What do medical sources say about Ondansetron (Zofran) during pregnancy?

1st Trimester: MotherToBaby says a few studies reported cleft lip or palate, an opening in the lip or roof of the mouth, or heart findings, but other studies did not confirm them. Huybrechts et al. (2018) estimated about 3 more oral cleft cases per 10,000 births among people who used oral ondansetron in the first trimester; after accounting for other factors, the study found no increase in heart or overall birth defects. The FDA label calls the findings inconsistent, while the European Medicines Agency said in 2019 that ondansetron should not be used during the first trimester. Pasternak et al. (2013) found no higher risk of miscarriage; studies of past medicine use cannot prove the medicine caused an outcome. ACOG says the decision depends on whether potential benefits outweigh risks. Ask your provider about your situation. 2nd Trimester: MotherToBaby reports that studies across pregnancy have not found higher rates of stillbirth, birth before 37 weeks, or low birth weight. Pasternak et al. (2013) also found no higher risk for these outcomes, but did not report a separate second-trimester estimate. A 2026 MotherToBaby Pregnancy Studies report found an association between ondansetron use and babies smaller than expected for their weeks of pregnancy, but gave no separate second-trimester result; its authors said more severe nausea may partly explain it. ACOG says decisions about ondansetron in pregnancy weigh potential benefits and risks. Ask your provider about your situation. 3rd Trimester: MotherToBaby reports that studies across pregnancy have not found higher rates of stillbirth, birth before 37 weeks, or low birth weight. Pasternak et al. (2013) also found no higher risk for these outcomes, but did not report a separate third-trimester estimate. A 2026 study of 260 pregnancies found no clear difference in major birth defects or newborn complications, but its authors said it was too small to detect very rare outcomes. Another 2026 study found an association with babies smaller than expected for their weeks of pregnancy; its authors said more severe nausea may partly explain it, and did not give a third-trimester estimate. Ask your provider about your situation.

What do medical sources say about Ondansetron (Zofran) while breastfeeding?

LactMed reports small amounts in milk after use just after delivery, an estimated infant dose equal to 3.7% of the mother's weight-adjusted dose from measurements in 78 mothers, and no infant effects in the studied setting. The 2025 Zofran label reports low milk and infant blood levels in samples from 80 women and 20 infants. MotherToBaby also reports small amounts in milk and no reported infant side effects. LactMed says use beyond the days just after birth has not been studied well, and the FDA label reports no milk-production data. Ask your provider about your situation.

Where do sources disagree on Ondansetron (Zofran) in pregnancy or breastfeeding?

First-trimester birth-defect findings and advice Huybrechts et al. found a small adjusted increase in oral clefts after first-trimester oral exposure, while EMA's 2019 PRAC recommendation says ondansetron should not be used during the first trimester. Huybrechts et al. found no adjusted increase in cardiac or overall congenital malformations. The FDA label describes inconsistent findings and important study limitations, and ACOG says the fetal evidence is unclear and that the decision depends on balancing potential benefits and risks. The sources emphasize different outcomes and apply different precaution thresholds. The oral-cleft signal is small in absolute terms and does not establish causation, while the overall and cardiac estimates in the largest cohort did not show an adjusted increase. The first-trimester oral-cleft finding is small in absolute terms and does not establish causation. The wider studies do not show an overall malformation increase, but the EMA recommendation differs from US sources. The evidence is mixed, so the sources should be shown side by side.

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Ondansetron

Medication

Zofran

5-HT3 receptor antagonist antiemetic

Pregnancy

Huybrechts et al. (2018) studied 1,816,414 Medicaid pregnancies, including 88,467 with first-trimester ondansetron exposure. Adjusted estimates showed no increase in cardiac malformations (RR 0.99) or overall congenital malformations (RR 1.01), but oral clefts had an adjusted RR of 1.24 and an adjusted risk difference of 2.7 per 10,000 births (95% CI 0.2 to 5.2). Pasternak et al. (2013) studied a Danish cohort of 608,385 pregnancies and found no significantly increased risk of spontaneous abortion, stillbirth, major birth defects, preterm delivery, low birth weight, or small-for-gestational-age birth. Yang et al. (2026) studied people with hyperemesis gravidarum in US healthcare records and found a lower observed risk of spontaneous abortion with ondansetron than with no antiemetic, with no association with stillbirth; the retrospective design cannot show that ondansetron caused the difference. Sillis et al. (2026) studied 2,711 pregnancies, including 286 ondansetron exposures. Ondansetron exposure was associated with small-for-gestational-age birth compared with untreated NVP (adjusted RR 1.80, 95% CI 1.23 to 2.60) and no NVP (adjusted RR 1.99, 95% CI 1.22 to 3.24); the authors said greater NVP severity may partly explain this finding. Tolchinsky et al. (2026) reported no significant difference in major congenital malformations or neonatal complications in a prospective cohort of 260 women, including 137 exposed, but noted that the small sample could miss rare outcomes. A 2026 scoping review included 39 studies, 34 of them on ondansetron; it found no overall congenital-anomaly increase but conflicting cardiac and orofacial findings. The review's search ended in May 2025, so it did not include the later 2026 cohorts.

