women with less than a high school education who lived in neighbourhoods where a majority of residents had not graduated from high school [95% CI 1.3, 3.1]. No consistent risk gradients were observed between NTD-affected pregnancies and indicators of lower neighbourhood SES. Results for phenotype subgroups were similar to those for all cases. Low maternal education was associated with an elevated risk of NTD in offspring. This risk varied by the education profile of the neighbourhood: women who did not graduate from high school and lived in less educated neighbourhoods exhibited a higher risk.

    View details for DOI 10.1111/j.1365-3016.2008.00992.x

    View details for Web of Science ID 000262645600003

    View details for PubMedID 19159398

  • The Estimated Probability of Dizygotic Twins: A Comparison of Two Methods TWIN RESEARCH AND HUMAN GENETICS Hardin, J., Selvin, S., Carmichael, S. L., Shaw, G. M. 2009; 12 (1): 79-85

    Abstract

    This study presents a general model of two binary variables and applies it to twin sex pairing data from 21 twin data sources to estimate the frequency of dizygotic twins. The purpose of this study is to clarify the relationship between maximum likelihood and Weinberg's differential rule zygosity estimation methods. We explore the accuracy of these zygosity estimation measures in relation to twin ascertainment methods and the probability of a male. Twin sex pairing data from 21 twin data sources representing 15 countries was collected for use in this study. Maximum likelihood estimation of the probability of dizygotic twins is applied to describe the variation in the frequency of dizygotic twin births. The differences between maximum likelihood and Weinberg's differential rule zygosity estimation methods are presented as a function of twin data ascertainment method and the probability of a male. Maximum likelihood estimation of the probability of dizygotic twins ranges from 0.083 (95% approximate CI: 0.082, 0.085) to 0.750 (95% approximate CI: 0.749, 0.752) for voluntary ascertainment data sources and from 0.374 (95% approximate CI: 0.373, 0.375) to 0.987 (95% approximate CI: 0.959, 1.016) for active ascertainment data sources. In 17 of the 21 twin data sources differences of 0.01 or less occur between maximum likelihood and Weinberg zygosity estimation methods. The Weinberg and maximum likelihood estimates are negligibly different in most applications. Using the above general maximum likelihood estimate, the probability of a dizygotic twin is subject to substantial variation that is largely a function of twin data ascertainment method.

    View details for Web of Science ID 000263635000009

    View details for PubMedID 19210182

  • Trends in the Probability of Twins and Males in California, 1983-2003 TWIN RESEARCH AND HUMAN GENETICS Hardin, J., Carmichael, S. L., Selvin, S., Shaw, G. M. 2009; 12 (1): 93-102

    Abstract

    This study examines the probability of twins by birth year, maternal race-ethnicity, age, and parity and the influences of these demographic factors on the probability of male in twins and singletons in a large, racially diverse population. Recent publications note steep increases in twin births while the probability of male births has been reported to vary by parental race-ethnicity and age and birth order. Probability of male stratified by plurality has not been investigated in California prior to this study. Cubic spline estimates and Poisson regression techniques were employed to describe trends in twins and males using California vital statistics birth and fetal death records over the period from 1983-2003. This study includes 127,787 twin pair and 11,025,106 singleton births. The probability of twins varied by birth year, maternal race-ethnicity, age, and parity. The probability of twins increased by 10.1% from 1983-1992 and increased by 20.1% from 1993-2003, nearly doubling the previous increase. All maternal race-ethnicity groups showed increases in probability of twins with increasing maternal age. Parous women compared to nulliparous women had larger increases in the probability of twins. The probability of males in twins decreased from 1983-1992 and increased from 1993-2003; while in singletons the probability appeared unchanged. These findings show increases in the probability of twins in California from 1983-2003 and identify maternal age, race-ethnicity, and parity groups most likely to conceive twins. The cause of the increase in twins is unknown but coincides with trends towards delayed childbearing and increased use of subfertility treatments.

    View details for Web of Science ID 000263635000011

    View details for PubMedID 19210184

  • Mid-Pregnancy Cotinine and Risks of Orofacial Clefts and Neural Tube Defects JOURNAL OF PEDIATRICS Shaw, G. M., Carmichael, S. L., Vollset, S. E., Yang, W., Finnell, R. H., Blom, H., Midttun, O., Ueland, P. M. 2009; 154 (1): 17-19

    Abstract

    Past studies of cigarette smoking as a contributor to orofacial clefts and neural tube defects (NTDs) used self-reports of smoke exposures. We have correlated measurements of cotinine (a nicotine metabolite) in mid-pregnancy sera with clefts and NTDs.From a repository of >180 000 mid-pregnancy serum specimens collected in California from 2003 to 2005 and linked to delivery outcome information, we identified 89 orofacial cleft-associated pregnancies, 80 NTD-affected pregnancies, and randomly selected 409 pregnancy specimens that corresponded to infants without malformations as control subjects. Cotinine was measured by liquid chromatography-mass spectrometry. No smoke exposure was defined as cotinine values <2 ng/mL, and any exposure was defined as >or=2 ng/mL.We observed odds ratios of 2.1 (95% CI, 1.0-4.4) for clefts and 0.4 (95% CI, 0.1-1.7) for NTDs associated with exposure. After adjusting for race/ethnicity, age, and serum folate levels, odds ratios were 2.4 (95% CI, 1.1-5.3) and 0.6 (95% CI, 0.1-2.5). We explored 2 cotinine levels, 2 to 10 ng/mL and >10 ng/mL for clefts (data were too sparse for NTDs). Odds ratios for these levels were 3.3 (95% CI, 0.9-11.9) and 1.7 (95% CI, 0.7-4.2), respectively.Smoking exposures, as measured with cotinine levels during mid-pregnancy, were associated with increased risks of clefts and possibly reduced risks of NTDs.

    View details for DOI 10.1016/j.jpeds.2008.08.006

    View details for Web of Science ID 000262272500006

    View details for PubMedID 18990410

  • Nutrient Pathways and Neural Tube Defects A Semi-Bayesian Hierarchical Analysis EPIDEMIOLOGY Carmichael, S. L., Witte, J. S., Shaw, G. M. 2009; 20 (1): 67-73

    Abstract

    We used conventional and hierarchical logistic regression to examine the association of neural tube defects (NTDs) with intake of 26 nutrients that contribute to the mechanistic pathways of methylation, glycemic control, and oxidative stress, all of which have been implicated in NTD etiology. The hierarchical approach produces more plausible, more stable estimates than the conventional approach, while adjusting for potential confounding by other nutrients.Analyses included 386 cases and 408 nonmalformed controls with complete data on nutrients and potential confounders (race/ethnicity, education, obesity, and intake of vitamin supplements) from a population-based case-control study of deliveries in California from 1989 to 1991. Nutrients were specified as continuous, and their units were standardized to have a mean of zero and standard deviation (SD) of 1 for comparability of units across pathways. ORs reflect a 1-SD increase in the corresponding nutrient.Among women who took vitamin supplements, semi-Bayesian hierarchical modeling results suggested no associations between nutrient intake and NTDs. Among women who did not take supplements, both conventional and hierarchical models (HM) suggested an inverse association between lutein intake and NTD risk (HM odds ratio [OR] = 0.6; 95% confidence interval = 0.5-0.9) and a positive association with sucrose (HM OR 1.4; 1.1-1.8) and glycemic index (HM OR 1.3; 1.0-1.6).Our findings for lutein, glycemic index, and sucrose suggest that further study of NTDs and the glycemic control and oxidative stress pathways is warranted.

    View details for DOI 10.1097/EDE.0b013e31818f6375

    View details for Web of Science ID 000261930800013

    View details for PubMedID 19234400

  • Chromosomal Abnormalities among Children Born with Conotruncal Cardiac Defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Lammer, E. J., Chak, J. S., Iovannisci, D. M., Schultz, K., Osoegawa, K., Yang, W., Carmichael, S. L., Shaw, G. M. 2009; 85 (1): 30-35

    Abstract

    Conotruncal heart defects compose 25% to 30% of nonsyndromic congenital heart defects. This study describes the frequency of chromosome abnormalities and microdeletion of 22q11 associated among infants and fetuses delivered with conotruncal heart malformations.From a population base of 974,579 infants/fetuses delivered, 622 California infants/fetuses were ascertained with a defect of aortopulmonary septation. Infants whose primary cardiac defect was tetralogy of Fallot (n = 296) or d-transposition of the great arteries (n = 189) were screened for microdeletion of 22q11.Of the infants who had routine karyotypes, 5% had chromosomal abnormalities, including four with extra sex chromosomes. Thirty infants had chromosome 22q11 microdeletions, providing a cause for 10% of infants whose primary defect was tetralogy of Fallot. Right aortic arch, abnormal branching patterns of the major arteries arising from the thoracic aorta, and pulmonary artery abnormalities were observed more frequently among infants with tetralogy of Fallot caused by 22q11 microdeletion.We found an unusual number of infants with an extra sex chromosome and a conotruncal defect. Infants with tetralogy of Fallot owing to 22q11 microdeletion showed more associated vascular anomalies than infants with tetralogy without a 22q11 microdeletion. Although these associated vascular anomalies provide clues as to which infants with tetralogy of Fallot are more likely to carry the microdeletion, the overall risk of 10% among infants with tetralogy of Fallot warrants chromosome analysis and fluorescent in situ hybridization (FISH) testing routinely, which may be supplanted by genome-wide copy number testing as it becomes more widely utilized.

