Use of TOPAMAX in Pregnancy and Lactation

SUMMARY

• TOPAMAX^® can cause fetal harm when administered to a pregnant woman.¹
• Consider the benefits and the risks of TOPAMAX when administering this drug in women of childbearing potential, particularly when TOPAMAX is considered for a condition not usually associated with permanent injury or death.¹
• TOPAMAX should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.¹
• Data from pregnancy registries, the FAERS database², and routinely collected healthcare encounters indicate that infants exposed to TOPAMAX in utero have an increased risk of major congenital malformations (MCMs), including but not limited to, small for gestational age (SGA)^1,3-5, cardiovascular malformations and neurodevelopmental disorders^6-10, and cleft lip and/or cleft palate (oral clefts [OCs])^11-13.
  • The prevalence of SGA is greater in infants of women who received higher doses of TOPAMAX during pregnancy. The prevalence of SGA in infants of women who continued TOPAMAX use until later in pregnancy is higher compared to the prevalence in infants of women who stopped TOPAMAX use before the third trimester.¹
• The effect of TOPAMAX-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients and their newborns should be monitored for metabolic acidosis and treated as in the nonpregnant state.¹
• TOPAMAX is excreted in human milk. The effects of TOPAMAX on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive TOPAMAX treatment. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TOPAMAX and any potential adverse effects on the breastfed infant from TOPAMAX or from the underlying maternal condition.¹
• To provide information regarding the effects of in utero exposure to TOPAMAX, physicians are advised to recommend that pregnant patients taking TOPAMAX enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number, 1-888-233-2334, and must be done by the patients themselves. Information about the NAAED can be found at www.aedpregnancyregistry.org.¹

CLINICAL AND DATABASE ANALYSES

Ji et al (2025)² reported a retrospective disproportionality analysis of fetal disorder reports associated with AEDs identified from the Food and Drug Administration Adverse Event Reporting System (FAERS) database between the first quarter of 2004 and the fourth quarter of 2023. A total of 3046 reports of fetal disorders associated with AED exposure were included in the analysis. See Table: Signal Strength of Topamax-Related Fetal Disorders and Table: ROR and PRR Values for Fetal Diseases Associated with the Combined Use of 2 AEDs.

Seo et al (2026)⁸ reported a retrospective cohort study using National Health Insurance Service (NHIS) claims data from January 2010 to December 2020. The study included pregnancies among women aged 19-44 years who delivered between January 2012 and December 2020 and had a diagnosis of epilepsy (G40) or status epilepticus (G41) recorded at least twice, or at least 1 hospitalization with either diagnosis, within the 2 years before pregnancy onset. Pregnant women were categorized into 4 exposure subgroups based on ASM use: exposure during the first trimester (T1), exposure during the first 140 days of pregnancy, exposure only after day 141 until delivery, and continuous exposure throughout pregnancy. The nonexposed comparator group comprised pregnant women with epilepsy who had no ASM prescriptions from 90 days before conception through delivery. Following propensity score adjustment, the exposed and nonexposed groups each included 2,662 pregnancies. See Table: Risk of Congenital Malformations in Infants Exposed to TOPAMAX Monotherapy and Table: Risks of Individual Categories of Defects in Infants Following Maternal Exposure to TOPAMAX Dual Therapy During the First Trimester.