Breastfeeding

LactMed (last revised June 15, 2025) summarizes a pharmacokinetic study of 78 postpartum women receiving intravenous ondansetron. The estimated daily infant dose from measured milk was 0.002 mg/kg and the relative infant dose was 3.7%; 20 infant plasma samples were collected, and no adverse infant effects were reported. Job et al. (2022) used a physiologically based pharmacokinetic model, predicting a daily infant dose of 0.005 mg/kg/day and a relative infant dose of 3.0% after a single 4 mg intravenous dose at two days postpartum. The FDA's February 2025 Zofran label reports low milk and infant plasma levels, a daily infant dose of 0.002 mg/kg/day, a relative infant dose of 3.7%, and no adverse effects attributed to ondansetron among exposed infants; it reports no milk-production data. The FDA label reports samples from 80 women, while LactMed and the primary study report 78 women in the analyzed cohort; the sources may be using different denominators. These data concern immediate-postpartum or perioperative use and do not establish longer-term outcomes during ongoing nursing.

First-trimester birth-defect findings and advice

Source A says: Huybrechts et al. found a small adjusted increase in oral clefts after first-trimester oral exposure, while EMA's 2019 PRAC recommendation says ondansetron should not be used during the first trimester. (Huybrechts et al., JAMA 2018: Association of Maternal First-Trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring, EMA PRAC Recommendations on Signals, adopted July 2019: Ondansetron in pregnancy)
Source B says: Huybrechts et al. found no adjusted increase in cardiac or overall congenital malformations. The FDA label describes inconsistent findings and important study limitations, and ACOG says the fetal evidence is unclear and that the decision depends on balancing potential benefits and risks. (Huybrechts et al., JAMA 2018: Association of Maternal First-Trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring, FDA-approved Zofran Prescribing Information, revised February 2025, ACOG: Morning Sickness: Nausea and Vomiting of Pregnancy)
Why they differ: The sources emphasize different outcomes and apply different precaution thresholds. The oral-cleft signal is small in absolute terms and does not establish causation, while the overall and cardiac estimates in the largest cohort did not show an adjusted increase.
Other sources: MotherToBaby reports that a few studies found small cleft or heart signals, that other studies did not confirm them, and that its summary of pregnancy studies found no overall increase in birth defects. (MotherToBaby: Ondansetron (Zofran) Fact Sheet)
What the evidence shows overall: The first-trimester oral-cleft finding is small in absolute terms and does not establish causation. The wider studies do not show an overall malformation increase, but the EMA recommendation differs from US sources. The evidence is mixed, so the sources should be shown side by side.

Small-for-gestational-age birth

Source A says: The 2026 MotherToBaby Pregnancy Studies cohort found an association between ondansetron exposure and small-for-gestational-age birth compared with untreated NVP and no NVP. (Sillis et al., Pharmacoepidemiology and Drug Safety 2026: Medications for NVP and adverse birth outcomes)
Source B says: Pasternak et al. (2013) did not find a significantly increased risk of small-for-gestational-age birth; the 2025 FDA label also summarizes a large retrospective cohort with no association for this outcome. (Pasternak et al., New England Journal of Medicine 2013: Ondansetron in pregnancy and risk of adverse fetal outcomes, FDA-approved Zofran Prescribing Information, revised February 2025)
Why they differ: The newer cohort included 286 ondansetron-exposed pregnancies and reported imprecise estimates. The authors noted that greater NVP severity among treated women may partly explain the association. Study populations, exposure definitions, and adjustment methods differ.
What the evidence shows overall: This is an association, not proof of cause. The study authors say more severe nausea may partly explain the result, and further study is needed.

Human milk information in older and newer labels

Source A says: The generic DailyMed entry and the 2021 Zofran label say it is not known whether ondansetron is present in human milk and report no data on breastfed infants or milk production. (DailyMed: Ondansetron hydrochloride tablets, oral use, FDA-approved Zofran Prescribing Information, revised October 2021)
Source B says: LactMed, the Job et al. primary study, and the February 2025 Zofran label report measured milk and infant-plasma levels after postpartum use, with low estimated infant doses and no reported infant effects in the studied setting. (LactMed: Ondansetron, Job et al., Clinical Pharmacology in Drug Development 2022: Development of a generic physiologically based pharmacokinetic model for lactation and prediction of ondansetron exposure via breast milk, FDA-approved Zofran Prescribing Information, revised February 2025)
Why they differ: The older label wording predates the published human pharmacokinetic study. The 2025 brand label incorporates those data, while the generic DailyMed label retains the earlier statement that human-milk presence is unknown.
What the evidence shows overall: The human data show measured low levels after immediate-postpartum intravenous use, but say little about longer-term exposure while nursing. The older generic label wording does not reflect the newer measurements.

Last reviewed 2026-10-16

Independent check 2026-10-16

Not yet clinician-reviewed

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