Objective To examine the effect of maternal folic acid supplementation and maternal plasma folate and antiepileptic drug (AED) concentrations on language delay in AED-exposed children of mothers with epilepsy. Methods Children of mothers with and without epilepsy enrolled from 1999 to 2008 in the Norwegian Mother and Child Cohort study were included. Information on medical history, AED use, and folic acid supplementation during pregnancy was collected from parent-completed questionnaires. Maternal plasma folate and maternal plasma and umbilical cord AED concentrations were measured in blood samples from gestational weeks 17 to 19 and immediately after birth, respectively. Language development at 18 and 36 months was evaluated by the Ages and Stages Questionnaires. Results A total of 335 AED-exposed children of mothers with epilepsy and 104,222 children of mothers without epilepsy were surveyed. For those with no maternal periconceptional folic acid supplementation, the fully adjusted odds ratio (OR) for language delay in AED-exposed children compared to the controls at 18 months was 3.9 (95% confidence interval [CI] 1.9–7.8, p < 0.001) and at 36 months was 4.7 (95% CI 2.0–10.6, p < 0.001). When folic supplementation was used, the corresponding ORs for language delay were 1.7 (95% CI 1.2–2.6, p = 0.01) and 1.7 (95% CI 0.9–3.2, p = 0.13), respectively. The positive effect of folic acid supplement use on language delay in AED-exposed children was significant only when supplement was used in the period from 4 weeks before the pregnancy and until the end of the first trimester. Conclusion Folic acid use early in pregnancy may have a preventive effect on language delay associated with in utero AED exposure.

Background and purpose: The purpose was to examine the consequences of antiepileptic drug (AED) exposure during pregnancy on language abilities in children aged 5 and 8 years of mothers with epilepsy.Methods: The study population included children of mothers with and without epilepsy enrolled in the Norwegian Mother and Child Cohort Study 1999–2008. Mothers prospectively provided information on epilepsy diagnosis, AED use during pregnancy and the child’s language abilities at age 5 and 8 years, in questionnaires with validated language screening tools. AED concentrations in gestation week 17–19 and in the umbilical cord were measured.Results: The study population included 346 AED‐exposed and 388 AED‐unexposed children of mothers with epilepsy, and 113 674 children of mothers without epilepsy. Mothers of 117 and 121 AED‐exposed children responded to the questionnaires at age 5 and 8 years, respectively. For AED‐exposed children, the adjusted odds ratio for language impairment was 1.6 [confidence interval (CI) 1.1–2.5, P = 0.03] at age 5 years and 2.0 (CI 1.4–3.0, P < 0.001) at age 8 years, compared to children of mothers without epilepsy. Children exposed to carbamazepine monotherapy had a significantly increased risk of language impairment compared to control children at age 8 years (adjusted odds ratio 3.8, CI 1.6–9.0, P = 0.002). Higher maternal valproate concentrations correlated with language impairment at age 5 years. Periconceptional folic acid supplement use protected against AED‐associated language impairment.Conclusion: Foetal AED exposure in utero is associated with an increased risk of language impairment in children aged 5 and 8 years of mothers with epilepsy. Periconceptional folic acid use had a protective effect on AED‐associated language impairment.

Background and Objectives Women with epilepsy treated with antiseizure medication (ASM) have increased risk of pregnancy complications including preterm birth, fetal growth restriction, and preeclampsia. We aimed to investigate whether folic acid supplementation is associated with these pregnancy complications in women with epilepsy using ASM. Methods Singleton pregnancies in the prospective Norwegian Mother and Child Cohort Study (MoBa) (1999–2008) were included. Information on maternal epilepsy, ASM, folic acid supplementation, and pregnancy outcomes was obtained from the MoBa questionnaires and the Norwegian Medical Birth Registry. The main exposure, periconceptional folic acid supplementation, was defined as intake between 4 weeks before pregnancy and 12 weeks into pregnancy, retrospectively collected by recall of the mothers in weeks 17–19. The primary outcomes were preterm birth (gestational age <37 weeks at birth), small for gestational age (SGA), and preeclampsia. Results The study included 100,105 pregnancies: 99,431 without maternal epilepsy, 316 with maternal epilepsy and ASM exposure in pregnancy, and 358 with untreated maternal epilepsy. Among ASM-treated women with epilepsy, the risk of preterm birth was higher in those who did not use periconceptional folic acid (n = 64) compared with those who did (n = 245, the reference) (adjusted odds ratio [aOR] 3.3, 95% CI 1.2–9.2), while the risk of preterm birth among the reference was similar to the risk among women without epilepsy using folic acid periconceptionally (aOR 0.9, 95% CI 0.5–1.6). ASM-treated women with epilepsy starting folic acid after the first trimester had a higher risk compared with women without epilepsy with similar timing of folic acid (aOR 2.6, 95% CI 1.1–6.5), and even higher if not using folic acid (aOR 9.4, 95% CI 2.6–34.8). Folic acid was not associated with risk of preterm birth among women with epilepsy without ASM or among women without epilepsy. Folic acid was not associated with risk of preeclampsia or SGA among women with epilepsy. Discussion In women with epilepsy using ASM, periconceptional folic acid was associated with a lower risk of preterm birth. This finding supports the recommendation that ASM-treated women with epilepsy of childbearing potential should use folic acid supplementation on a regular basis. Classification of Evidence This study provides Class III evidence that for women with epilepsy using ASM, periconceptional folic acid supplementation decreases the risk of preterm birth.

