Importance: Evidence for the fetal safety of ondansetron, a 5-HT3 receptor antagonist that is commonly prescribed for nausea and vomiting in pregnancy, is limited and conflicting. Objective: To evaluate the association between ondansetron exposure during pregnancy and risk of congenital malformations. Design, Setting, and Participants: A retrospective cohort study nested in the 2000–2013 nationwide Medicaid Analytic eXtract. The cohort consisted of 1,816,414 pregnancies contributed by 1,502,895 women enrolled in Medicaid from 3 months before the last menstrual period through ≥1 month after delivery; infants were enrolled in Medicaid for ≥3 months after birth. The final date of follow-up was December 31, 2013. Propensity score stratification was used to control for treatment indication and other confounders. Exposure: Ondansetron dispensing during the first trimester, the period of organogenesis. Main Outcome(s) and Measure(s): Primary outcomes were cardiac malformations and oral clefts diagnosed during the first 90 days after delivery. Secondary outcomes included congenital malformations overall and subgroups of cardiac malformations and oral clefts. Results: Among 1,816,414 pregnancies (mean age, 24.3 [5.8] years), 88,467 (4.9%) were exposed to ondansetron during the first trimester. Overall, 14,577 of 1,727,947 unexposed and 835 of 88,467 exposed infants were diagnosed with a cardiac malformation, for an absolute risk of 84.4 (95% CI, 83.0 – 85.7) and 94.4 (88.0 – 100.8) per 10,000 births respectively. The absolute risks of oral clefts were 11.1 (10.6 – 11.6) and 14.0 (11.6 – 16.5) per 10,000 (1,912 unexposed and 124 exposed cases); and the risks of any congenital malformation were 370.4 (358.0 – 382.9) and 313.5 (310.9 – 316.1) per 10,000 (3,277 exposed and 54,174 unexposed cases). The adjusted relative risk (RR) for cardiac malformations was 0.99 (95% CI, 0.93 – 1.06) and the adjusted risk difference (RD) was −0.8 (−7.3 – 5.7 per 10,000 births). For oral clefts, the adjusted RR was 1.24 (1.03 – 1.48) and the RD was 2.7 (0.2 – 5.2 per 10,000 births). The adjusted estimate for congenital malformations overall was RR = 1.01 (0.98 – 1.05) and RD = 5.4 (−7.3 – 18.2 per 10,000 births). Conclusions and Relevance: Among offspring of mothers enrolled in Medicaid, first-trimester exposure to ondansetron was not associated with cardiac malformations or congenital malformations overall after accounting for measured confounders, but was associated with a small increased risk of oral clefts.

The genetic susceptibility to preeclampsia, a pregnancy-specific complication with significant maternal and fetal morbidity, has been poorly characterized. To identify maternal genes associated with preeclampsia risk, we assembled 498 cases and 1864 controls of European ancestry from preeclampsia case-control collections in 5 different US sites (with additional matched population controls), genotyped samples on a cardiovascular gene-centric array composed of variants from ≈2000 genes selected based on prior genetic studies of cardiovascular and metabolic diseases and performed case-control genetic association analysis on 27 429 variants passing quality control. In silico replication testing of 9 lead signals with <10 was performed in independent European samples from the SOPHIA (Study of Pregnancy Hypertension in Iowa) and Inova cohorts (212 cases, 456 controls). Multiethnic assessment of lead signals was then performed in samples of black (26 cases, 136 controls), Hispanic (132 cases, 468 controls), and East Asian (9 cases, 80 controls) ancestry. Multiethnic meta-analysis (877 cases, 3004 controls) revealed a study-wide statistically significant association of the rs9478812 variant in the pleiotropic gene (odds ratio, 1.40 [1.23-1.60];=5.90×10). The rs9478812 effect was even stronger in the subset of European cases with known early-onset preeclampsia (236 cases diagnosed <37 weeks, 1864 controls; odds ratio, 1.59 [1.27-1.98]; =4.01×10). variants have previously been implicated in genome-wide association studies of blood pressure, body weight, and neurological disorders. Although larger studies are required to further define maternal preeclampsia heritability, this study identifies a novel maternal risk locus for further investigation.