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

Educational Objective
To understand the benefits and risks of ondansetron use in pregnancy.
1 Credit CME
Key Points

Question  Is the use of ondansetron during pregnancy associated with increased risk of cardiac malformations and oral clefts in offspring?

Findings  In this cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10 000 women treated; adjusted relative risk, 1.24) but not cardiac malformations.

Meaning  Maternal use of ondansetron in the first trimester was associated with a small increased risk of oral clefts but no increased risk of cardiac malformations.

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.

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Article Information

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 (khuybrechts@bwh.harvard.edu).

Accepted for Publication: October 26, 2018.

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, Hernández-Díaz, Gray, Patorno, Desai, Bateman.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Huybrechts, Hernández-Díaz, Straub, Bateman.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Huybrechts, Hernández-Díaz, Straub, Mogun, Bateman.

Obtained funding: Huybrechts, Hernández-Díaz, Bateman.

Administrative, technical, or material support: Huybrechts, Straub, Bateman.

Supervision: Huybrechts, Hernández-Díaz, Bateman.

Conflict of Interest Disclosures: Dr Huybrechts reports receiving research grants to her institution from Eli Lilly, Pfizer, GlaxoSmithKline, and Boehringer-Ingelheim. Dr Patorno reports receiving research grants to her institution from Boehringer Ingelheim and GlaxoSmithKline. Dr Desai reports receiving grants to his institution from Merck, Bayer, and Vertex. Dr Bateman reports receiving grants to his institution from Eli Lilly, GlaxoSmithKline, Pacira, Baxalta, Pfizer, and Aetion and having served 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. Dr Hernández-Díaz reports receiving research grants to her institution from Eli Lilly, GlaxoSmithKline, and the National Institutes of Health and consulting fees from Roche and having served as an epidemiologist with the North America AED pregnancy registry, which is funded by multiple companies. Dr Gray reports consulting for Quest Diagnostics. No other conflicts of interest were reported.

Funding/Support: This study was supported by grant R03 HD091699 from the National Institute of Child Health and Human Development. Dr Huybrechts was supported by career development grant K01MH099141 from the National Institute of Mental Health. Dr Bateman was supported by career development grant K08HD075831 from the National Institute of Child Health and Human Development. Dr Gray was supported by career and development grant NIH K12 BIRCWH from the National Institutes of Health to Harvard Medical School. Dr Patorno was supported by career development grant K08AG055670 from the National Institute on Aging.

Role of the Funder/Sponsor: The National Institutes of Child Health and Human Development 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.