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.

Fetal exposure to unmetabolized folic acid (UMFA) during pregnancy may be associated with adverse neurodevelopment. Antiseizure medication (ASM) may interact with folate metabolism. Women with epilepsy using ASM are often recommended high-dose folic acid supplement use during pregnancy. The aim was to determine the association between UMFA concentrations in pregnant women with epilepsy using ASM and risk of autistic traits or language impairment in their children aged 1.5–8 y. We included children of women with epilepsy using ASM and with plasma UMFA measurement enrolled in the Norwegian Mother, Father, and Child Cohort Study (MoBa). Data on ASM use, folic acid supplement use, autistic traits, and language impairment were obtained from parent-reported questionnaires during pregnancy and when the child was 1.5, 3, 5, and 8 y old. Plasma UMFA concentrations were measured during gestational weeks 17–19. A total of 227 ASM-exposed children of 203 women with epilepsy were included. Response rates at ages 1.5, 3, 5, and 8 y were 67% (n = 151), 54% (n = 122), 36% (n = 82), and 37% (n = 85), respectively. For 208 (94%) children, the mother reported intake of folic acid supplement. There was no association between UMFA concentrations and autistic traits score in the adjusted multiple regression analyses at age 3 y (unstandardized B: −0.01; 95% CI: −0.03, 0.004) or 8 y (unstandardized B: 0.01; 95% CI: −0.02, 0.03). Children exposed to UMFA had no increased risk of autistic traits at age 3 y [adjusted OR (aOR): 0.98; 95% CI: 0.2, 4.2] or 8 y (aOR: 0.1; 95% CI: 0.01, 1.4) compared with unexposed children. We found no association between UMFA concentrations and language impairment in children aged 1.5–8 y. Our findings do not support any adverse neurodevelopmental effects of UMFA exposure in utero in children of women with epilepsy using ASM.

Summary: Objective: Antiseizure medication (ASM) use interacts with vitamin B status in nonpregnant epilepsy populations. We aimed to examine the association between ASM and vitamin B status in pregnant women with epilepsy.Methods: We performed a cross‐sectional study of pregnancies in women with epilepsy enrolled in the Norwegian Mother, Father and Child Cohort Study from 1999 to 2008. Data on ASM and vitamin supplement use were collected from questionnaires. We analyzed maternal plasma concentrations of ASM and metabolites of folate, including unmetabolized folic acid (UMFA), riboflavin (vitamin B2), pyridoxine (vitamin B6), and niacin (vitamin B3) during gestational weeks 17–19.Results: We included 227 singleton pregnancies exposed to ASM with available plasma samples (median maternal age 29 years, range 18 to 41 years). From the preconception period to gestational week 20, any supplement of folic acid was reported in 208 of pregnancies (94%), riboflavin in 72 (33%), pyridoxine in 77 (35%), and niacin in 45 (20%). High ASM concentrations correlated with high concentrations of UMFA and inactive folate metabolites, and with low concentrations of riboflavin and metabolically active pyridoxine. There was no association between ASM and niacin status.Significance: ASM concentrations during pregnancy were associated with vitamin B status in pregnant women with epilepsy. Additional studies are needed to determine the clinical impact of these findings, and to define the optimal vitamin doses that should be recommended to improve pregnancy outcomes.