- Neonatal-Perinatal Medicine
Clinical Associate Professor, Pediatrics - Neonatal and Developmental Medicine
Boards, Advisory Committees, Professional Organizations
Council Member, Western Society for Pediatric Research (2020 - Present)
Secretary, California Association of Neonatologists (CAN) (2020 - Present)
Chair, Research Committee, California Association of Neonatologists (CAN) (2019 - Present)
Board Member, American Academy of Pediatrics-California Chapter 1 (2017 - Present)
Board Member, California Association of Neonatologists (2015 - 2018)
Instructor, Neonatal Resuscitation Program (2004 - Present)
Fellow, American Academy of Pediatrics (1996 - Present)
Residency: UCLA Pediatric Residency (1995) CA
Residency: California Pacific Medical Center Dept of Medicine (1996) CA
Board Certification: American Board of Pediatrics, Neonatal-Perinatal Medicine (2005)
Fellowship: UC Davis Neonatology Fellowship (2004) CA
Board Certification: American Board of Pediatrics, Pediatrics (1996)
Internship: Childrens Hospital of Michigan Pediatric Residency (1994) MI
Medical Education: Kilpauk Medical College (1991) India
Current Research and Scholarly Interests
1. My recent clinical research involved being a recipient of Stanford’s Maternal and Child Health Research Institute (MCHRI) Clinician Educator Grant Program to study "Barriers to Optimal Breast Milk Provision and Successful Breastfeeding in the NICU Setting".
2. I also serve as the PI for the multicenter study of transcutaneous bilirubin use in extremely preterm infants less than 30 week gestation in California NICU's.
3. My previous clinical research projects include being the site PI and a recipient of UCSF sub-award grant for a Multicenter clinical research study-PDA Tolerate Trial- ( PDA: TO LEave it alone or Respond And Treat Early - Trial)Trial of Early Treatment of the patent ductus arteriosus versus Conservative Treatment.
I have been interested in clinical research on studying factors determining patent ductus arteriosus closure in preterm infants. My initial research project looked at the factors determining closure of a PDA in preterm infants and examined the role of prophylactic indomethacin treatment in achieving ductal closure. The study found that prophylactic indomethacin improved the rate of permanent ductus closure by increasing the degree of initial constriction. Prophylactic indomethacin did not affect the remodeling process, nor did it alter the inverse relationship between infant maturity and subsequent reopening. Even when managed with prophylactic indomethacin, the rate of ductus reopening remained unacceptably high in the most immature infants. By providing evidence and clinical solutions, this body of work has been widely cited and informed practical applications for clinicians who care for preterm infants.
My interest in PDA in preterm infants extended to research in assessing the safety and efficacy of medications used in the management of PDA. We looked at Mednax National group’s extensive database and identified infants <28weeks gestational age discharged from neonatal intensive care units who were treated with indomethacin or ibuprofen between postnatal days 2 and 14. We observed similar effectiveness and safety profiles for indomethacin and ibuprofen in the medical management of PDA in premature infants.
In an effort to study parental knowledge and education in caring for very low birth weight infants, we collaborated with investigators at Center for Policy, Outcomes and Prevention research. We specifically focused on Retinopathy of prematurity (ROP) which is a disorder of the developing retina that occurs in two-thirds of infants born preterm or very low birth weight (VLBW). Use of visual modalities, rather than standard verbal or written instructions, may improve parents’ understanding and adherence with recommended outpatient ROP care.
Does crossover treatment of control subjects invalidate results of randomized trials of patent ductus arteriosus treatment?
Journal of perinatology : official journal of the California Perinatal Association
Optimal management of patent ductus arteriosus (PDA) in extremely preterm infants remains controversial. There is paucity of evidence on the benefits of PDA treatment in reducing mortality and morbidities in extremely preterm infants. Failure of randomized clinical trials to demonstrate beneficial effects of PDA treatment on outcomes has often been attributed to open treatment of control subjects. This perspective examines the PDA treatment trials to date, with specific focus on rates of and ages of subjects at open rescue treatment. Although these trials demonstrate that ductal closure is significantly increased with treatment, that does not translate to a significant decrease in major morbidities or mortality in premature infants, even when trials with high rates of rescue treatment of controls are excluded. Trials in which enrollment occurred after 7 days of age include insufficient numbers of subjects to evaluate this relationship.
