Association of Maternal First-Trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring

Abstract

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.

Validating the effect of Ondansetron and Mirtazapine In Treating hyperemesis gravidarum (VOMIT): protocol for a randomised placebo-controlled trial

“…However, two recent cohort studies, one including almost 90 000 pregnancies exposed to prescription ondansetron and one including over 23 000 pregnancies exposed to intravenous ondansetron, did not find an association between exposure and cardiac or general congenital malformations in the newborn. They did, however, find that exposure was associated with a small increased risk of oral cleft (3 in 10 000) 33 34. Considering this relatively small increased risk and the fact that ondansetron is already being used in pregnant women with hyperemesis gravidarum, compared with the risk of severe hyperemesis gravidarum, we find it ethically acceptable to randomise participants to treatment with ondansetron.…”

Use of real‐world evidence from healthcare utilization data to evaluate drug safety during pregnancy

“…For example, if a positive association is found between drug exposure during the first trimester and the risk of congenital malformations but residual confounding is a concern, the risk of malformations can be assessed in women who filled their first prescription for the medication of interest outside of the etiologically relevant window. A null finding in this analysis provides indirect evidence of no substantial residual confounding; a positive association suggests that residual confounding is highly likely . Alternatively, one can assess the association between first‐trimester exposure and a different outcome that is not expected to be associated with first‐trimester exposure, but is likely to be equally confounded if residual confounding is present (negative control outcome).…”

“…We have employed this data source to study the safety of drugs during pregnancy with respect to a wide variety of important fetal and maternal outcomes. [7][8][9][10][11][12][13][14][15][16]…”

“…A null finding in this analysis provides indirect evidence of no substantial residual confounding; a positive association suggests that residual confounding is highly likely. 15 Alternatively, one can assess the association between first-trimester exposure and a different outcome that is not expected to be associated with firsttrimester exposure, but is likely to be equally confounded if residual confounding is present (negative control outcome). A null finding would again provide reassurance that the results are unlikely to be explained by residual confounding whereas a positive association would strengthen the concern.…”

Validation of algorithms to estimate gestational age at birth in the Medicaid Analytic eXtract—Quantifying the misclassification of maternal drug exposure during pregnancy

“…We used pharmacy dispensing records to ascertain maternal exposure to (1) sertraline or paroxetine-drugs typically used chronically and likely to be discontinued during pregnancy due to FDA warnings; (2) azithromycin or amoxicillin-drugs typically used short-term and the most commonly used antibiotics during pregnancy 23 ; (3) promethazine or ondansetron-antiemetics often initiated during the first trimester. 24,25 We examined the performance of all four algorithms in defining four utilization patterns of interest. (1) Exposure anytime during pregnancy: the gold-standard index onset of pregnancy (day 0) was defined as the delivery date minus the GA estimate from the birth certificates, and the algorithm-derived onset of pregnancy was defined as the delivery date minus the GA estimate from the tested algorithm.…”