References
1.
Committee on Practice Bulletins-Obstetrics.  ACOG Practice Bulletin No. 189: Nausea and vomiting of pregnancy.  Obstet Gynecol. 2018;131(1):e15-e30. doi:10.1097/AOG.0000000000002456PubMedGoogle ScholarCrossref
2.
Siminerio  LL, Bodnar  LM, Venkataramanan  R, Caritis  SN.  Ondansetron use in pregnancy.  Obstet Gynecol. 2016;127(5):873-877. doi:10.1097/AOG.0000000000001375PubMedGoogle ScholarCrossref
3.
Abas  MN, Tan  PC, Azmi  N, Omar  SZ.  Ondansetron compared with metoclopramide for hyperemesis gravidarum: a randomized controlled trial.  Obstet Gynecol. 2014;123(6):1272-1279. doi:10.1097/AOG.0000000000000242PubMedGoogle ScholarCrossref
4.
Kashifard  M, Basirat  Z, Kashifard  M, Golsorkhtabar-Amiri  M, Moghaddamnia  A.  Ondansetrone or metoclopromide? which is more effective in severe nausea and vomiting of pregnancy? a randomized trial double-blind study.  Clin Exp Obstet Gynecol. 2013;40(1):127-130.PubMedGoogle Scholar
5.
Oliveira  LG, Capp  SM, You  WB, Riffenburgh  RH, Carstairs  SD.  Ondansetron compared with doxylamine and pyridoxine for treatment of nausea in pregnancy: a randomized controlled trial.  Obstet Gynecol. 2014;124(4):735-742. doi:10.1097/AOG.0000000000000479PubMedGoogle ScholarCrossref
6.
Taylor  LG, Bird  ST, Sahin  L,  et al.  Antiemetic use among pregnant women in the United States: the escalating use of ondansetron.  Pharmacoepidemiol Drug Saf. 2017;26(5):592-596. doi:10.1002/pds.4185PubMedGoogle ScholarCrossref
7.
Pasternak  B, Svanström  H, Hviid  A.  Ondansetron in pregnancy and risk of adverse fetal outcomes.  N Engl J Med. 2013;368(9):814-823. doi:10.1056/NEJMoa1211035PubMedGoogle ScholarCrossref
8.
Colvin  L, Gill  AW, Slack-Smith  L, Stanley  FJ, Bower  C.  Off-label use of ondansetron in pregnancy in Western Australia.  Biomed Res Int. 2013;2013:909860. doi:10.1155/2013/909860PubMedGoogle ScholarCrossref
9.
Einarson  A, Maltepe  C, Navioz  Y, Kennedy  D, Tan  MP, Koren  G.  The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study.  BJOG. 2004;111(9):940-943. doi:10.1111/j.1471-0528.2004.00236.xPubMedGoogle ScholarCrossref
10.
Anderka  M, Mitchell  AA, Louik  C, Werler  MM, Hernández-Diaz  S, Rasmussen  SA; National Birth Defects Prevention Study.  Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects.  Birth Defects Res A Clin Mol Teratol. 2012;94(1):22-30. doi:10.1002/bdra.22865PubMedGoogle ScholarCrossref
11.
Andersen  JT, Andersen  NL, Poulsen  HE.  Ondansetron use in early pregnancy and the risk of congenital malformationsa register based nationwide cohort study.  [abstract] Montreal, Canada: International Society of Pharmacoepidemiology; 2013.
12.
Parker  SE, Van Bennekom  C, Anderka  M, Mitchell  AA; National Birth Defects Prevention Study.  Ondansetron for treatment of nausea and vomiting of pregnancy and the risk of specific birth defects.  Obstet Gynecol. 2018;132(2):385-394. doi:10.1097/AOG.0000000000002679PubMedGoogle ScholarCrossref
13.
Practice Bulletin No.  Practice Bulletin No. 153: Nausea and vomiting of pregnancy.  Obstet Gynecol. 2015;126(3):e12-e24. doi:10.1097/AOG.0000000000001048PubMedGoogle ScholarCrossref
14.
Palmsten  K, Huybrechts  K, Mogun  H,  et al.  Harnessing the Medicaid Analytic eXtract (MAX) to evaluate medications in pregnancy: design considerations.  PLoS ONE. 2013;8(6):e67405. doi:10.1371/journal.pone.0067405PubMedGoogle ScholarCrossref
15.
Huybrechts  KF, Palmsten  K, Avorn  J,  et al.  Antidepressant use in pregnancy and the risk of cardiac defects.  N Engl J Med. 2014;370(25):2397-2407. doi:10.1056/NEJMoa1312828PubMedGoogle ScholarCrossref
16.
Patorno  E, Huybrechts  KF, Bateman  BT,  et al.  Lithium use in pregnancy and the risk of cardiac malformations.  N Engl J Med. 2017;376(23):2245-2254. doi:10.1056/NEJMoa1612222PubMedGoogle ScholarCrossref
17.
Bateman  BT, Hernandez-Diaz  S, Fischer  MA,  et al.  Statins and congenital malformations: cohort study.  BMJ. 2015;350:h1035. doi:10.1136/bmj.h1035PubMedGoogle ScholarCrossref