    View details for DOI 10.1002/bdra.20541

    View details for Web of Science ID 000262904800005

    View details for PubMedID 19067405

  • Hypospadias and Intake of Nutrients Related to One-Carbon Metabolism JOURNAL OF UROLOGY Carmichael, S. L., Yang, W., Correa, A., Olney, R. S., Shaw, G. M. 2009; 181 (1): 315-321

    Abstract

    We examined whether hypospadias is associated with maternal intake of folic acid containing vitamin/mineral supplements or dietary intake of nutrients related to one-carbon metabolism (folate, choline, vitamins B12 and B6, thiamine, riboflavin, methionine and zinc).The study included births from October 1997 to December 2003 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews. Analyses included 915 cases with second or third degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 2,266 male, liveborn, nonmalformed controls. All ORs and 95% CIs were estimated from logistic regression models that included several potential confounders. Nutrient based analyses also included energy intake.Hypospadias risk was not associated with supplement use (adjusted ORs were 1.2, 95% CI 0.9-1.6 for intake beginning in the month before or the first month of pregnancy and 1.1, 95% CI 0.8-1.4 for intake beginning in the second or third month, relative to no intake). Among women who took supplements reduced hypospadias risk was associated with higher dietary intakes of choline, methionine and vitamin B12. The respective ORs (CIs) for the highest vs lowest quartiles were 0.7 (0.5-1.1), 0.6 (0.4-0.9) and 0.7 (0.5-1.0). Among women who did not take supplements increased risk of hypospadias was associated with higher vitamin B12 intake. The OR (CI) for the highest vs lowest quartile was 3.1 (1.1-9.0).This study suggests an association of hypospadias with intake of certain nutrients related to one-carbon metabolism.

    View details for DOI 10.1016/j.juro.2008.09.041

    View details for Web of Science ID 000261705900175

    View details for PubMedID 19013591

  • Periconceptional glycaemic load and intake of sugars and their association with neural tube defects in offspring PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Siega-Riz, A. M. 2008; 22 (6): 514-519

    Abstract

    In a California population, we previously observed increased neural tube defect (NTD) risks associated with maternal intakes of periconceptional diets predicting higher glycaemic responses and higher sucrose. Our objective here was to replicate these results in a larger study of multiple regions within the United States. This population-based case-control study included deliveries from 1997 to 2003 from the National Birth Defects Prevention Study. NTD cases were infants or fetuses born with spina bifida or anencephaly. Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. There were 720 NTD case and 4699 control mothers with completed interviews included in analyses. Diet was assessed using a 58-item food frequency questionnaire focusing on the year before conception, whereas cereals, beverages and supplement use was assessed periconceptionally. We found no increased risks of NTD-affected pregnancies with increased intakes (adjusted for kcal/day) of sucrose, glucose, fructose or with maternal diets with a higher glycaemic load. The reasons for current findings to be inconsistent with previous findings are unknown.

    View details for DOI 10.1111/j.1365-3016.2008.00964.x

    View details for Web of Science ID 000259818200003

    View details for PubMedID 19000288

  • Markers of Acculturation and Risk of NTDs among Hispanic Women in California BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Song, J., Abrams, B. 2008; 82 (11): 755-762

    Abstract

    Prevalences of NTDs are typically 50-100% greater among Hispanic women compared to non-Hispanic Whites. This article examines whether markers of acculturation such as "language preference" allow the identification of high-risk groups within the Hispanic population. It also examines whether known NTD risk factors explain observed differences in risk among Hispanic women who are more and less acculturated.This population-based case-control study of deliveries in selected California counties from 1999-2003 included 337 NTD cases and 626 nonmalformed, liveborn controls.Relative to less acculturated US-born Hispanic women (i.e., women who preferred reading and speaking Spanish), other subgroups (i.e., US-born Hispanic women who preferred English, foreign-born Hispanic women regardless of "language preference", and non-Hispanic White women) had approximately twofold increased risks of spina bifida. Only the less acculturated foreign-born women (i.e., women with a preference for Spanish) had substantially increased risk of anencephaly (OR 1.7; 95% CI 0.9, 3.4). Adjustment for several NTD risk factors (maternal intake of folic acid-containing supplements, dietary folate intake, body mass index, food insecurity, stressful life events, smoking, alcohol intake, education, income, and neighborhood education and poverty) resulted in modest or no reductions in most of the ORs.The explanation for variability in NTD risks among Hispanic and non-Hispanic White women therefore likely extends beyond most known NTD risk factors.

    View details for DOI 10.1002/bdra.20517

    View details for Web of Science ID 000261567200004

    View details for PubMedID 18985703

  • Autoantibodies to folate receptor during pregnancy and neural tube defect risk JOURNAL OF REPRODUCTIVE IMMUNOLOGY Cabrera, R. M., Shaw, G. M., Ballard, J. L., Carmichael, S. L., Yang, W., Lammer, E. J., Finnell, R. H. 2008; 79 (1): 85-92

    Abstract

    Periconceptional folic acid can reduce the occurrence of neural tube defects (NTDs) by up to 70%, and autoantibodies for folate receptors (FRs) have been observed in serum from women with a pregnancy complicated by an NTD. This population-based cohort study has examined serum from pregnant mothers for autoantibodies to FRs, antibodies to bovine folate binding protein (FBP), and inhibition of folic acid binding to FR and FBP in association with NTD risk. The mid-gestational maternal serum specimens used for this study were collected during the 15-18th week of pregnancy. Samples were obtained from the California Birth Defects Monitoring Program; 29 mothers had a pregnancy complicated by spina bifida and 76 mothers had unaffected children. The presence of IgG and IgM antibodies to human FR, bovine FBP, and inhibition of folic acid binding to FR and FBP was determined. Higher activity of IgM to FBP in cases verses controls was observed (P=0.04). Higher activity of IgM and IgG autoantibodies to FR was observed (P<0.001 and P=0.04, respectively). Risk estimates at two standard deviations above average control antibody concentrations were OR=2.07 (CI=1.02, 4.06) for anti-FBP IgM, OR=2.15 (CI=1.02, 4.69) for anti-FR IgG and OR=3.19 (CI=1.47, 6.92) for anti-FR IgM. These data support the hypothesis that high titers of antibodies and blocking of folic acid binding to FRs by maternal serum should be regarded as risk factors for NTDs.

    View details for DOI 10.1016/j.jri.2008.08.002

    View details for Web of Science ID 000260989000012

    View details for PubMedID 18804286

  • NTD prevalences in central California before and after folic acid fortification International Neural Tube Defect Meeting Chen, B. H., Carmichael, S. L., Selvin, S., Abrams, B., Shaw, G. M. WILEY-BLACKWELL. 2008: 547–52

    Abstract

    In many regions, NTD prevalences were already declining prior to folic acid fortification. This study examined whether the declining prefortification (1989-1996) NTD prevalences continued into the postfortification period (1998-2003) in selected California counties.This population-based study used vital statistics data and birth defects registry data that were actively ascertained from medical records. The study population included all live births and stillbirths delivered in central California counties from 1989 to 2003. Cases included deliveries with NTDs during the same time period.For all NTDs combined, the slopes indicated that NTD prevalence was decreasing by 7.5 (slope: -7.5; 95% CI: -12.4, -2.5) cases per 100,000 deliveries per year before fortification, whereas NTD prevalence was no longer decreasing after fortification. Comparison of the difference in the two slopes indicated that the postfortification slope exceeded the prefortification slope by 12.6 (95% CI: 2.6, 22.6) cases per 100,000 deliveries per year.Annual NTD prevalences in central California did not continue to decrease after implementation of folic acid fortification.

