ImportanceWomen with epilepsy are recommended high doses of folic acid before and during pregnancy owing to risk of congenital anomalies associated with antiseizure medications. Whether prenatal exposure to high-dose folic acid is associated with increases in the risk of childhood cancer is unknown.ObjectiveTo assess whether high-dose folic acid supplementation in mothers with epilepsy is associated with childhood cancer.Design, Setting, and ParticipantsObservational cohort study conducted with nationwide registers in Denmark, Norway, and Sweden from 1997 to 2017. Analyses were performed during January 10, 2022, to January 31, 2022. Mother-child pairs were identified in medical birth registers and linked with information from patient, prescription, and cancer registers, as well as with sociodemographic information from statistical agencies, and were categorized by maternal diagnosis of epilepsy. The study population consisted of 3 379 171 children after exclusion of 126 711 children because of stillbirth or missing or erroneous values on important covariates.ExposuresMaternal prescription fills for high-dose folic acid tablets (≥1 mg daily) between 90 days before pregnancy start and birth.Main Outcomes and MeasuresFirst onset of childhood cancer at younger than 20 years. Cox proportional hazards models were used to calculate adjusted hazard ratios with corresponding 95% CIs, adjusted for potential confounders. Cumulative incidence at aged 20 years was used as a measure of absolute risk.ResultsThe median age at the end of follow-up in the study population of 3 379 171 children was 7.3 years (IQR, 3.5-10.9 years). Among the 27 784 children (51.4% male) born to mothers with epilepsy, 5934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with 18 exposed cancer cases compared with 29 unexposed, producing an adjusted hazard ratio of 2.7 (95% CI, 1.2-6.3), absolute risk if exposed of 1.4% (95% CI, 0.5%-3.6%), and absolute risk if unexposed of 0.6% (95% CI, 0.3%-1.1%). In children of mothers without epilepsy, 46 646 (1.4%) were exposed to high-dose folic acid (mean dose, 2.9 mg), with 69 exposed and 4927 unexposed cancer cases and an adjusted hazard ratio of 1.1 (95% CI, 0.9-1.4; absolute risk, 0.4% [95% CI, 0.3%-0.5%]). There was no association between children born to mothers with epilepsy who were prenatally exposed to antiseizure medications, but not high-dose folic acid, and an increased risk of cancer (absolute risk, 0.6%; 95% CI, 0.2%-1.3%).Conclusions and RelevancePrenatal exposure to high-dose folic acid was associated with increased risk of cancer in children of mothers with epilepsy.

COMMENT & RESPONSEIn Reply We thank Voinescu and colleagues for their comments on our recent article in JAMA Neurology. 1 We agree that there is no study to date to help in determining the optimal dose of folic acid supplementation for women with epilepsy. Our findings of an increased risk of cancer in children of mothers with epilepsy who are taking antiseizure medication and are exposed to high-dose folic acid indicate that there could be an upper dose limit above which the risks outweigh the benefits. This suggests an upper limit below the 4 to 5 mg per day recommended dosage to mothers with epilepsy by some major guidelines (eg, National Institute for Health and Care Excellence, Scottish Intercollegiate Guidelines Network).Unfortunately, for mothers with epilepsy, high-level evidence of the dose-related beneficial effects of folic acid supplementation on pregnancy outcomes is lacking. The classic randomized double-blind study demonstrating the efficacy of folic acid, 4 mg daily, in reducing the risk of neural tube defects in high-risk pregnancies excluded women with epilepsy. 2 Observational studies, such as the large-scale antiepileptic drugs and pregnancy registers, have failed to find an association between periconceptional folic acid supplementation and a reduced prevalence of major congenital malformations. 3,4 In contrast to studies of structural teratogenicity, other observational studies have reported improved developmental outcomes in the offspring of women with epilepsy associated with folic acid supplementation as referred to by Voinescu and colleagues in their letter, including full-scale IQ. 5 Although provision of folic acid supplementation to mothers with epilepsy who are taking antiseizure medications during pregnancy was clearly associated with important improvements in outcome, the appropriate dose remained unclear. The most frequently prescribed folic acid dose in the study by Meador and colleagues 5 was 4 mg or more daily, but only 6 of 225 children used doses of 0.4 mg or less. As stated by the authors, the group with the lowest dose (>0-0.4 mg daily) had an intermediate IQ between those of the group without folic acid and the group receiving greater than 0.4 mg daily, but it did not differ statistically from other groups.As stressed by Voinescu and colleagues, the results of our observational study indicating increased childhood cancer risk with high-dose folic acid supplementation needs to be replicated in independent studies. However, this discussion also highlights the need to determine what dose levels of folic acid are needed to obtain the beneficial effects. In the absence of this information, we suggest following guidelines for preg-nant women in general and to supplement at least 0.4 mg daily for women with epilepsy keeping folic acid doses less than or equal to 4 mg daily. Given the importance of the issue, it seems appropriate to consider performing randomized clinical studies comparing different dose levels of periconceptional folic acid supplementation to mothers receiv...

Women using antiseizure medication in pregnancy are often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that have emerged.

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Background Although some antiseizure medications (ASMs) are teratogenic, most people with epilepsy need treatment in pregnancy. The risk of ASM fetotoxicity may be mitigated with folic acid. High-dose folic acid supplementation has traditionally been recommended before and during gestation despite little evidence of efficacy and safety for this patient group. Several studies have investigated the potential benefits and risks of folic acid supplements. Objective To provide an updated overview of the risks, benefits, and rationale for use of folic acid supplementation in relation to pregnant people of childbearing age using ASM. Materials and methods This is a narrative review based on an unstructured literature search of PubMed. We also scrutinized neurological and obstetrical guidelines. Results Antiseizure medication can decrease folate concentrations. In children exposed to ASM prenatally, those born to persons using folic acid supplements periconceptionally had lower risk of adverse neurodevelopment and preterm birth. It remains unclear whether the risk for congenital malformations can be equally alleviated. In studies of the general population, high plasma folate concentrations and/or high-dose folic acid supplements were associated with adverse neurodevelopmental outcomes. This has not been seen in children of mothers with epilepsy. However, an increased cancer risk has been found in children of mothers with epilepsy using high-dose folic acid supplements in pregnancy. Conclusion The optimal folic acid dose is not clear for persons of childbearing potential with epilepsy using ASM. Both low and excess folate status during pregnancy have been associated with adverse neurodevelopment. We propose an individual folic acid supplement dose that should be titrated based on maternal plasma folate concentrations during pregnancy.