​Who we are

The Harvard Program on Perinatal and Pediatric Pharmacoepidemiology includes investigators from Brigham and Women’s Hospital, Harvard Medical School, the Harvard T.H. Chan School of Public Health, and Stanford University School of Medicine. Our multidisciplinary team consists of epidemiologists, physicians, statisticians, and pharmacists.  LEARN MORE.

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What we do

Our team generates evidence regarding the safety of medications used during pregnancy and in childhood. To accomplish this, we use advanced epidemiological and statistical methods applied primarily to large databases derived from health data collected in the context of routine medical care. LEARN MORE.

​We strive to produce studies of the highest scientific standard and rigor, and many of our studies have been published in high-impact journals. LEARN MORE.
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Our team members are also active teaching faculty at local institutions and lecture nationally and internationally on related topics. LEARN MORE.

Our most recent publications

Modern Evidence Generation on Medication Effectiveness and Safety During Pregnancy: Study Design Considerations

• Author list: Krista F Huybrechts, Brian T Bateman, Sonia Hernández-Díaz
• ​We discuss special considerations to keep in mind when emulating target trials of drug effects in pregnancy including the alignment of treatment initiation with the appropriate gestational age, conditioning on conception and fetal survival, and varying etiologically relevant time widows and outcome rates throughout gestation. The target trial framework can guide us through the specification of the causal questions, the study population and the treatment strategies to be compared and helps to identify biases and assumptions.​

Accounting for Twins and Other Multiple Births in Perinatal Studies of Live Births Conducted Using Healthcare Administration Data

• Jeremy P Brown, Jennifer J Yland, Paige L Williams, Krista F Huybrechts, Sonia Hernández-Díaz
• ​Twins and other multiple births complicate the analysis of perinatal studies. Common approaches to handling multiples in analyses of infant outcomes include restriction to singletons, counting outcomes at the pregnancy level (i.e., counting if at least one twin experienced a binary outcome), and infant-level analysis (i.e., including all infants and accounting for clustering of outcomes). Several healthcare administration databases only support restriction to singletons or pregnancy-level approaches; however, little attention has been given to the differences that can arise from these approaches. In their study published in Epidemiology, Jeremy P. Brown, Jennifer J. Yland, Paige L. Williams, Krista F. Huybrechts, and Sonia Hernández-Díaz demonstrate these differences using Monte Carlo simulations, algebraic formulas, and an applied example. Their analyses highlight the importance of understanding both the study question and the role of multiples in a study when choosing an analytical approach.

Maternal periconception hyperglycemia, preconception diabetes, and risk of major congenital malformations in offspring

• Ran S Rotem, Marc G Weisskopf, Brian Bateman, Krista Huybrechts, Sonia Hernández-Diáz
• ​The study examined the relationship between preconception maternal diabetes, associated periconceptional hyperglycemia, and the risk of congenital malformations in newborns. Findings revealed that maternal preconception diabetes was linked to multiple congenital heart defects, with risks that, although reduced, remained elevated even at periconceptional HbA1c levels below 5.6%. The results highlight a subgroup of pregnant women at higher risk for early neonatal complications and suggest potential pharmaceutical interventions to attenuate these risks. Furthermore, the study indicated that the connection between maternal preconception diabetes and congenital malformations may, in part, involve mechanisms that are independent of maternal serum glucose levels during early pregnancy.

Development and validation of claims-based algorithms for estimating gestational age of spontaneous abortion and termination​

• Yanmin Zhu, Sonia Hernandez-Diaz, Brian T Bateman, Kathryn J Gray, Ethan M Alt, Loreen Straub, Lockwood G Taylor, Rita Ouellet-Hellstrom, Yong Ma, Yandong Qiang, Seanna Vine, Helen Mogun, Wei Hua, Krista F Huybrechts
• ​We developed and validated algorithms to estimate gestational age (GA) for spontaneous abortion and termination cases in Medicaid data. Using linked medical records as the gold standard, we tested three approaches—median assignment, population-based sampling, and regression modeling. Approach 1 and 3 had similar performance, though Random forest models were slightly better. SABs and terminations can be studied in claims data with careful implementation of validated algorithms.​

Development and Validation of an Algorithm to Predict Stillbirth Gestational Age in Medicaid Billing Records

• Thuy N Thai, Nicole E Smolinski, Sabina Nduaguba, Steven Bird, Loreen Straub, Brian T Bateman, Sonia Hernandez-Diaz, Krista F Huybrechts, Sonja A Rasmussen, Almut G Winterstein
• ​After linking stillbirths identified in MAX 1999-2013 to Florida Fetal Death Records (FDRs) to obtain clinical estimates of gestational age (GA), we developed and validated an algorithm to predict GA for stillbirth, exhibiting good validity and consistent performance across different external validation samples. Our algorithm can facilitate research on stillbirths in the Medicaid population