    View details for DOI 10.1002/bdra.20466

    View details for Web of Science ID 000258763500001

    View details for PubMedID 18496833

  • Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies 20th Annual Meeting of the Society-for-Pediatric-and-Perinatal-Epidemiologic-Research Grewal, J., Carmichael, S. L., Ma, C., Lammer, E. J., Shaw, G. M. WILEY-BLACKWELL. 2008: 519–26

    Abstract

    This study examined the association between maternal smoking and alcohol use (including binge drinking) during the periconceptional period (i.e., 2 months before through 2 months after conception) and the risk of orofacial clefts, NTDs, and conotruncal heart defects in offspring.Data were drawn from a population-based case-control study of fetuses and live-born infants among a cohort of California births between July 1999 and June 2003. The 1,355 cases comprised of 701 orofacial clefts, 337 NTDs, and 323 conotruncal heart defects. Information on smoking and alcohol consumption was obtained via telephone interviews with mothers of 1,355 (80% of eligibles) cases and 700 (77% of eligibles) nonmalformed, live-born controls.Maternal smoking of five cigarettes or less per day was associated with reduced risks of NTDs (OR 0.7; 95% CI: 0.3, 1.4), whereas the risk associated with higher cigarette consumption was lower for conotruncal heart defects (OR 0.5; 95% CI: 0.2, 1.2). Maternal intake of alcohol less than 1 day per week was associated with a 1.6- to 2.1-fold higher risk of NTDs (95% CI: 0.9, 2.6), d-transposition of the great arteries (95% CI: 1.1, 3.2), and multiple cleft lip with or without cleft palate (CLP) (95% CI: 0.8, 4.5). Risks associated with more frequent alcohol intake were 2.1 for NTDs (95% CI: 1.1, 4.0) and 2.6 for multiple CLP (95% CI: 1.1, 6.1).This study observed that maternal alcohol intake increased the risk for d-transposition of the great arteries, NTDs, and multiple CLP in infants. By contrast, smoking was associated with a lower risk of NTDs and conotruncal heart defects.

    View details for DOI 10.1002/bdra.20461

    View details for Web of Science ID 000257906800004

    View details for PubMedID 18481814

  • Nutrient intakes in women and congenital diaphragmatic hernia in their offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, W., Shaw, G. M., Carmichael, S. L., Rasmussen, S. A., Waller, D. K., Pober, B. R., Anderka, M. 2008; 82 (3): 131-138

    Abstract

    Congenital diaphragmatic hernia (CDH) is a severe birth defect where there is an opening in the diaphragm through which a portion of the abdominal contents protrudes into the thoracic cavity. The etiologies of CDH remain unknown, although experimental animal data suggest dietary factors might play a role. This study examined whether maternal nutrient intakes were associated with delivering infants with CDH.We analyzed infants with isolated CDH who were born from 1997 to 2003 and recruited into the National Birth Defects Prevention Study (NBDPS), a multisite, population-based case-control study. Exposure data were obtained from telephone interviews, which were completed within 24 months after delivery, and were available for 377 case mothers and 5,008 control mothers. A food frequency questionnaire was used to derive nutrient intakes during the year before pregnancy.A crude OR of 0.6 (95% CI: 0.3-1.0) was observed for higher intake of choline. Elevated ORs (1.4 to 1.7) were found for lower intakes of choline, cysteine, methionine, and protein. Among women who took vitamin supplements, higher intakes of B vitamins (i.e., folate, vitamin B1, B2, B6, and B12), minerals (i.e., calcium, iron, magnesium, and zinc), and vitamin E were inversely associated with CDH (ORs from 0.7-0.3). Moreover, among women who did not take vitamin supplements, lower intakes of calcium, retinol, selenium, vitamin B12, and vitamin E had positive associations with CDH (ORs from 1.4 to 2.1).Our observations contribute to a limited body of evidence suggesting a woman's periconceptional diet might be associated with CDH in her offspring.

    View details for DOI 10.1002/bdra.20436

    View details for Web of Science ID 000254601400002

    View details for PubMedID 18181217

  • Craniosynostosis and maternal smoking 47th Annual Meeting of the Teratology-Society Carmichael, S. L., Ma, C., Rasmussen, S. A., Honein, M. A., Lammer, E. J., Shaw, G. M. WILEY-BLACKWELL. 2008: 78–85

    Abstract

    Several previous studies suggested increased risk of craniosynostosis among infants born to women who smoked.This study used data from the National Birth Defects Prevention Study, a multi-state, population-based case-control study of infants delivered from 1997-2003. Nonmalformed, liveborn controls were selected randomly from birth certificates or birth hospitals. Data from maternal telephone interviews were available for 531 cases and 5008 controls.Smoking during the first month of pregnancy was not associated with craniosynostosis. Smoking later in pregnancy was associated with increased risk, but only among mothers who smoked at least one pack/day. For example, during the second trimester, the odds ratio for smoking <5 cigarettes/day was 1.0 (95% confidence interval [CI] 0.6, 1.8), but the odds ratio (OR) for smoking 15 or more cigarettes/day was 1.6 (95% CI 0.9, 2.8), after adjustment for maternal age, education, race-ethnicity, sub-fertility, parity, folic acid supplement intake, body mass index, and study center. Among women who did not smoke, adjusted odds ratios suggested that secondhand smoke exposure at home, but not at work/school, was associated with modestly increased risk; the OR for home exposure was 1.3 (95% CI 0.9, 1.9). Results followed a similar pattern for some, but not all, specific suture types, but numbers for some groupings were small.The results suggest moderately increased risk of craniosynostosis among mothers who were the heaviest smokers and who continued to smoke after the first trimester. Results are somewhat equivocal, given that most confidence intervals included one.

    View details for DOI 10.1002/bdra.20426

    View details for Web of Science ID 000253624800002

    View details for PubMedID 18050313

  • Socioeconomic status in relation to selected birth defects in a large multicentered US case-control study AMERICAN JOURNAL OF EPIDEMIOLOGY Yang, J., Carmichael, S. L., Canfield, M., Song, J., Shaw, G. M. 2008; 167 (2): 145-154

    Abstract

    This study examined individual and household socioeconomic status (SES) in relation to phenotypes of neural tube defects, orafacial clefts, and conotruncal heart defects using data from the National Birth Defects Prevention Study with 2,551 nonmalformed liveborn controls and 1,841 cases delivered in 1997-2000. The individual SES was measured by maternal and paternal education, occupation, and household income. All individual SES measures were combined to create a household SES index. Elevated risks were found for maternal low education in association with anencephaly and dextrotransposition of the great arteries (dTGA) (adjusted odds ratios (AORs) > or = 1.4); paternal low education in association with anencephaly, cleft palate, tetralogy of Fallot (TOF), and dTGA (AORs > or = 1.4); low household income in association with TOF (AOR = 1.4, 95% confidence interval (CI): 0.8, 2.5); maternal operator/laborer occupation in association with cleft palate, TOF, and dTGA (AORs > or = 1.4); paternal operator/laborer occupation in association with spina bifida (AOR = 1.4, 95% CI: 1.0, 2.0); and either parent's unemployment in association with dTGA (AOR > or = 1.4). Subjects with the lowest household SES index had the greatest risks of all selected birth defects except TOF. This study reveals consistently increased risks of selected birth defects in association with household SES index but not individual SES measures.

    View details for DOI 10.1093/aje/kwm283

    View details for Web of Science ID 000252498200003

    View details for PubMedID 17947220

  • Maternal corticosteroid use and orofacial clefts AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Carmichael, S. L., Shaw, G. M., Ma, C., Werler, M. M., Rasmussen, S. A., Lammer, E. J. 2007; 197 (6)

    Abstract

    The purpose of this study was to examine whether maternal corticosteroid use during pregnancy is associated with delivering an infant with an orofacial cleft.This study included data on deliveries from the National Birth Defects Prevention Study, which is a population-based case-control study. Exposures were assessed by telephone interviews for mothers of 1141 cases with cleft lip +/- cleft palate (CLP), 628 with cleft palate (CP), and 4143 controls.Mothers of 33 infants with CLP (2.9%), mothers of 6 infants with CP (1.0%), and 72 control subjects (1.7%) reported corticosteroid use from 4 weeks before through 12 weeks after conception. The crude odds ratio for "any" vs "no" use was 1.7 (95% CI, 1.1-2.6) for CLP and 0.5 (0.2-1.3) for CP. When analyzed by route of administration and medication components, odds ratios for CLP tended to be elevated, and odds ratios for CP tended to be close to 1.Our results suggest a moderately increased risk of CLP among women who use corticosteroids during early pregnancy.

    View details for DOI 10.1016/j.ajog.2007.05.046

    View details for Web of Science ID 000251675700008

    View details for PubMedID 18060943

  • Nutrient intakes in women and risks of anophthalmia and microphthalmia in their offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Louik, C., Finnell, R. H., Lammer, E. J. 2007; 79 (10): 708-713

    Abstract

    There is a paucity of information about risk factors for the human eye anomalies anophthalmia and microphthalmia. In this population-based case-control study we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, vitamin A, and several other nutrients were associated with these eye defects.This study included data on deliveries that had estimated due dates from 1997-2002 and were part of the National Birth Defects Prevention Study (the National Birth Defects Prevention Study is a population-based case-control study of a wide spectrum of birth defects, incorporating data from 10 birth defects surveillance systems in the United States [Arkansas, California, Georgia/Centers for Disease Control and Prevention, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah]). Cases were those infants or fetuses born with either anophthalmia or microphthalmia. Liveborn infants without major malformations were eligible as controls. Maternal interviews were conducted, primarily by telephone, in English or Spanish. Participation in the interview was 71% among case mothers and 68% among control mothers. Interviews were completed with 89 case mothers and 4,143 control mothers. A shortened version of the food frequency questionnaire from the Nurse's Health Study was used to assess frequency of intake of 58 food items during the year before pregnancy.Our results did not indicate reduced risks for these eye malformations associated with maternal intake of vitamin supplements containing folic acid. The data did not show an association between malformation risk and higher or lower intakes of vitamin A. We also did not observe strong evidence that an abundance or a lack of dietary intake of any other nutrient was associated with increased risk of the studied eye malformations.Our observations contribute to a limited body of findings on these rare eye defects.