Sheehy et al (2026)⁹ reported a multiprovincial, multinational cohort study including 5 cohorts of live-born children from Canada (Alberta, Manitoba, Ontario, and Quebec) and the US (US AM-PREGNANT). The study included all live births to pregnant individuals aged 15-45 years with at least 12 months of follow-up. In utero antiseizure medication (ASM) exposure was assessed during the 60 days before birth using dispensations classified under Anatomical Therapeutic Chemical (ATC) code N03A. Children were considered exposed if an ASM was dispensed within 60 days before birth or earlier, provided that the duration of exposure overlapped this period. The study included 2,910,206 children, with data spanning 2009-2019 for Alberta, 1996-2020 for Manitoba, 1998-2015 for Ontario and Quebec, and 2003-2021 for the US cohort. Overall, 13,805 (0.47%) children were exposed in utero to ASMs during the 60 days preceding birth. For combined neurodevelopmental disorders (NDDs), TOPAMAX exposure was reported with a pooled-adjusted hazard ratio (P-aHR) of 1.56 (95% CI, 1.04-2.34; 69 exposed cases). TOPAMAX exposure was also associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD; P-aHR, 1.62; 95% CI, 1.06-2.48; 33 exposed cases) and behavioral disorders (BDs; P-aHR, 1.43; 95% CI, 1.01-2.03; 39 exposed cases).

Straub et al (2026)¹⁰ reported a population-based cohort study using the Medicaid Analytic eXtract/Transformed Medicaid Statistical Information System Analytic Files (MAX/TAF; 2000-2018) and the Merative MarketScan Commercial Claims and Encounters Database (MarketScan; 2003-2021). The study included publicly and commercially insured pregnant women with epilepsy and their live-born children. Children were classified as exposed if their mothers had filled at least one prescription for an ASM, either as monotherapy or polytherapy, during the second half of pregnancy. The analysis included 7245 unexposed and 10,345 ASM-exposed pregnancies in MAX/TAF and 1642 unexposed and 4648 ASM-exposed pregnancies in MarketScan. Among 23,880 eligible children, the average follow-up length was 3.4 years; 5,505 children were followed for ≥5 years and 2516 for ≥8 years. TOPAMAX exposure was associated with an increased risk of intellectual disability, with a hazard ratio of 3.3 (95% CI, 1.29-8.41). See Table: HRs (95% CIs) for Neurodevelopmental Disorders Associated With Prenatal TOPAMAX Exposure.

Laspro et al (2025)¹¹ used data from Epic Cosmos, a database containing deidentified electronic health records from healthcare institutions across the US, to analyze a population isolated from all patients on or after January 1, 2013, and before January 1, 2023. Gestational medication exposure was identified from medications prescribed, provider-administered, or reported by mothers at any time during pregnancy. A total of 12,098 newborns with available maternal pharmacologic data were identified. Among patients with OC, TOPAMAX was among the notable significant exposures reported during gestation (OR, 1.35; 95% CI, 1.13-1.62). See Table: TOPAMAX Data from Cohort Subgroup Analyses (95% CIs).

Blotiere et al (2019)¹² reported an observational cohort analysis of pregnancies ≥20 weeks exposed to one of 10 different antiepileptic drugs (AEDs) collected from French nationwide healthcare databases, January 2011-March 2015. Exposure was defined as an AED dispensed 1 month before and 2 months after the beginning of pregnancy. A sensitivity analysis was also conducted, which limited the dispensing window to the first 2 months of pregnancy. There were 517 pregnancies exposed to TOPAMAX out of a cohort of 1,886,825 pregnancies, where exposure to TOPAMAX was associated with an increased risk of cleft lip, with or without cleft palate (odds ratio [OR], 6.8; 95% confidence interval [CI], 1.4-20). In the sensitivity analysis, exposure to TOPAMAX was associated with an increased risk of hypospadias (OR 4.9, 95% CI, 1.0-14.6). This is consistent with previous literature.

Mines et al (2014)¹³ conducted a retrospective cohort study using 4 large United States (US) healthcare databases. The study included women with an identifiable infant born between 1997 and 2010 and had at least 90 days of post-delivery enrollment. TOPAMAX exposure was identified using prescription claims data or Kaiser Permanente Northern California (KPNC) pharmacy records, with first-trimester exposure defined as mediation dispensed during or before the first trimester with sufficient supply extending into that period. Across all centers, 1945 TOPAMAX-exposed mother-infant dyads, 13,512 formerly exposed dyads, and 13,614 dyads with similar medical profiles (the two comparator cohorts) were identified. The pooled birth prevalence (95% CI) of OCs was 3.6 (0.9-6.3) per 1000 infants in the TOPAMAX cohort, 1.4 (0.8-2.1) per 1000 infants in the formerly exposed cohort, and 0.7 (0.2-1.1) per 1000 infants in the similar medical profiles cohort.