Comparative Safety of In Utero Exposure to Buprenorphine Combined With Naloxone vs Buprenorphine Alone

• Loreen Straub, Brian T Bateman, Sonia Hernández-Díaz, Yanmin Zhu, Elizabeth A Suarez, Seanna M Vine, Hendrée E Jones, Hilary S Connery, Jonathan M Davis, Kathryn J Gray, Barry Lester, Mishka Terplan, Heidi Zakoul, Helen Mogun, Krista F Huybrechts
• ​This observational study noted similar and, in some instances, more favorable neonatal and maternal outcomes for pregnancies exposed to buprenorphine combined with naloxone compared to buprenorphine alone. The findings demonstrate comparative safety for the combination of buprenorphine with naloxone for the outcomes considered, supporting both formulations as reasonable options for treating opioid use disorder during pregnancy.

Hierarchical Clustering Analysis to Inform Classification of Congenital Malformations for Surveillance of Medication Safety in Pregnancy

• Loreen Straub, Shirley V Wang, Sonia Hernandez-Diaz, Kathryn J Gray, Seanna M Vine, Massimiliano Russo, Leena Mittal, Brian T Bateman, Yanmin Zhu, Krista F Huybrechts
• ​This study suggests that augmenting existing clinical classifications typically used in tree-based scan statistic approaches with clusters identified through large data exploration may be a promising approach when defining phenotypes for surveillance activities and causal inference studies of congenital malformations.

Perinatal Outcomes Associated With Metformin Use During Pregnancy in Women With Pregestational Type 2 Diabetes Mellitus

• Jennifer J Yland, Krista F Huybrechts, Amelia K Wesselink, Loreen Straub, Yu-Han Chiu, Ellen W Seely, Elisabetta Patorno, Brian T Bateman, Helen Mogun, Lauren A Wise, Sonia Hernández-Díaz
• ​We emulated an adaptation of the MiTy randomized trial to compare the perinatal outcomes among those continuing versus discontinuing metformin during pregnancy in women with type 2 diabetes treated with metformin plus insulin before conception. Findings were consistent with those from the MiTy randomized trial. Continuing metformin during pregnancy was not associated with increased risk of a neonatal composite adverse outcome. However, metformin continuers had more infants born small for their gestational age, which warrants further consideration.

Patterns of paternal medication dispensation around the time of conception​

• Isobel McEwen, Krista F Huybrechts, Loreen Straub, Sonia Hernández-Díaz
• ​To inform the research agenda on the potential effects of paternal drug exposures during the spermatogenesis period preceding pregnancies, we assessed drug dispensation patterns in a US healthcare utilization database. The most common prescription medications dispensed to fathers preconception were psychotropics, antibiotics and analgesics. Known or suspected teratogens were used by less than 0.05%.

Metformin Use in the First Trimester of Pregnancy and Risk for Nonlive Birth and Congenital Malformations: Emulating a Target Trial Using Real-World Data

• Yu-Han Chiu, Krista F Huybrechts, Elisabetta Patorno, Jennifer J Yland, Carolyn E Cesta, Brian T Bateman, Ellen W Seely, Miguel A Hernán, Sonia Hernández-Díaz
• ​We emulated a hypothetical target trial to evaluate the teratogenicity of metformin when used in the first trimester of pregnancy in women with type 2 diabetes on metformin monotherapy preconception. Compared with switching to insulin monotherapy, continuing metformin and adding insulin in early pregnancy did not result in an increased risk of congenital malformations.

Paternal Use of Metformin During the Sperm Development Period Preceding Conception and Risk for Major Congenital Malformations in Newborns

• Ran S Rotem, Marc G Weisskopf, Krista F Huybrechts, Sonia Hernández-Díaz
• ​The study examined the association between paternal use of metformin in the preconception period and risk of congenital malformation in the newborn. Such a link had been previously proposed by a large Danish study, which had raised concerned given the frequent use of metformin as a first-tier diabetes medication. The research, which examined 383,851 births, showed that the use of metformin alone is safe. Through a series of analyses, we showed that an initial association between paternal metformin exposure and malformation risk is entirely explain by familial cardiometabolic confounding. Higher risks were observed for fathers who used metformin in tandem with another diabetes medication, likely stemming from a worse paternal cardiometabolic health profile