    View details for DOI 10.1002/bdra.20398

    View details for Web of Science ID 000250222400007

    View details for PubMedID 17847120

  • Association between 49 infant gene polymorphisms and preterm delivery AMERICAN JOURNAL OF MEDICAL GENETICS PART A Chen, B. H., Carmichael, S. L., Shaw, G. M., Iovannisci, D. M., Lammer, E. J. 2007; 143A (17): 1990-1996

    Abstract

    The occurrence of preterm delivery has been increasing in the U.S. Previous studies have identified risk factors for preterm delivery that may have genetic influences. We conducted a case-control study comparing the frequencies of 49 genetic polymorphisms among 62 preterm infants and 553 term infants. The polymorphisms that we examined were involved in xenobiotic-metabolism, blood pressure, coagulation, the inflammatory response, cell-cell interaction, or folate-homocysteine metabolism. Univariate analyses on the individual polymorphisms revealed a statistically significant effect for the variant genotypes compared to the wildtype genotypes in SERPINE1 11053G > T (OR = 0.4, 95% CI = 0.2-0.8). This finding suggests the coagulation/thrombophilic pathway may influence the development of preterm delivery.

    View details for DOI 10.1002/ajmg.a31868

    View details for Web of Science ID 000249173900007

    View details for PubMedID 17676631

  • Maternal food insecurity is associated with increased risk of certain birth defects JOURNAL OF NUTRITION Carmichael, S. L., Yang, W., Herring, A., Abrams, B., Shaw, G. M. 2007; 137 (9): 2087-2092

    Abstract

    Food insecurity represents a lack of access to enough food to meet basic needs. We hypothesized that food insecurity may increase birth defect risks, because it is an indicator of increased stress or compromised nutrition, which are both implicated in birth defect etiologies. This study used population-based case-control data. Included in the analysis were 1,189 case mothers and 695 control mothers who were interviewed by telephone. We calculated a food insecurity score as the number of affirmative responses to 5 questions from a shortened instrument designed to measure food insecurity. OR for the food insecurity score specified as a linear term indicated that a higher score was associated with increased risk of cleft palate, d-transposition of the great arteries, tetralogy of Fallot, spina bifida, and anencephaly, but not with cleft lip with or without cleft palate, after adjustment for maternal race-ethnicity, education, BMI, intake of folic acid-containing supplements, dietary intake of folate and energy, neighborhood crime, and stressful life events. In addition, several models suggested effect modification by certain factors. For example, for anencephaly, among women with the worst score for neighborhood crime (i.e. 6), the OR associated with a 1-unit change in the food insecurity score was 1.57 (95% CI 1.06, 2.33), whereas among women with a low crime score (i.e. 2), the corresponding OR was 1.16 (95% CI 0.96, 1.38). This study suggests that increased risks of certain birth defects may be included among the negative consequences of food insecurity.

    View details for Web of Science ID 000249110600016

    View details for PubMedID 17709447

  • Maternal thyroid disease as a risk factor for craniosynostosis 27th David W Smith Workshop on Malformations and Morphogenesis Rasmussen, S. A., Yazdy, M. M., Carmichael, S. L., Jamieson, D. J., Canfield, M. A., Honein, M. A. LIPPINCOTT WILLIAMS & WILKINS. 2007: 369–77

    Abstract

    To study the relationship between maternal thyroid disease and craniosynostosis using data from the National Birth Defects Prevention Study, a multisite, case-control study.Case infants (n=431) were identified through population-based birth defects surveillance systems at eight sites and had craniosynostosis verified by radiographic imaging. Control infants (n=4,094) consisted of a random sample of live births with no major birth defects from the same population as the case infants. Information on thyroid disease was based on self-report: mothers who reported either a thyroid disorder or use of a medication to treat a thyroid disorder during pregnancy were considered to have thyroid disease. Using an unconditional logistic regression model, we considered potential confounding factors (maternal age, race or ethnicity, smoking, body mass index, preexisting diabetes, plurality, gravidity, family history, infant sex).Among case mothers, 19 (4.4%) were classified as having thyroid disease, compared with 65 (1.6%) of control mothers. Maternal thyroid disease was associated with craniosynostosis after controlling for maternal age (adjusted odds ratio 2.47, 95% confidence interval 1.46-4.18), the only factor that remained significant in the final model.These data provide additional evidence that maternal thyroid disease (most likely Graves' disease) or its treatment is associated with craniosynostosis. Given the frequency of maternal thyroid disease, this association warrants further investigation.II.

    View details for Web of Science ID 000248290500021

    View details for PubMedID 17666613

  • Maternal stressful life events and risks of birth defects EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Yang, W., Abrams, B., Lammer, E. J. 2007; 18 (3): 356-361

    Abstract

    Several previous studies suggest that maternal stress may be associated with increased risk of certain birth defects. This study examined the association of maternal stressful life events with risks of several birth defects.The data are from a recent, population-based case-control study. Telephone interviews were conducted with 1355 eligible case mothers and 700 control mothers. Maternal stress was measured by responses to 18 yes/no questions about life events that occurred from 2 months before through 2 months after conception.An increase in the stressful life events index (ie, number of "yes" responses to the 18 life-events questions) was associated with increased risk of cleft palate, cleft lip with or without cleft palate, d-transposition of the great arteries, and tetralogy of Fallot, after adjustment for maternal race-ethnicity, education, obesity, age, smoking, drinking, intake of folic acid-containing supplements, neighborhood crime, and food insecurity. For example, the odds ratio for a 3-unit change in the stress index was 1.45 (95% confidence interval = 1.03-2.06) for cleft palate. Increased stress was associated with an increased risk of spina bifida and anencephaly particularly among women who did not take folic acid supplements. A 3-unit change in stress was associated with a 2.35-fold increased risk of anencephaly among women who did not take supplements (CI =1.47-3.77) and a 1.42-fold increased risk among women who did (CI = 0.89-2.25).The adverse health effects of stress may include increased risks of certain birth defects.

    View details for DOI 10.1097/01.ede.0000259986.85239.87

    View details for Web of Science ID 000245993300010

    View details for PubMedID 17435445

  • Maternal reproductive and demographic characteristics as risk factors for hypospadias PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Laurent, C., Olney, R. S., Lammer, E. J. 2007; 21 (3): 210-218

    Abstract

    This study examined the association of hypospadias risk with several maternal reproductive and demographic characteristics: age, parity, body mass index (BMI), nausea and vomiting of pregnancy (NVP), multiple pregnancy, fertility treatments and procedures, education and race-ethnicity. The study included data on deliveries with estimated due dates from October 1997 to December 2000 that were part of the National Birth Defects Prevention Study, a multi-state case-control study of many birth defects. The analysis included 502 cases with second or third degree hypospadias (i.e. the urethra opened at the penile shaft, scrotum or perineum) and 1286 male, liveborn, non-malformed controls. Risks were estimated from a multivariable logistic regression model that included all exposures of interest. Results indicated particularly elevated risks among births to women who were primiparae, aged >or=35 years and had a BMI of >26, compared with women who were multiparae, aged <30 years and had a BMI of

    View details for Web of Science ID 000245676100003

    View details for PubMedID 17439529

  • Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Cheng, S., Lammer, E. J. 2006; 140A (22): 2433-2440
  • Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Yang, W., Iovannisci, D. M., Lammer, E. 2006; 140A (18): 1915-1922
  • Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake. American journal of medical genetics. Part A Carmichael, S. L., Shaw, G. M., Yang, W., Iovannisci, D. M., Lammer, E. 2006; 140 (18): 1915-1922

    Abstract

    Increasing epidemiologic evidence suggests that genetic susceptibilities contribute to birth defects risks, especially in combination with other environmental exposures. This analysis examines the association of risk of limb deficiency defects with infant genotypes for N-acetyltranferases (NAT1, NAT2), glutathione-S-tranferases (GSTT1, GSTM1), and endothelial nitric oxide synthase (NOS3). The combined effects of infant genotype with maternal smoking and supplement intake were also examined. The authors genotyped 92 cases and 201 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Several of the infant genotypes were associated with an at least 1.5-fold increased risk for limb deficiency defects: homozygosity for the NAT1 1088 and 1095 polymorphisms, heterozygosity and homozygosity for the NOS3 A(-922)G polymorphism, and heterozygosity (but not homozygosity) for the NOS3 G894T polymorphism. The authors hypothesized that the effects of selected variant genotypes in the presence of maternal smoking, or in the absence of supplement intake, may exceed effects of any of these factors alone. A few observations suggested that risks were greatest among infants with variant genotypes, whose mothers also smoked or did not take supplements, but most did not, and risk estimates were imprecise. Further studies exploring genetic susceptibility and combined gene-environment effects with respect to limb development will be important to continued improvement of our understanding of the etiology of limb anomalies.