View details for DOI 10.1038/s41372-020-00848-z
View details for PubMedID 33024260
- Prolonged tracheal intubation and the association between patent ductus arteriosus and bronchopulmonary dysplasia: a secondary analysis of the PDA-TOLERATE trial. The Journal of pediatrics 2020
PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age.
The Journal of pediatrics
To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given.A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial.At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%).In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation.ClinicalTrials.gov: NCT01958320.
View details for DOI 10.1016/j.jpeds.2018.09.012
View details for PubMedID 30340932
Behavior Profiles at 2Years for Children Born Extremely PretermwithBronchopulmonary Dysplasia.
The Journal of pediatrics
OBJECTIVE: To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD).STUDY DESIGN: We studied children born at 22-26weeks of gestation and assessed at 22-26months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior.RESULTS: Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P<.001) and pervasive developmental problems (P<.001) increased with worsening BPD grade. Sleep problems (P=.008) and aggressive behavior (P=.023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values<.05).CONCLUSIONS: BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.
View details for DOI 10.1016/j.jpeds.2019.12.028
View details for PubMedID 32008764
Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial (NCT01958320)
JOURNAL OF PERINATOLOGY
2019; 39 (5): 599–607
To evaluate the effectiveness of drugs used to constrict patent ductus arteriosus (PDA) in newborns < 28 weeks.We performed a secondary analysis of the multi-center PDA-TOLERATE trial (NCT01958320). Infants with moderate-to-large PDAs were randomized 1:1 at 8.1 ± 2.1 days to either Drug treatment (n = 104) or Conservative management (n = 98). Drug treatments were assigned by center rather than within center (acetaminophen: 5 centers, 27 infants; ibuprofen: 7 centers, 38 infants; indomethacin: 7 centers, 39 infants).Indomethacin produced the greatest constriction (compared with spontaneous constriction during Conservative management): RR (95% CI) = 3.21 (2.05-5.01)), followed by ibuprofen = 2.03 (1.05-3.91), and acetaminophen = 1.33 (0.55-3.24). The initial rate of acetaminophen-induced constriction was 27%. Infants with persistent moderate-to-large PDA after acetaminophen were treated with indomethacin. The final rate of constriction after acetaminophen ± indomethacin was 60% (similar to the rate in infants receiving indomethacin-alone (62%)).Indomethacin was more effective than acetaminophen in producing ductus constriction.
View details for DOI 10.1038/s41372-019-0347-4
View details for Web of Science ID 000465460900001
View details for PubMedID 30850756
View details for PubMedCentralID PMC6561645
Lack of Equipoise in the PDA-TOLERATE Trial: A Comparison of Eligible Infants Enrolled in the Trial and Those Treated Outside the Trial.
The Journal of pediatrics
The PDA: TO LEave it alone or Respond And Treat Early trial compared the effects of 2 strategies for treatment of patent ductus arteriosus (PDA) in infants <280/7 weeks of gestation; however 137 potentially eligible infants were not recruited and received treatment of their PDA outside the PDA-TOLERATE trial due to "lack-of-physician-equipoise" (LPE). Despite being less mature and needing more respiratory support, infants with LPE had lower rates of mortality than enrolled infants. Infants with LPE treated before day 6 had lower rates of late respiratory morbidity than infants with LPE treated ≥day 6. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958320.
View details for DOI 10.1016/j.jpeds.2019.05.049
View details for PubMedID 31255386
PDA: To treat or not to treat.
Congenital heart disease
2019; 14 (1): 46–51
Management of patent ductus arteriosus in extremely preterm infants remains a topic of debate. Treatment to produce ductal closure was widely practiced until the past decade, despite lack of evidence that it decreases morbidities or mortality. Meta-analyses of trials using nonsteroidal anti-inflammatory drugs have shown effectiveness in accelerating ductal closure, but no reduction in neonatal morbidities, regardless of agent used, indication, timing, gestational age, or route of administration. Surgical ligation closes the ductus but is associated with adverse effects. Recent experience with conservative approaches to treatment suggest improved neonatal outcomes and a high rate of spontaneous ductal closure after discharge. Careful postdischarge follow-up is important, however, because potential adverse effects of long-standing aortopulmonary shunts may be an indication for catheter-based ductal closure. Identification of extremely preterm infants at greatest risk of potential harm from a persistently patent ductus, who may benefit most from treatment are urgently needed.
