Relative risks and 95% CIs are presented to show the risk of any congenital malformation, cardiac malformations, and oral clefts among infants born to women with exposure to intravenous ondansetron during the first trimester compared with infants born to women without such exposure.
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Huybrechts KF, Hernandez-Diaz S, Straub L, et al. Intravenous Ondansetron in Pregnancy and Risk of Congenital Malformations. JAMA. 2020;323(4):372–374. doi:10.1001/jama.2019.18587
A population-based cohort study previously evaluated the association between first-trimester exposure to the oral formulations of ondansetron and congenital malformations. After accounting for potential confounding variables, there was no significant association with congenital malformations overall or cardiac malformations, but a small increased risk of oral clefts could not be excluded.1 Subsequent research has suggested that intravenous administration of ondansetron may be associated with greater risks of cardiac malformations and oral clefts.2 Potential explanations for the apparent difference in teratogenic effect of intravenous compared with oral formulations include (1) residual confounding by indication and associated factors (eg, nutritional deficiencies) in women with hyperemesis severe enough to require intravenous medication, (2) higher doses administered intravenously vs orally, and (3) higher specificity for exposure because studies of oral use in health care utilization data are based on dispensed medication, and not all women may consume the medication as prescribed. We therefore conducted a follow-up study to examine the association between intravenous ondansetron and congenital malformations.
The data source, study design, and analytic methods were the same as described in our previously published evaluation of oral ondansetron.1 Briefly, we used a mother-infant–linked cohort nested in the 2000 to 2014 Medicaid Analytic eXtract.3 The research was approved by the institutional review board of Brigham and Women’s Hospital, with waiver of informed consent.
Women were considered exposed if a claim for Healthcare Common Procedure Coding System code J2405 indicating ondansetron injection was recorded during the first trimester of pregnancy. The reference group consisted of women without exposure to either oral or intravenous ondansetron from 3 months before the start of pregnancy through the end of the first trimester. Outcomes included cardiac malformations, oral clefts, and congenital malformations overall. Potential confounders and proxies for confounders considered are shown in the Table.
Relative risks (RRs) and risk differences (RDs) with their 95% CIs were estimated using generalized linear models. Propensity score (PS) fine stratification was used for confounding adjustment (50 strata based on the PS distribution in the exposed); all covariates listed in the Table were used to estimate the PS. Weighted regression models were used to derive the adjusted associations.4 All analyses were conducted using SAS version 9.4 (SAS Institute). Precision around the measures of association is provided using 2-sided 95% CIs.
The cohort consisted of 1 880 594 pregnancies, of which 23 877 (1.3%) received at least one ondansetron injection during the first trimester. Characteristics of exposed and unexposed women were well balanced after PS stratification (Table).
The adjusted RR for cardiac malformations was 0.97 (95% CI, 0.86-1.10) and the adjusted RD was −2.9 (95% CI, −15.7 to 9.8) per 10 000 births. For oral clefts, the adjusted RR was 0.95 (95% CI, 0.63-1.43) and the adjusted RD was −0.5 (95% CI, −4.5 to 3.5) per 10 000 births. For malformations overall, the RR was 1.02 (95% CI, 0.96-1.08) and the RD was 7.1 (95% CI, −17.9 to 32.2) per 10 000 births (Figure).
Evidence from this national cohort of publicly insured pregnant women with confounding adjustment suggests that intravenously administered ondansetron was not associated with an increase in the risk of cardiac malformations, oral clefts, or congenital malformations overall. While the point estimate for oral clefts was lower for intravenous ondansetron compared with oral ondansetron (RR, 1.24 [95% CI, 1.03-1.48]), the CI was wide with an upper limit similar to that for oral ondansetron.1
The strengths and limitations of using large health care databases to evaluate drug safety in pregnancy have been described.5 Limitations of this study include the potential for residual confounding due to unmeasured or poorly measured characteristics, restriction of the cohort to live births and individuals with Medicaid, and availability of data through 2014 only.1 An advantage of studying intravenous administration of ondansetron is the high specificity for exposure because a claim for reimbursement is generated. Overall, these findings suggest that ondansetron is not a major teratogen.1
Accepted for Publication: October 23, 2019.
Corresponding Author: Krista F. Huybrechts, MS, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, 1620 Tremont St, Ste 3030, Boston, MA 02120 (firstname.lastname@example.org).
Published Online: November 15, 2019. doi:10.1001/jama.2019.18587
Author Contributions: Dr Huybrechts had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Huybrechts, Hernandez-Diaz, Gray, Bateman.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Huybrechts, Hernandez-Diaz, Straub, Bateman.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Huybrechts, Hernandez-Diaz, Straub, Mogun, Bateman.
Obtained funding: Huybrechts, Hernandez-Diaz, Bateman.
Administrative, technical, or material support: Huybrechts, Straub, Zhu, Bateman.
Supervision: Huybrechts, Hernandez-Diaz, Bateman.
Conflict of Interest Disclosures: Dr Huybrechts reported receiving research grants to her institution from Eli Lilly, Pfizer, GlaxoSmithKline, and Boehringer-Ingelheim outside the submitted work. Dr Hernandez-Diaz reported receiving research grants to her institution from Eli Lilly and GlaxoSmithKline outside the submitted work; consulting fees from Roche; and serving as an epidemiologist with the North America Antiepileptic Drug Pregnancy Registry, which is funded by multiple companies. Dr Gray reported receiving personal fees from Quest Diagnostics and nonfinancial support from Illumina Inc. Dr Bateman reported receiving research grants to his institution from Eli Lilly, Pfizer, GlaxoSmithKline, Pacira, and Baxalta outside the submitted work; consulting for Aetion; and serving on an expert panel for a postpartum hemorrhage quality improvement project that was conducted by the Association of Women's Health, Obstetric, and Neonatal Nurses and funded by a grant from Merck for Mothers. No other disclosures were reported.
Funding/Support: This study was supported by an R03 grant (R03 HD091699) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Gray was supported by the NIH K12 BIRCWH career development grant to Harvard Medical School.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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