    View details for PubMedID 16906563

  • Maternal nutrient intakes and risk of orofacial clefts EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Rasmussen, S. A. 2006; 17 (3): 285-291

    Abstract

    Information about nutritional factors as potential risks of orofacial clefts is limited.In this population-based case-control study, we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, and several other nutrients were associated with orofacial clefts. We included data on deliveries from 1997 through 2000 in the National Birth Defects Prevention Study. Orofacial cleft cases were infants or fetuses born with cleft palate (CP) or with cleft lip with or without cleft palate (CLP). Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. Interviews were completed for 704 CLP cases, 404 CP cases, and 2594 controls.The odds ratio (OR) for CLP associated with use of vitamin supplements containing folic acid was 0.88 (95% confidence interval = 0.73-1.07) and for CP was 1.09 (0.84-1.40). Adjusting for maternal race/ethnicity, age, and education produced an OR of 1.01 (0.82-1.24) for CLP and 1.02 (0.77-1.34) for CP. We found some evidence for decreased CLP risks (>or=30% reduction in risk) with increasing intakes of total protein, choline, and methionine. Decreased CP risk was associated with increased intake of cysteine. Intakes of only 2 micronutrients, iron and riboflavin, were found to reduce CLP risk when adjusted for other nutrients.Our observations contribute to the limited body of evidence suggesting a woman's periconceptional diet may influence clefting risks in her offspring. Our finding of no reduction in clefting risk with periconceptional use of supplements containing folic acid is inconsistent with many previous observations but not all.

    View details for DOI 10.1097/01.ede.0000208348.30012..35

    View details for Web of Science ID 000236926500014

    View details for PubMedID 16570024

  • Correlates of intake of folic acid-containing supplements among pregnant women AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Carmichael, S. L., Shaw, G. M., Yang, W., Laurent, C., Herring, A., Royle, M. H., Canfield, M. 2006; 194 (1): 203-210

    Abstract

    This study describes the timing and correlates of folic acid supplement intake among pregnant women.Data from 2518 women with estimated delivery dates from 1997 to 2000, collected for the National Birth Defects Prevention Study, a population-based case-control study, were analyzed. Multinomial logistic regression was used to identify correlates of supplement intake.Fifty-three percent of women began taking folic acid supplement during the periconceptional period, 35% during early pregnancy, and 8% during late pregnancy (ie, 3 months before through 1 month after conception, 2-3 months after conception, or more than 3 months after conception, respectively). Women who did not take folic acid supplement periconceptionally tended to be nonwhite, speak Spanish, have low education, be younger than 25 years old, be nulliparous, smoke, have no previous miscarriage and no fertility treatments, begin prenatal care and become aware of their pregnancy after the first trimester, have nonplanned pregnancies, and eat less breakfast cereal.This study identifies correlates of folic acid supplement intake, which may contribute to the design of interventions to improve intake during early pregnancy.

    View details for DOI 10.1016/j.ajog.2005.06.018

    View details for Web of Science ID 000234386200031

    View details for PubMedID 16389033

  • Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Carmichael, S. L., Cheng, S., Lammer, E. J. 2005; 162 (12): 1207-1214

    Abstract

    Orofacial clefts have been associated with maternal cigarette smoking and lack of folic acid supplementation (which results in higher plasma homocysteine concentrations). Because endothelial nitric oxide synthase (NOS3) activity influences homocysteine concentration and because smoking compromises NOS3 activity, genetic variation in NOS3 might interact with smoking and folic acid use in clefting risk. The authors genotyped 244 infants with isolated cleft lip with or without cleft palate (CL/P), 99 with isolated cleft palate, and 588 controls from a California population-based case-control study (1987-1989 birth cohort) for two NOS3 polymorphisms: A(-922)G and G894T. Analyses of gene-only effects for each polymorphism revealed a 60% increased risk of CL/P among NOS3 A(-922)G homozygotes (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.6). There was some evidence for higher risk of CL/P with maternal periconceptional smoking in infants with an NOS3 -922G allele (for homozygotes, OR = 2.5, 95% CI: 1.2, 5.6) but not in those with an 894T allele. For CL/P risk, odds ratios were over 4 among mothers who smoked, who did not use vitamins, and whose infants had at least one variant allele for each NOS3 polymorphism (for A(-922)G, OR = 4.6, 95% CI: 2.1, 10.2; for 894T, OR = 4.4, 95% CI: 1.8, 10.7). No similar patterns were observed for risk of cleft palate.

    View details for DOI 10.1093/aje/kwi336

    View details for Web of Science ID 000233850400009

    View details for PubMedID 16269583

  • Hypospadias and maternal exposures to cigarette smoke PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Laurent, C., Lammer, E. J., Olney, R. S. 2005; 19 (6): 406-412

    Abstract

    The few previous studies of hypospadias and smoking have suggested either no association or a reduced risk. This study, which uses data from the National Birth Defects Prevention Study, a multi-state, population-based case-control study, includes data on males born with severe hypospadias (i.e. the urethra opens at the penile shaft, scrotum or perineum) from 1997 to 2000. Non-malformed, liveborn male controls were selected randomly from birth certificates or from birth hospitals. Maternal interviews were completed by telephone with 453 case mothers and 1267 control mothers. Maternal smoking was not associated with hypospadias risk. For example, during the third month of pregnancy, smoking < 0.5 pack/day had an odds ratio (OR) of 1.1 [95% CI 0.6, 1.9]; 0.5 pack/day, 0.6 [0.4, 1.1]; and > or = 1 pack/day, 0.8 [0.4, 1.6]. Exposure to any secondhand smoke at home during the third month of pregnancy showed an OR of 0.6 [95% CI 0.4, 1.0], and exposure at work or school, an OR of 0.7 [0.5, 1.1]. Similar risks were observed for other months during the periconceptional period, and adjustment for several potential confounders did not substantially alter results. This analysis does not confirm a recent report suggesting that maternal smoking is associated with a reduced risk of having offspring with hypospadias.

    View details for Web of Science ID 000233020700002

    View details for PubMedID 16269066

  • Maternal progestin intake and risk of hypospadias ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Carmichael, S. L., Shaw, G. M., Laurent, C., Croughan, M. S., Olney, R. S., Lammer, E. J. 2005; 159 (10): 957-962

    Abstract

    Previous studies have suggested that maternal intake of progestins during early pregnancy may be associated with an increased risk of hypospadias. Progesterone and its derivatives are commonly prescribed during early pregnancy, for example, in cases of luteal phase dysfunction and in conjunction with ovulation stimulation drugs.To examine whether risk of hypospadias was associated with periconceptional progestin intake.The National Birth Defects Prevention Study, a population-based, multistate, case-control study including deliveries that had estimated due dates from October, 1997 to December, 2000.Participation in the study was 71% among case mothers and 68% among control mothers. This analysis included 502 subjects diagnosed with second- or third-degree hypospadias (ie, the urethra opened at the penile shaft, scrotum, or perineum) and 1286 male, live-born, nonmalformed control subjects.Forty-two case mothers (8.4%) and 31 control mothers (2.4%) reported any pregnancy-related progestin intake from 4 weeks before through 14 weeks after conception, resulting in an odds ratio of 3.7 (95% confidence interval [CI], 2.3-6.0). Analyses stratified by several potential covariates also suggested elevated risks. For example, among the 10 cases and 13 controls who did not report any fertility-related procedures or treatments other than progestins, the odds ratio was 2.2 (95% CI, 1.0-5.0). Progestin intake for the purpose of contraception was not associated with increased risk.This study found that pregnancy-related intake of progestins was associated with increased hypospadias risk.