View details for PubMedID 30811796
- Parents' Knowledge and Education of Retinopathy of Prematurity in Four California Neonatal Intensive Care Units AMERICAN JOURNAL OF OPHTHALMOLOGY 2018; 191: 7–13
Comparative effectiveness and safety of indomethacin versus ibuprofen for the treatment of patent ductus arteriosus
EARLY HUMAN DEVELOPMENT
2015; 91 (12): 725-729
Patent ductus arteriosus (PDA) is common in extremely premature infants and associated with increased morbidity and mortality. Medical management of PDA uses either indomethacin or ibuprofen. Despite numerous studies, uncertainty exists as to which drug is safer or more effective; we sought to fill this knowledge gap.We identified infants <28weeks gestational age discharged from neonatal intensive care units included in the Pediatrix Medical Group Clinical Data Warehouse between 2006 and 2012 who were treated with indomethacin or ibuprofen between postnatal days 2 and 14. Infants treated with both drugs or infants with a congenital malformation were excluded. We used multivariable logistic regression to determine the association of indomethacin versus ibuprofen on clinical outcomes.Of 6349 patients who met study criteria, 1177 (19%) received ibuprofen and 5172 (81%) received indomethacin. The median gestational age was 25weeks (interquartile range 24-26), and 2894 (46%) infants were <750g at birth. On unadjusted analysis, infants who received ibuprofen had significantly higher incidences of death prior to discharge, surgical ligation of the PDA prior to discharge, death or spontaneous intestinal perforation within 7days of therapy, death or surgical ligation of the PDA prior to discharge, and an elevated creatinine within 7days of treatment. However, on multivariable analysis, no significant differences in outcomes were observed (odds ratio for death/PDA ligation for ibuprofen vs. indomethacin=1.12 [95% CI 0.91-1.39]).We observed similar effectiveness and safety profiles for indomethacin and ibuprofen in the medical management of PDA in premature infants.
View details for DOI 10.1016/j.earlhumdev.2015.08.003
View details for Web of Science ID 000366440000013
View details for PubMedID 26386610
View details for PubMedCentralID PMC4662898
Utility of Genetic Testing for the Detection of Late-Onset Hearing Loss in Neonates
AMERICAN JOURNAL OF AUDIOLOGY
2013; 22 (2): 209-215
The purpose of this study was to demonstrate the utility of molecular testing in the detection of potentially important causes of delayed hearing loss missed by current audiometric screening at birth.We enrolled infants who had received a newborn audiometric hearing screen and a filter paper blood collection for state newborn screening. A central laboratory ran the SoundGene® panel.Of 3,681 infants studied, 35 (0.95%) had a positive SoundGene panel, 16 had mitochondrial mutations, 9 had Pendred mutations, 5 were cytomegalovirus (CMV) DNA positive, 2 had connexin mutations, and 3 had a combination of different mutations. Infants with an abnormal SoundGene panel were at increased risk for hearing loss compared to neonates without mutations. Three (8.6%) of the 35 subjects had persistent hearing loss compared to 5 (0.21%) of 2,398 subjects with no report of mutation (p < .01). Of 3,681 infants studied, 8 (0.22%) had persistent hearing loss: 5 (62.5%) had abnormal newborn audiometric screens, 2 (25%) had an abnormal SoundGene panel (1 was CMV positive, 1 had a mitochondrial mutation), and 1 (12.5%) had no identifiable risk factors.A positive SoundGene panel identifies infants who are not identified by audiometric testing and may be at risk for hearing loss.