Pregnancy Registries

Additional Pregnancy Registry Data

Additional registry citations have been identified in the published literature.^4,20-22Specific reports on TOPAMAX outcomes are limited. AED pregnancy registries that did not include TOPAMAX data were beyond the scope of this communication.

Clinical Data - Use in Lactation

Kacirova (2021)²³ reported levels of TOPAMAX found in colostrum, mature maternal milk, and breastfed infants of 27 women treated with TOPAMAX at delivery and/or during breastfeeding from 2004 to 2020. Maternal, umbilical cord, breast milk and infant serum TOPAMAX levels were measured in three subgroups: delivery, colostrum (3-4 days postpartum) and mature milk (7-30 days postpartum).

TOPAMAX levels ranged from 1.0 to 7.1 mg/L in maternal serum and from 0.8 to 6.2 mg/L in umbilical cord serum. The mean umbilical cord/maternal serum ratio was 0.93±0.11 mg/L confirming transplacental passage of TOPAMAX. There was a significant correlation between umbilical cord serum and maternal serum levels (P< 0.0001)

TOPAMAX concentrations 3-4 days post-delivery ranged from 1.4-8.4 mg/L in maternal serum, 1.5-8.6 mg/L in breast milk, and 0.3-4.4 mg/L in infant serum. Significant correlations were found between milk and maternal serum levels (P=0.0001) and infant serum and maternal levels (P=0.0009). The mean breast milk/maternal serum ratio was 0.99±0.45 and the infant/maternal serum ratio was 0.25±0.15. The infant/maternal serum ratio was significantly lower than the milk/maternal serum ratio (P<0.0001).

At 7-30 days post-delivery, maternal serum levels varied from 1.9 to 9.7 mg/L, milk levels ranged from 2.3 to 10.6 mg/L and infant serum levels ranged from 0.3 to 6.5 mg/L. Paired breast milk and maternal serum levels were not significantly different (P=0.8712). The mean milk/maternal serum ratio was 1.07±0.31, and the mean infant/maternal serum ratio was 0.51±0.27. Sixty percent of maternal serum concentrations were in the reference range used for the general epileptic population (5-20 mg/L).²⁴ One infant serum level (6.5 mg/L) was found to be in the reference range; the remaining were lower (2 were found below the lower limit of quantification).

Ohman (2002)²⁵ reported on TOPAMAX concentrations in plasma and breast milk in 5 women with epilepsy treated with TOPAMAX during lactation. Blood samples were collected from mothers at delivery, the umbilical cord and newborns at 24, 48 and 72 hours after delivery. Transplacental transfer of TOPAMAX was evident as umbilical cord and maternal plasma levels were similar. At 24 hours, infant TOPAMAX plasma levels were 33-45% lower than levels in the umbilical cord. TOPAMAX plasma levels and milk/plasma ratios at the time of breastfeeding, 2-3-weeks, 1 month and 3 months after delivery were collected. Three weeks after delivery, the mean milk/maternal plasma ratio was 0.86 (range, 0.67-1.1) before nursing. TOPAMAX concentrations in milk and maternal plasma levels were similar from 2 to 3 weeks up to 3 months (0.69) after delivery. The concentrations in the breastfed infants were approximately 10-20% of the mothers’ plasma levels. The absolute approximate dose to infant was 0.1-0.7 mg/kg/day assuming a daily milk intake of 150 mL/day/kg.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 30 June 2026. Additional relevant citations identified in the published literature are provided here for your reference.^26-29