    View details for Web of Science ID 000232322000008

    View details for PubMedID 16203941

  • Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Carmichael, S. L., Cheng, S., Lammer, E. J. 2005; 138A (1): 21-26
  • Epidemiologic characteristics of anophthalmia and bilateral microphthalmia among 2.5 million births in California, 1989-1997 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Carmichael, S. L., Yang, W., Harris, J. A., Finnell, R. H., Lammer, E. J. 2005; 137A (1): 36-40
  • Periconceptional dietary intake of myo-inositol and neural tube defects in offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Schaffer, D. M. 2005; 73 (3): 184-187

    Abstract

    Periconceptional intake of nutrients in addition to folic acid may contribute to neural tube defect (NTD) etiologies; a likely candidate is myo-inositol. We investigated whether maternal periconceptional dietary intake of myo-inositol influenced NTD risk.Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 454 NTD cases and with mothers of 462 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess nutrient intake.We observed small increases in risk, with increases slightly more evident for anencephaly, associated with intakes of myo-inositol less than the highest intake quartile, e.g., risk of anencephaly was 1.3 (0.7-2.4) among fetuses whose mothers consumed lowest versus highest intakes of myo-inositol. These small increases, however, were imprecise, and also did not indicate increasing risk with decreasing level of myo-inositol intake. Adjusted risk estimates did not differ considerably from their unadjusted counterparts.Our results do not indicate that myo-inositol intake, as measured in this study, is strongly associated with risk of human NTDs.

    View details for DOI 10.1002/bdra.20112

    View details for Web of Science ID 000228049200010

    View details for PubMedID 15744734

  • Risks of selected congenital malformations among offspring of mixed race-ethnicity BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, J., Carmichael, S. L., Kaidarova, Z., Shaw, G. M. 2004; 70 (10): 820-824

    Abstract

    Little is known about the occurrence of specific congenital malformations among offspring of mixed race-ethnicity.Using data from a population-based registry, we explored the occurrence of selected malformation phenotypes in offspring to parents who were of different race-ethnicity. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.6 million live births and stillbirths occurred during 1989-2000. Information on parental race-ethnicity (non-Hispanic white, Hispanic, black, and Asian) was obtained from birth certificates and fetal death files. Malformation phenotypes studied were spina bifida, anencephaly, cleft lip, cleft palate, tetralogy of Fallot, d-transposition of great arteries, hypospadias, small intestinal atresia, preaxial polydactyly, microtia, and hypertrophic pyloric stenosis.A total of 11.2% of births were to parents of mixed race-ethnicity. Compared to births of parents who were both white, moderately increased risks (risk ratio >/= 1.7) of anencephaly, polydactyly, and microtia, and decreased risks (risk ratio

    View details for DOI 10.1002/bdra.20025

    View details for Web of Science ID 000224970800005

    View details for PubMedID 15390318

  • Gene-nutrient interactions: importance of folates and retinoids during early embryogenesis TOXICOLOGY AND APPLIED PHARMACOLOGY Finnell, R. H., Shaw, G. M., Lammer, E. J., Brandl, K. L., Carmichael, S. L., Rosenquist, T. H. 2004; 198 (2): 75-85

    Abstract

    The role that nutritional factors play in mammalian development has received renewed attention over the past two decades, as the scientific literature exploded with reports of retinoid compounds disrupting craniofacial development, and with other reports that folic acid supplementation in the periconceptional period can protect embryos from highly significant malformations. As was often the case, the situation became far more complicated, as the interaction between nutritional factors with selected genes was recognized. In this review, we attempt to summarize a complex clinical and experimental literature of nutritional factors, their biological transport mechanisms, and the impact that they have during early embryogenesis. Although not exhaustive, our goal was to provide an overview of important gene-nutrient interactions and a framework for their investigation.

    View details for DOI 10.1016/j.taap.2003.09.031

    View details for Web of Science ID 000222713900001

    View details for PubMedID 15236946

  • Periconceptional dietary intake of choline and betaine and neural tube defects in offspring AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Selvin, S., Schaffer, D. M. 2004; 160 (2): 102-109

    Abstract

    Periconceptional intake of folic acid prevents some neural tube defects (NTDs). Other nutrients may also contribute to NTD etiologies; a likely candidate is choline. Similar to folic acid, choline is involved in one-carbon metabolism for methylation of homocysteine to methionine. The authors investigated whether maternal periconceptional dietary intakes of choline and its metabolite betaine influence NTD risk. Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. In-person interviews were conducted with mothers of 424 NTD cases and with mothers of 440 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess nutrient intake. Dietary intakes of choline were associated with reduced NTD risks. Controlling for intake of supplemental folic acid, dietary folate, dietary methionine, and other covariates did not substantially influence risk estimates for choline. NTD risk estimates were lowest for women whose diets were rich in choline, betaine, and methionine. That is, for women whose intake was above the 75th percentile compared with below the 25th percentile for all three nutrients, the odds ratio was 0.17 (95% confidence interval: 0.04, 0.76). Study findings for dietary components other than folic acid offer additional clues about the complex etiologies of NTDs.

    View details for DOI 10.1093/aje/kwh187

    View details for Web of Science ID 000222556600002

    View details for PubMedID 15234930

  • Epidemiologic characteristics of anotia and microtia in California, 1989-1997 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Kaidarova, Z., Harris, J. A. 2004; 70 (7): 472-475

    Abstract

    There is a paucity of epidemiologic information about the external ear malformations anotia and microtia.Using data from a large population-based registry, we explored prevalences and maternal/infant characteristics associated with anotia and microtia. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.5 million births (live-born and stillborn) occurred during the ascertainment period, 1989-1997. Information on maternal and infant/fetal characteristics was obtained from California birth certificate and fetal death files.The prevalence of anotia/microtia was 2.50 per 10,000 live births and stillbirths. Isolated cases, i.e., those live births and stillbirths with no other accompanying anomaly diagnoses, revealed a prevalence of 0.63 per 10,000, whereas among nonisolated cases, the prevalence was 1.53 per 10,000 live births and stillbirths. Prevalences of isolated anotia/microtia were substantially higher among U.S.-born Hispanics, foreign-born Hispanics, and Asians compared to non-Hispanic whites, with relative risks ranging from three- to seven-fold. Similar prevalences for maternal race/ethnicity (except for Asians) were observed for live births and stillbirths with nonisolated cases of anotia/microtia, but the magnitude of risks were lower than those observed for isolated cases. Prevalence of nonisolated anotia/microtia was substantially lower among women whose education was 12 years or more.These data reveal descriptive epidemiologic features of anotia/microtia most notably substantial risks associated with race/ethnic groups and lower maternal education. Additional study for factors associated with these characteristics could reveal clues for the etiology of these ear anomalies.

    View details for DOI 10.1002/bdra.20042

    View details for Web of Science ID 000222987400006

    View details for PubMedID 15259037

  • Congenital malformations in offspring of Hispanic and African-American women in California, 1989-1997 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Kaidarova, Z. 2004; 70 (6): 382-388

    Abstract

    Little is known about risks of most specific birth defects among infants born to U.S.-born and foreign-born Hispanic or African-American women.Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of U.S.-born and foreign-born Hispanic and African-American women, relative to non-Hispanic white women, in California. Approximately 2.2 million live births and stillbirths occurred during the ascertainment period, 1989-1997. Information on maternal racial-ethnic background and other covariates was obtained from birth certificate and fetal death files.Adjusted relative risks (ARRs) for the 20 groupings of malformations designated by three-digit British Pediatric Association (BPA) codes ranged from 0.6 (genital organ malformations, among infants born to foreign-born Hispanics) to 1.7 (anencephaly, also among infants born to foreign-born Hispanics). Grouping by four-digit BPA codes revealed that among infants born to U.S.-born Hispanics, 46 of the ARRs were < or = 0.8 and 12 were > or = 1.3; among infants born to foreign-born Hispanics, 75 of the ARRs were < or = 0.8 and 15 were > or = 1.3; and among infants born to African-American women, 45 ARRs were < or = 0.8 and 25 were > or = 1.3. For each racial-ethnic group of women, the observed variability in risks covered most organ systems.Although the results suggested that (in comparison with non-Hispanic whites) each racial-ethnic group was more likely to have reduced risk for specific defects (rather than elevated risk), in general, the range of the relative risks was comparatively narrow.

    View details for DOI 10.1002/bdra.20012

    View details for Web of Science ID 000222419100002

    View details for PubMedID 15211706

  • Limb deficiency defects, MSX1, and exposure to tobacco smoke AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Yang, W., Lammer, E. J., Zhu, H. P., Finnell, R. H. 2004; 125A (3): 285-289

    Abstract

    There is increasing evidence from epidemiologic studies that genetic susceptibilities may modify the teratogenic effects of smoking. A previous study suggested that maternal smoking in the presence of a dinucleotide repeat polymorphism for MSX1 produced an almost fivefold increased risk for limb anomalies, providing evidence for a gene-environment interaction. The current study examined this potential interaction, using case-control data with several methodologic improvements, including a larger sample size and more detailed information on cigarette smoke exposures. Cases (n = 92) were ascertained from pregnancies ending in 1987-1989, and controls (n = 180) were randomly selected from eligible liveborn infants. In telephone interviews, women reported smoking behaviors during the month before pregnancy through the end of the first trimester. Odds ratios (OR) for maternal and paternal smoking ranged from 1.0 to 1.4, risk estimates were imprecise; for example, the OR for maternal smoking >or=20 cigarettes per day, versus none, was 1.3 (95% confidence interval (CI) 0.5-3.4). Relative to the homozygous wildtype, the OR was 1.5 (95% CI 0.7-3.5) for the homozygous variant genotype and 0.8 (95% CI 0.5-1.4) for the heterozygous variant genotype. There was no evidence that maternal smoking or both parents smoking, in combination with a susceptible MSX1 genotype, conferred an additional increase in risk of limb defects. This study did not find a gene-environment interaction between maternal smoking, infant MSX1 CA repeat polymorphism, and risk of limb deficiency defects. This finding contrasts with results of a previous study, which provided initial evidence for such an interaction. Several important methodological differences may have contributed to the differences in findings between the two studies.