View details for DOI 10.1044/1059-0889(2013/12-0078)
View details for Web of Science ID 000330024500002
View details for PubMedID 23824432
The influence of amino-acid supplementation, gestational age and time on thyroxine levels in premature neonates
JOURNAL OF PERINATOLOGY
2008; 28 (4): 270-274
Newborn screening laboratories vary in the values that are used to define congenital hypothyroidism. Defining congenital hypothyroidism is particularly complex in premature neonates because prematurely born infants often have a low free thyroxine value and low or normal TSH value, termed as transient hypothyroxinemia of prematurity. In a multicenter (n=11 sites) trial, we randomly allocated premature neonates with a gestational age of 23 to 29 and 6/7 weeks to one of two parenteral nutrition approaches. The primary objective of our trial was to measure the effect of two distinct strategies of parenteral nutrition on neonatal growth and blood amino acids. A protocol defined secondary aim of our clinical trial was the evaluation of the influence of gestational age, time and the degree of amino-acid supplementation on total thyroxine levels. We hypothesized that an increase of amino-acid supplementation would be associated with the normalization of serum amino acids and that this would improve thyroxine synthesis.Premature neonates (23 to 29 and 6/7 weeks) were randomly allocated to one of two approaches to intravenous amino-acid administration. In one group, amino-acid supplementation started at 1.0 g kg(-1) per day and advanced by 0.5 g kg(-1) per day to a maximum of 2.5 g kg(-1) per day (2.5 group). The other group received amino acids at 1.5 g kg(-1) per day and advanced by 1.0 g kg(-1) per day to a maximum of 3.5 g kg(-1) per day (3.5 group). Filter paper blood spots were obtained on the day of randomization, and on days 7 and 28 of age to monitor laboratory values.Enrollment included 122 neonates, 64 in the 3.5 group and 58 in the 2.5 group. There were no differences in demographics or baseline characteristics between the two treatment groups. There were no significant differences in thyroid levels at baseline, on days 7 and 28 between the two treatment groups. Growth was similar in both groups. It was noted that thyroxine levels changed over time and that the changes with time were greatest in the most preterm neonates.The degree of amino-acid supplementation does not influence thyroxine levels and both time from birth and gestational age do influence thyroxine levels.
View details for Web of Science ID 000254782000005
View details for PubMedID 18288119
Demographic and nutritional factors associated with prolonged cholestatic jaundice in the premature infant.
Journal of perinatology : official journal of the California Perinatal Association
2008; 28 (2): 129–35
The primary aim of this study was to determine if an association exists between amino-acid levels and development of cholestasis. The secondary aim of our amino-acid dose comparison trial was to identify factors associated with the development of prolonged cholestatic jaundice.We compared demographic characteristics and amino-acid levels in neonates who developed cholestasis with those who did not. Parenteral-associated cholestatic liver disease was defined as a direct serum bilirubin above 5 mg per 100 ml any time during the first 28 days after birth in neonates with no history of biliary atresia or viral hepatitis. We obtained filter paper blood spots for amino acid and acylcarnitine measurements on the day of randomization and days 7 and 28 of age to identify a profile of values that could be used to identify neonates with evidence of abnormal liver function.We enrolled 122 neonates in our study; 13 (10.7%) developed cholestasis. Neonates who developed cholestasis were more immature, had lower birth weight, were exposed to parenteral nutrition for a longer period, had a higher cumulative dose of amino acids, were less often on enteral nutrition by day 7 of age, more often had a patent ductus arteriosus and severe intraventricular hemorrhage and were more commonly treated with steroids by 28 days of age. Amino acid and acylcarnitine values were not different for the two groups on the day of randomization. On day 7 (parenteral phase of nutrition), blood urea nitrogen, citrulline, histidine, methionine and succinyl carnitine were higher, and serine, glutamate and thyroxine levels were lower in the neonates who developed cholestasis than in who did not.Cholestasis remains an important complication of parenteral nutrition, and several clinical and biochemical factors may be helpful in identifying high-risk patients.
View details for DOI 10.1038/sj.jp.7211889
View details for PubMedID 18059467
Effects of two different doses of amino acid supplementation on growth and blood amino acid levels in premature neonates admitted to the neonatal intensive care unit: a randomized, controlled trial.
