Using Pharmacogenomics to Better Understand the Role of Selected Medications and Birth Defect Risk

Through a funding opportunity from CDC’s Office of Genomics and Precision Public Health in collaboration with the Office of Advanced Molecular Detection, CDC’s Birth Defects Monitoring and Research Branch in the National Center on Birth Defects and Developmental Disabilities will conduct a 2-year project to gather genome-wide genotyping data to look at relationships between pharmacogenomic variants, commonly prescribed medications during pregnancy, and birth defects.

Researchers will use information collected in one of the largest studies on birth defects in the United States, the National Birth Defects Prevention Study (NBDPS). The NBDPS was a multisite, population-based, case-control study of genetic and non-genetic risk factors for major structural birth defects that included women with deliveries between 1997 and 2011. Over 40,000 women completed telephone interviews in English or Spanish with questions on pregnancy exposures, including medication use three months before pregnancy through delivery. Following the interview, women were mailed cytobrushes to collect buccal (cheek) cell samples for themselves, their child (if living), and the child’s father. DNA specimens were collected from more than 23,000 families in 10 states (Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah). The combination of pregnancy exposure information, genetic data, detailed clinical information about the birth defects, and family histories is a unique resource. It can help advance our understanding of the biological pathways involved in fetal development and reveal possible gene-environment interaction effects associated with birth defects.

Birth defects remain a leading cause of infant mortality.

Birth defects are common, costly, and critical conditions that affect 1 in every 33 babies born in the United States each year. They are a leading cause of infant mortality, accounting for approximately 20% of infant deaths. While the causes of most birth defects remain unknown, there are likely to be combinations of genetic and environmental risk factors involved. The mission of the Birth Defects Monitoring and Research Branch is to conduct surveillance of birth defects, research the causes of birth defects, and enhance birth defects awareness and prevention activities to help reduce morbidity and mortality associated with birth defects.

Defining interactions among pharmacogenomic variants and medication use during pregnancy will help inform risk of birth defects.

Using these unique NBDPS data allows researchers to better understand medication safety among pregnant women. Given ethical and logistical difficulties, there is limited information on medication safety for pregnant women, those trying to conceive, and their healthcare providers. Yet, evidence from observational studies indicates that use of certain medications during pregnancy is associated with risk of birth defects. NBDPS data has shown that periconceptional (i.e., one month before conception through the third month of pregnancy) use of trimethoprim-sulfamethoxazole (e.g., Bactrim) or venlafaxine (e.g., Effexor) was associated with increased risk of a wide range of birth defects. To get a better understanding of a possible mechanism for the teratogenicity of these and other medications, such as gene-medication interaction, the Birth Defects Monitoring and Research Branch is planning a genome-wide association study (GWAS) with enhanced pharmacogenomic content among mothers of infants with and without birth defects who used specific medications. Data generated from such a GWAS can be used in a variety of different study designs, including polygenic risk score development; gene-based association and gene-set analyses; single nucleotide polymorphism-heritability assessments; and Mendelian randomization studies, which can be used to infer a causal role for a teratogenic effect of a medication. These methods would provide information that could help protect the health of pregnant women and their babies.

The NBDPS allows researchers to investigate gene-medication associations because it collected information on the timing, duration, and frequency of medication use, and has a diverse racial and ethnic study population, representative of the population of the United States. Analyzing GWAS data from this unique dataset could lead to improvements in health equity for medication safety for pregnant women. These analyses are expected to advance precision medicine by identifying individuals with higher genetic risk for birth defects via polygenic risk scores, as well as identifying medication targets. This project provides an unprecedented opportunity to identify gene-medication interaction effects in pregnant women and the risk of birth defects, which will inform medication safety during pregnancy.