    View details for DOI 10.1002/ajmg.a.20517

    View details for Web of Science ID 000189316800011

    View details for PubMedID 14994238

  • Congenital malformations in births with orofacial clefts among 3.6 million California births, 1983-1997 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Carmichael, S. L., Yang, W., Harris, J. A., Lammer, E. J. 2004; 125A (3): 250-256

    Abstract

    Few population-based epidemiologic data are available on malformation phenotypes that co-occur with orofacial clefts. We explored the occurrence of structural congenital malformations in offspring with cleft palate (CP) and in offspring with cleft lip with or without CP (CLP), using data from a population-based active surveillance system. Ascertainment was performed among 3548991 liveborn and 23239 stillborn offspring of California women who delivered in nonmilitary hospitals during the period, 1983-1997. Structural congenital malformations were found in 91888 births. Among them, 2343 had CP and 4072 had CLP. Malformations were grouped according to 3- and 4-digit codes of the British Pediatric Association (BPA). Prevalences of each malformation grouping, defined by these codes, were calculated among: (1). all births with CP; (2). all births with CLP; (3). all births without CP or CLP but with another structural malformation; and (4). all births in the population at risk. These various prevalence measures were the basis of estimating relative risks. Observed relative risks indicated that some phenotypes were more likely and some were less likely to co-occur with either CP or CLP, with relative risks ranging from 0.5 to 2.4. For both CP and CLP, estimated relative risks were highest for malformations involving the respiratory system and lowest for spina bifida. The exclusion of all births (n = 10702) with chromosomal anomalies from comparisons did not materially alter observed relative risk estimates. Computations extended to 4-digit level BPA codes revealed elevated risks for a number of more specific diagnoses seen within the larger (3-digit level) groupings defined as eye, ear, respiratory, upper alimentary tract, and other musculoskeletal anomalies. In this large population-based cohort of infants and fetuses with CLP or CP, we observed several noncleft malformation groupings to be more common and others to be less common in their co-occurrence with orofacial clefts relative to their co-occurrence with any other malformation. These observed patterns tended to be similar for CP and for CLP.

    View details for DOI 10.1002/ajmg.a.20508

    View details for Web of Science ID 000189316800005

    View details for PubMedID 14994232

  • Occurrence of low birthweight and preterm delivery among California infants before and after compulsory food fortification with folic acid PUBLIC HEALTH REPORTS Shaw, G. M., Carmichael, S. L., Nelson, V., Selvin, S., Schaffer, D. M. 2004; 119 (2): 170-173

    Abstract

    Studies suggest that folic acid intake influences the occurrence of low birthweight and preterm delivery. Since 1998, there has been compulsory fortification of flour and other grains with folic acid in the U.S. The objective of this study was to investigate the frequencies of low birthweight and preterm delivery after mandatory folic acid fortification among approximately six million California births.The authors investigated prevalences of low birthweight and preterm delivery before and after compulsory fortification among 5,916,630 singleton California live births that occurred from January 1990 through December 2000.The unadjusted prevalences of very low birthweight, low birthweight, and preterm delivery did not substantially vary across birth years. That is, substantial decreased prevalences during the fortification period relative to the period preceding it were not observed. However, analyses that simultaneously adjusted for maternal age, parity, race/ethnicity, education, year of birth, and fortification period revealed the following relative risk ratios (RR) and 95% confidence intervals (CI): RR = 0.91, CI 0.88, 0.94 for very low birthweight, RR = 0.94; 95% CI 0.93, 0.96 for low birthweight, and RR = 0.96; 95% CI 0.94, 0.97 for preterm delivery.Findings indicate small reductions in prevalences of these outcomes associated with the timing of fortification of the U.S. food supply.

    View details for Web of Science ID 000226363500011

    View details for PubMedID 15192904

  • Differential risks to males and females for congenital malformations among 2.5 million California births, 1989-1997 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Kaidarova, Z., Harris, J. A. 2003; 67 (12): 953-958

    Abstract

    Although many studies have observed variations in the prevalence of specific malformations by sex, there is a lack of population-based data on potential malformation prevalence differences by sex at birth.Our objective was to explore differences in the prevalence of structural congenital malformation phenotypes between sexes in a California population of 2.5 million live- and stillbirths, using data from a population-based active surveillance system. Ascertainment was performed among offspring of California women who delivered in nonmilitary hospitals during the period of 1989-1997. Malformations were grouped according to the four-digit malformation codes of the British Pediatric Association.Overall, 32,619 males and 21,835 females were considered to have structural congenital malformations, with prevalences of 2.52% and 1.76%, respectively. Thus, males demonstrated a malformation prevalence that was 22% higher than that in females. Using a criterion of a 40% increase or decrease in the relative risk for males, increased risks for 15 and decreased risks for 17 specific malformation categories were observed. Increased risks were associated with most organ systems, with the notable exception of the nervous system (increased risks for nervous system malformations were observed among female births). Risks were not substantially influenced by adjusting for maternal age, race/ethnicity, parity, or education.Our observations extend the relatively few studies that have investigated differential prevalences of a large number of specific structural malformations between male and female births.

    View details for DOI 10.1002/bdra.10129

    View details for Web of Science ID 000187445400001

    View details for PubMedID 14745913

  • Socio-economic status and risk of conotruncal heart defects and orofacial clefts PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Nelson, V., Shaw, G. M., Wasserman, C. R., Croen, L. A. 2003; 17 (3): 264-271

    Abstract

    Studies of socio-economic status (SES) have figured prominently in research related to a variety of health outcomes, although the question remains as to whether SES contributes to the aetiologies of congenital anomalies. This study examines the association of SES with risks of conotruncal heart defects and orofacial clefts, using interview data from 696 case mothers (86% of eligible) and 734 (78%) control mothers from a population-based case-control study. Socio-economic measures from maternal interview included mother's education and employment. Reported addresses were linked with the US census to characterise six measures of neighbourhood SES (education, poverty, unemployment, occupation, crowding and rental occupancy). Results were adjusted for race-ethnicity, multivitamin/mineral supplement intake, cigarette smoking and binge drinking. Results for individual and neighbourhood measures suggested that low SES was associated with increased risk of d-transposition of the great arteries (dTGA), reduced risk of tetralogy of Fallot (TOF), but was not associated with risk of orofacial clefts. For example, when examining odds ratios (OR) that compared risks among women whose neighbourhoods were in the lowest vs. highest quartile of the census-based SES measures, ORs for five of the six measures were> 1.4 for dTGA, and ORs for all six measures were < 0.7 for TOF. ORs for clefts tended to be closer to 1. This study suggests that SES risks are birth defect specific.

    View details for Web of Science ID 000184158900007

    View details for PubMedID 12839538

  • Diet quality and risk of neural tube defects MEDICAL HYPOTHESES Carmichael, S. L., Shaw, G. M., Selvin, S., Schaffer, D. M. 2003; 60 (3): 351-355

    Abstract

    Many studies have examined the impact of single nutrients on neural tube defect (NTD) risk, particularly folate. The impact of dietary patterns or nutrients in combination has received much less attention. This study examines the association of diet quality with NTD risk, using food frequency data from a population-based case-control study of NTDs (n=454 cases and 462 controls). The diet quality score was based on low (<10th percentile among controls) versus high (>90th percentile) values for intakes of iron, vitamins B(6) and A, calcium, folate, and percentage of kilocalories from fat and from sweets (range=0-14). Women with a low score (i.e., <4, or <10th percentile) had an elevated risk of an NTD-affected pregnancy (odds ratio 1.6, 95% CI 1.0-2.6). Stratified analyses suggested that the effect may be restricted to certain groups of women who may be at greater nutritional risk (i.e., women who did not take vitamin supplements or regularly consume breakfast cereals before pregnancy).