2007; 120 (6): 1286–96
The goal was to measure the effects of 2 distinct strategies for parenteral nutrition on neonatal growth and blood amino acid profiles.In a multicenter trial (n = 11 sites), we randomly allocated premature (23-29 weeks and 6 days of gestation) neonates to 1 of 2 approaches to intravenous amino acid administration. In one group, amino acid supplementation was started at 1.0 g/kg per day and advanced by 0.5 g/kg per day to a maximum of 2.5 g/kg per day (2.5 g/kg per day group). The other group received amino acids starting at 1.5 g/kg per day and advancing by 1.0 g/kg per day to a maximum of 3.5 g/kg per day (3.5 g/kg per day group). Filter paper blood spots were obtained from each infant on the day of random assignment and on days 7 and 28 of age, to monitor blood amino acid levels.We enrolled 122 neonates (64 in the 3.5 g/kg per day group and 58 in the 2.5 g/kg per day group). There were no differences in demographic or baseline characteristics between the 2 treatment groups. There was no significant difference in growth by day 28 after birth (median weight gain: 12.9 and 11.4 g/kg per day for the 3.5 and 2.5 g/kg per day groups, respectively), and the incidences of secondary morbidities were similar in the 2 groups. On day 7, blood levels of several amino acids and the serum urea nitrogen level were higher in the 3.5 g/kg per day group, compared with the 2.5 g/kg per day group; none of the amino acid levels were lower.Higher doses of amino acid supplementation did not improve neonatal growth and were associated with increased blood amino acid and urea nitrogen levels.
View details for DOI 10.1542/peds.2007-0545
View details for PubMedID 18055678
- Pharmacologic closure of the Patent Ductus Arteriosus in the Premature Neonate NeoReviews 2003
Prophylactic indomethacin: Factors determining permanent ductus arteriosus closure
JOURNAL OF PEDIATRICS
2000; 136 (3): 330-337
Permanent closure of the ductus arteriosus (DA) requires both effective muscular constriction to block luminal blood flow and anatomic remodeling to prevent later reopening.We examined the role of prophylactic indomethacin in producing permanent DA closure and the mechanism by which this occurs.We studied 2 separate approaches to managing a patent DA in 257 preterm infants (gestation 24 to 27 weeks): (1) prophylactic indomethacin (all infants treated during the first 15 hours after birth) or (2) symptomatic treatment (infants in this group received indomethacin only if clinical symptoms appeared; infants whose ductus closed spontaneously and never received indomethacin were included in this group). Echocardiography was performed 24 to 36 hours after the last dose of indomethacin was administered or by age 5 days if spontaneous closure occurred. Infants were monitored for the development of ductus reopening.The prophylactic treatment group had a greater degree of initial ductus constriction, a higher rate of permanent anatomic closure, and a decreased need for surgical ligation than did the symptomatic treatment group. The degree of initial ductus constriction was the most important factor determining the rate of ductus reopening. Post-treatment echocardiography proved to be the best test for predicting eventual reopening.Prophylactic indomethacin improved the rate of permanent ductus closure by increasing the degree of initial constriction. Prophylactic indomethacin did not affect the remodeling process, nor did it alter the inverse relationship between infant maturity and subsequent reopening. Even when managed with prophylactic indomethacin, the rate of ductus reopening remained unacceptably high in the most immature infants.
View details for Web of Science ID 000085859200014
View details for PubMedID 10700689
- Patent Ductus Arteriosus- A physiologic basis for current treatment practices Current topics in Neonatology edited by Hansen, T. N. WB Saunders, Harcourt Publishers Limited . 2000; 4
Incidence and outcome of a 10-fold indomethacin overdose in premature infants
JOURNAL OF PEDIATRICS
1999; 135 (1): 105-107
We reviewed the incidence and morbidity of a 10-fold medication error among all premature infants treated with indomethacin. We detected 4 incidents among 1059 indomethacin doses given to infants weighing less than 1000 g. None of the infants had intracranial hemorrhage, necrotizing enterocolitis, or significant deterioration of renal function.
View details for Web of Science ID 000081378900022
View details for PubMedID 10393614
- Congenital Lobar Emphysema- An Atypical Presentation Resident and Staff Physician 1997; 43 (7)