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 during 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 or longer after delivery; infants were enrolled in Medicaid for at least 3 months after birth. The final date of follow-up was December 31, 2013. Analyses were conducted between November 1, 2017, and June 30, 2018. Propensity score stratification was used to control for treatment indication and other confounders.

Exposures: Ondansetron dispensing during the first trimester, the period of organogenesis.

Main outcomes and measures: 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 of mothers, 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 to 85.7) and 94.4 (95% CI, 88.0 to 100.8) per 10 000 births respectively. The absolute risk of oral clefts was 11.1 per 10 000 births (95% CI, 10.6 to 11.6; 1921 unexposed infants) and was 14.0 per 10 000 births (95% CI, 11.6 to 16.5; 124 exposed infants). The risk of any congenital malformation was 313.5 per 10 000 births (95% CI, 310.9 to 316.1; 54 174 unexposed infants) and was 370.4 (95% CI, 358.0 to 382.9; 3277 exposed infants). The adjusted relative risk (RR) for cardiac malformations was 0.99 (95% CI, 0.93 to 1.06) and the adjusted risk difference (RD) was -0.8 (95% CI, -7.3 to 5.7 per 10 000 births). For oral clefts, the adjusted RR was 1.24 (95% CI, 1.03 to 1.48) and the RD was 2.7 (95% CI, 0.2 to 5.2 per 10 000 births). The adjusted estimate for congenital malformations overall was an RR of 1.01 (95% CI, 0.98 to 1.05) and an RD of 5.4 (95% CI, -7.3 to 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.

Figure 1. Risk of congenital malformations in infants following exposure to ondansetron during the first trimester: Main analyses

Relative risks and 95% confidence intervals are presented to show the risk of cardiac malformations, oral clefts, and any congenital malformation among infants born to women with exposure to ondansetron during the first trimester, as compared with the risk among infants born to women without such exposure. Propensity score stratified level 1 refers to analyses adjusted for treatment indications and associated factors. Propensity score stratified level 2 refers to analyses adjusted for all potential confounding variables as listed in Table S3. High-dimensional propensity score stratified refers to analyses adjusted for 200 empirically identified covariates, in addition to the pre-specified covariates.

Figure 2. Risk of congenital malformations in infants following exposure to ondansetron during the first trimester: Sensitivity analyses

Relative risks and 95% confidence intervals are presented to show the risk of cardiac malformations, oral clefts, and any congenital malformation among infants born to women with exposure to ondansetron during the first trimester. Results are presented for different sensitivity analyses: (i) changing the reference group to women exposed to any of the three alternative anti-emetics during the first trimester, (ii) changing the reference group to women exposed to metoclopramide during the first trimester, (iii) changing the reference group to women exposed to promethazine during the first trimester, (iv) changing the exposure group to women exposed to pyridoxine during the first trimester, (v) requiring ondansetron-exposed women to have filled at least two prescriptions during the first trimester, (vi) changing the exposure window to 6 to 12 weeks after the date of last menstrual period, (vii) using pregnancies with first exposure to ondansetron 5–8 months after the date of last menstrual period as the reference group, (viii) changing the exposure window to 5–8 months after the date of last menstrual period, which is after the etiologically-relevant window (negative control analysis). Panel A shows the unadjusted associations. Panel B shows the associations adjusted for all potential confounding variables (Propensity Score Level 2). For analyses (iv) and (vii), adjustment was done through 1:1 matching rather than fine stratification on the propensity score due to the relatively small size of the reference group compared to the exposed group.

Figure 2. Risk of congenital malformations in infants following exposure to ondansetron during the first trimester: Sensitivity analyses

Relative risks and 95% confidence intervals are presented to show the risk of cardiac malformations, oral clefts, and any congenital malformation among infants born to women with exposure to ondansetron during the first trimester. Results are presented for different sensitivity analyses: (i) changing the reference group to women exposed to any of the three alternative anti-emetics during the first trimester, (ii) changing the reference group to women exposed to metoclopramide during the first trimester, (iii) changing the reference group to women exposed to promethazine during the first trimester, (iv) changing the exposure group to women exposed to pyridoxine during the first trimester, (v) requiring ondansetron-exposed women to have filled at least two prescriptions during the first trimester, (vi) changing the exposure window to 6 to 12 weeks after the date of last menstrual period, (vii) using pregnancies with first exposure to ondansetron 5–8 months after the date of last menstrual period as the reference group, (viii) changing the exposure window to 5–8 months after the date of last menstrual period, which is after the etiologically-relevant window (negative control analysis). Panel A shows the unadjusted associations. Panel B shows the associations adjusted for all potential confounding variables (Propensity Score Level 2). For analyses (iv) and (vii), adjustment was done through 1:1 matching rather than fine stratification on the propensity score due to the relatively small size of the reference group compared to the exposed group.