    View details for DOI 10.1016/S0306-9877(02)00402-4

    View details for Web of Science ID 000181152100012

    View details for PubMedID 12581611

  • Social networks and risk of neural tube defects EUROPEAN JOURNAL OF EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Neri, E., Schaffer, D. M., Selvin, S. 2003; 18 (2): 129-133

    Abstract

    The contribution of social support and social networks to risk of neural tube defects (NTDs) has not been explored, despite evidence that various aspects of the social environment contribute to their etiology. Using data from a population-based case-control study of deliveries occurring in California from 1989 to 1991, this study investigates whether social networks, as measured by the presence and frequency of various types of social contacts, are associated with NTD risk. In-person interviews were conducted with 538 (88% of eligible) mothers of NTD cases and with mothers of 539 non-malformed controls (88%) on average 5 months from the term delivery date. Unadjusted results indicate that women who reported having close friends, close relatives, or monthly contacts with close friends or relatives had 30-70% lower risks of having NTD-affected pregnancies, relative to women reporting 'none' to any of these measures. Only the presence of close friends was associated with reduced NTD risk after adjustment for other aspects of the social network and several potential covariates. This study is the first to investigate the association between social networks and risk of NTDs. Stronger inferences await replication and extension of these results.

    View details for Web of Science ID 000182005200006

    View details for PubMedID 12733834

  • Maternal periconceptional vitamins: Interactions with selected factors and congenital anomalies? EPIDEMIOLOGY Shaw, G. M., Nelson, V., Carmichael, S. L., Lammer, E. J., Finnell, R. H., Rosenquist, T. H. 2002; 13 (6): 625-630

    Abstract

    The mechanisms by which folic acid may contribute to reductions in risk of several congenital anomalies are unknown. The data gap includes a lack of information on possible effect modification between maternal folic acid use and other maternal exposures. We hypothesized that effects of congenital anomalies associated with maternal fever, cigarette smoking or alcohol use would be modified by intake of vitamins.We explored case-control data that showed risk reductions among infants and fetuses whose mothers consumed vitamins. Data were from California deliveries of infants and fetuses in the period 1987-1989. Maternal telephone interviews were completed for 207 (87%) conotruncal cases, 489 (85%) orofacial cleft cases, 265 (84%) neural tube defect cases, 165 (82%) limb anomaly cases, and 734 controls (nonmalformed infants).Considering women who reported vitamin use and no periconceptional fever as referents, for each anomaly group we observed elevated effects for the combinations of maternal vitamin use/fever, no use/no fever and no use/fever. Effects were most elevated for the combination of no vitamin use and fever. Adjusted for maternal body mass index, education and race/ethnicity, odds ratios were 2.4 (95% confidence inter-val = 1.0-5.9) for conotruncal defects, 2.9 (1.4-5.8) for cleft lip with or without cleft palate, 1.3 (0.4-3.9) for cleft palate, 3.1 (1.4-6.8) for neural tube defects, and 2.6 (1.0-6.4) for limb-deficiency defects. These interactions were further investigated relative to maternal use of fever-reducing medications. Effects tended to be highest among those women who did not use vitamins, had fevers, and did not use fever-reducing medications. Compared with women who used vitamins and did not smoke periconceptionally, anomaly risks tended to be highest among women who did not use vitamins and smoked. No specific pattern emerged involving alcohol intake.These data further suggest that the underlying mechanisms of folic acid associated with congenital anomalies may be complex.

    View details for DOI 10.1097/01.EDE.0000032431.83648.8D

    View details for Web of Science ID 000178637200005

    View details for PubMedID 12410002

  • Congenital malformations in offspring of Vietnamese women in California, 1985-97 TERATOLOGY Shaw, G. M., Carmichael, S. L., Nelson, V. 2002; 65 (3): 121-124

    Abstract

    Little is known about reproductive outcome risks for Vietnamese women delivering infants and fetuses in the U.S.Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of Vietnamese women in California. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 3.4 million births (liveborn and stillborn) occurred during the ascertainment period, 1985-97. Information on maternal race/ethnic background was obtained from California birth certificate and fetal death files. Vietnamese women delivered 45,453 births and 1,257,853 births were delivered to non-Hispanic white women.The overall prevalence of structural congenital malformations was 1.92 among Vietnamese and 2.63 among non-Hispanic whites per 100 births and fetal deaths. Grouping by 20 3-digit malformation codes of the International Classification of Diseases-Ninth Revision revealed relative risks of 0.8 or less for spina bifida, eye, upper alimentary, genital, urinary, musculoskeletal, "other" limb, and "other" musculoskeletal anomalies, and relative risks of 1.3 or more for anencephaly and chromosomal anomalies. Grouping by the more specific 4-digit malformation codes revealed 50, among 178, malformation groupings with associated relative risks of >or=1.3 or

    View details for DOI 10.1002/tera.10020

    View details for Web of Science ID 000174119100007

    View details for PubMedID 11877775

  • Assessing combined chemical exposures as risk factors for neural tube defects REPRODUCTIVE TOXICOLOGY Shaw, G. M., Selvin, S., Carmichael, S. L., Schaffer, D. M., Nelson, V., Neri, E. 2001; 15 (6): 631-635

    Abstract

    Many studies have investigated whether chemical exposures early in pregnancy increase risks to women of delivering offspring with congenital anomalies. We investigated whether periconceptional exposures to chemicals in combination increased risks to women of having neural tube defect (NTD)-affected pregnancies. Women were asked about occupational tasks performed during the periconceptional period. These tasks were assigned by an industrial hygienist to a priori defined exposure categories. The exposure categories included 74 chemical groups. Two population-based case control studies were analyzed. Information on tasks was obtained from mothers of 538 NTD cases and their 539 controls in one study, and mothers of 265 NTD cases and 481 controls from another study. We used data from the first study to identify clues. Specifically, we estimated NTD risks for maternal occupational exposures to all possible pairs, triplets, and quadruplets of 74 chemical groups. Chemical combinations revealing elevated NTD risks in these "clue generation" analyses were then investigated in the second population-based case-control study for their contribution to risk of NTDs. We computed odds ratios for each of the total 192,374 possible comparisons and identified all combinations that produced odds ratios of 5 or more. A 5-fold elevated risk criterion revealed 53 combinations. These 53 reflected various combinations of exposures exclusive to 12 of 74 chemical groups. Analyses of data from the second study did not identify odds ratios of 2.0 or greater for maternal exposures to the 12 chemical groups that resulted in 5-fold elevated risks in the first study. Despite the use of a labor-intensive method to categorize exposures, we were unable to substantiate clues associated with combined chemical exposures identified in one large case-control study as NTD risk factors in a second case-control study.

    View details for Web of Science ID 000172676400004

    View details for PubMedID 11738516

  • Clinical anatomy and the physical examination part I: Thorax, abdomen, perineum, and pelvis - Educational Affairs Committee, American Association of Clinical Anatomists CLINICAL ANATOMY Leonard, R. J., Hoos, P. C., Lozanoff, S., MARKS, S. C., Mathers, L. H., Page, D. W., Pawlina, W., Petterborg, L. J., Abrahams, P., Akesson, E. J., Aker, F. D., Bedell, A. W., Carmichael, S., Cheng, J. C., Haukoos, J. S., Heller, R. F., Huddleston, H. T., Liang, A., Mau, C. K., Nguyen, C., Patwardhan, R., Schlunt, K., Seifert, M. F., Serrao, R., The, T. L., Weiglein, A. H., Williams, V. F., Blevins, C. E., Cahill, D. R. 2001; 14 (5): 332-348
  • FACTORS ASSOCIATED WITH THE PATTERN OF MATERNAL WEIGHT-GAIN DURING PREGNANCY OBSTETRICS AND GYNECOLOGY Abrams, B., Carmichael, S., Selvin, S. 1995; 86 (2): 170-176

    Abstract

    To examine the pattern of maternal weight gain using maternal characteristics and pregnancy outcome.We used maternal weight data measured prospectively from all deliveries between 1980-1990 at the University of California, San Francisco. Piecewise linear regression was used to estimate the rate of maternal weight gain in each trimester. Bivariate techniques were used to examine associations between maternal weight gain per trimester and maternal characteristics and pregnancy outcomes. We also used multiple regression analysis to examine the relationship between maternal characteristics and trimester weight gain.Weight data for at least one trimester were available for 10,418 women. The average rate of weight gain (kg/week) was lowest during the first trimester (0.169 +/- 0.268, n = 7587), peaked during the second trimester (0.563 +/- 0.236, n = 8000), and slowed slightly in the third trimester (0.518 +/- 0.234, n = 10,052). Maternal height, hypertension, cesarean delivery, and fetal size correlated positively with the rate of gain in each trimester, but pre-pregnancy body size, age, parity, smoking status, race-ethnicity, and diabetes were associated differently with gain, depending on which trimester was examined. The most important maternal predictors of weight gain per trimester were age and Asian race-ethnicity in the first trimester; pre-pregnancy body mass, parity, and height in the second; and hypertension, age, and parity in the third.Maternal weight gain per trimester is associated with a number of maternal characteristics and pregnancy outcomes, and these relationships vary according to which trimester is being examined.

    View details for Web of Science ID A1995RK50500003

    View details for PubMedID 7617345