18.
Huybrechts  KF, Bateman  BT, Palmsten  K,  et al.  Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn.  JAMA. 2015;313(21):2142-2151. doi:10.1001/jama.2015.5605PubMedGoogle ScholarCrossref
19.
Palmsten  K, Hernández-Díaz  S, Chambers  CD,  et al.  The most commonly dispensed prescription medications among pregnant women enrolled in the US Medicaid program.  Obstet Gynecol. 2015;126(3):465-473. doi:10.1097/AOG.0000000000000982PubMedGoogle ScholarCrossref
20.
Palmsten  K, Huybrechts  KF, Kowal  MK, Mogun  H, Hernández-Díaz  S.  Validity of maternal and infant outcomes within nationwide Medicaid data.  Pharmacoepidemiol Drug Saf. 2014;23(6):646-655. doi:10.1002/pds.3627PubMedGoogle ScholarCrossref
21.
Cooper  WO, Hernández-Díaz  S, Gideon  P,  et al.  Positive predictive value of computerized records for major congenital malformations.  Pharmacoepidemiol Drug Saf. 2008;17(5):455-460. doi:10.1002/pds.1534PubMedGoogle ScholarCrossref
22.
Centers for Medicare & Medicaid Services. Medicaid Analytic eXtract (MAX) General Information. https://www.cms.gov/Research-Statistics-Data-and-Systems/Computer-Data-and-Systems/MedicaidDataSourcesGenInfo/MAXGeneralInformation.html. Accessed November 2017.
23.
Bateman  BT, Mhyre  JM, Hernandez-Diaz  S,  et al.  Development of a comorbidity index for use in obstetric patients.  Obstet Gynecol. 2013;122(5):957-965. doi:10.1097/AOG.0b013e3182a603bbPubMedGoogle ScholarCrossref
24.
Schneeweiss  S, Seeger  JD, Maclure  M, Wang  PS, Avorn  J, Glynn  RJ.  Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data.  Am J Epidemiol. 2001;154(9):854-864. doi:10.1093/aje/154.9.854PubMedGoogle ScholarCrossref
25.
Austin  PC.  Using the standardized difference to compare the prevalence of a binary variable between two groups in observational research.  Commun Stat Simul Comput. 2009;38(6):1228-1234. doi:10.1080/03610910902859574Google ScholarCrossref
26.
Desai  RJ, Rothman  KJ, Bateman  BT, Hernández-Díaz  S, Huybrechts  KF.  A propensity-score-based fine stratification approach for confounding adjustment when exposure is infrequent.  Epidemiology. 2017;28(2):249-257. doi:10.1097/EDE.0000000000000595PubMedGoogle ScholarCrossref
27.
Schneeweiss  S, Rassen  JA, Glynn  RJ, Avorn  J, Mogun  H, Brookhart  MA.  High-dimensional propensity score adjustment in studies of treatment effects using health care claims data.  Epidemiology. 2009;20(4):512-522. doi:10.1097/EDE.0b013e3181a663ccPubMedGoogle ScholarCrossref
28.
Rothman  KJ, Greenland  S, Lash  T. Precision and Statistics in Epidemiologic Studies. In: Rothman  K, Greenland  S, Lash  T, eds.  Modern Epidemiology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:148-167.
29.
Lang  JM, Rothman  KJ, Cann  CI.  That confounded P-value.  Epidemiology. 1998;9(1):7-8. doi:10.1097/00001648-199801000-00004PubMedGoogle ScholarCrossref
30.
Poole  C.  Beyond the confidence interval.  Am J Public Health. 1987;77(2):195-199. doi:10.2105/AJPH.77.2.195PubMedGoogle ScholarCrossref
31.
Danielsson  B, Wikner  BN, Källén  B.  Use of ondansetron during pregnancy and congenital malformations in the infant.  Reprod Toxicol. 2014;50:134-137. doi:10.1016/j.reprotox.2014.10.017PubMedGoogle ScholarCrossref
32.
Mines  D, Tennis  P, Curkendall  SM,  et al.  Topiramate use in pregnancy and the birth prevalence of oral clefts.  Pharmacoepidemiol Drug Saf. 2014;23(10):1017-1025. doi:10.1002/pds.3612PubMedGoogle ScholarCrossref
33.
Stephansson  O, Kieler  H, Haglund  B,  et al.  Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality.  JAMA. 2013;309(1):48-54. doi:10.1001/jama.2012.153812PubMedGoogle ScholarCrossref
34.
Markus  AR, Andres  E, West  KD, Garro  N, Pellegrini  C.  Medicaid covered births, 2008 through 2010, in the context of the implementation of health reform.  Womens Health Issues. 2013;23(5):e273-e280. doi:10.1016/j.whi.2013.06.006PubMed
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