Motherisk Int J 2020;1;22
Yusuf Cem Kaplan MD (1), Gideon Koren MD (2, 3)
Independent Researcher, Berlin, Germany (1), Adelson Faculty of Medicine, Ariel University (2) and Motherisk Israel Program (3)
I have a patient who has been receiving lamotrigine for her focal onset seizures. She is considering pregnancy and asked me whether she should receive standart or higher dose of folate supplementation while she is on anti-epileptic drug (AED) therapy.
It is still unclear whether the standart supplemental dosages of folic acid is sufficient or higher doses would provide additional protective benefits for major malformations in women using AEDs. For the neurodevelopment outcomes, some studies have shown the beneficial effects of folate supplementation. Women on AEDs should receive between 0.4 mg to 1 mg folate per day beginning during preconception and continued through pregnancy. A higher dose of folate (at least 4 mg/day) is suggested for the women on specific AEDs such as valproate (VPA) or carbamazepine (CBZ) or those with other causes of high risk of having an infant with neural tube defects.
The suggestion for use of pre-conceptional folate use in women with epilepsy is based on the observations regarding its protective effect against some major malformations and negative neurodevelopmental outcomes in the general population, as well as the absence of demonstrated adverse effects following routinely prescribed dosages (1).
Currently, the data regarding the optimal dose of folate supplementation for women with epilepsy receiving AEDs are limited and therefore it is unclear whether the standard supplemental dosages (0.4 to 0.8 mg/day) of folate is sufficient or higher doses would provide additional protective benefits for major malformations in this population (2). Nevertheless, the beneficial effects of folic acid supplementation on neurodevelopmental outcomes among the children of women using AEDs were shown in some studies (3-6). For example, Husebye and colleagues have shown an apparent protective effect of folic acid when supplementation takes place during the first 4 months of pregnancy (4).
The National Institute for Health and Care Excellence recommends all women with epilepsy who are planning a pregnancy should start to use 5 mg/day folate three months prior to pregnancy and continue this dose until birth (7), while The American College of Obstetricians and Gynecologists (8) suggests a dose of 4 mg/day for women has a high risk of having an infant with neural tube defects. These suggestions stem from the fact that the only prospective interventional study showing the protective effect of folate against neural tube defects by Wald et al among mothers at risk for recurrence used 4 mg/d (9). The recent International League Against Epilepsy Task Force on Women and Pregnancy report suggests that the women in the reproductive age who use AEDs should receive at least 0.4 mg folate per day (10) which is in line with the recommendation of American Academy of Neurology and American Epilepsy Society back in 2009 (2). Pennell and McElrath suggest the use of 1 mg/day folate for the women in reproductive age beginning prior to conception and continued through pregnancy, who are using AEDs. (11) The authors recommend a higher dose (4 mg/day), for those who are on CBZ and VPA therapy, or for women who have a history of a neural tube defect in their previous pregnancies or presence of parent affected by a neural tube defect (12). Again, these are based on Wald et al interventional study (9).
To date, a consensus on the optimual dose of daily folate supplementation for women who use AEDs and planning pregnancy, has not been reached. In general, women using AED should receive 0.4 to 1 mg per day beginning preconception and continued through pregnancy (10,11). However, higher doses are suggested (4 to 5 mg/day) if: 1) the woman is on VPA or CBZ 2) has other causes for a high risk of having an infant with neural tube defects, such as having a history of a neural tube defect in her previous pregnancies and/or presence of a parent affected by a neural tube defect (8, 11) .
- Harden, C.L.; Meador, K.J.; Pennell, P.B.; Hauser, W.A.; Gronseth, G.S.; French, J.A.; Wiebe, S.; Thurman, D.; Koppel, B.S.; Kaplan, P.W.; Robinson, J.N.; Hopp, J.; Ting, T.Y.; Gidal, B.; Hovinga, C.A.; Wilner, A.N.; Vazquez, B.; Holmes, L.; Krumholz, A.; Finnell, R.; Hirtz, D.; Le Guen, C.; American Academy of, N.; American Epilepsy, S. Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia, 2009, 50(5), 1237-1246. [http://dx.doi.org/10.1111/j.1528-1167.2009.02129.x] [PMID: 19507301].
- Harden, C.L.; Pennell, P.B.; Koppel, B.S.; Hovinga, C.A.; Gidal, B.; Meador, K.J.; Hopp, J.; Ting, T.Y.; Hauser, W.A.; Thurman, D.; Kaplan, P.W.; Robinson, J.N.; French, J.A.; Wiebe, S.; Wilner, A.N.; Vazquez, B.; Holmes, L.; Krumholz, A.; Finnell, R.; Shafer, P.O.; Le Guen, C.L.; American Academy of, N.; American Epilepsy, S. Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia, 2009, 50(5), 1247-1255. [http://dx.doi.org/10.1111/j.1528-1167.2009.02130.x] [PMID: 19507305].
- Meador, K.J.; Baker, G.A.; Browning, N.; Cohen, M.J.; Bromley, R.L.; Clayton-Smith, J.; Kalayjian, L.A.; Kanner, A.; Liporace, J.D.; Pennell, P.B.; Privitera, M.; Loring, D.W.; Group, N.S. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol, 2013, 12(3), 244-252. [http://dx.doi.org/10.1016/S1474-4422(12)70323-X] [PMID: 23352199].
- Husebye, E.S.N.; Gilhus, N.E.; Riedel, B.; Spigset, O.; Daltveit, A.K.; Bjork, M.H. Verbal abilities in children of mothers with epilepsy: Association to maternal folate status. Neurology, 2018, 91(9), e811-e821. [http://dx.doi.org/10.1212/WNL.0000000000006073] [PMID: 30068633].
- Husebye, E.S.N.; Gilhus, N.E.; Spigset, O.; Daltveit, A.K.; Bjork, M.H. Language impairment in children aged 5 and 8 years after antiepileptic drug exposure in utero - the Norwegian Mother and Child Cohort Study. Eur J Neurol, 2020, 27(4), 667-675. [http://dx.doi.org/10.1111/ene.14140] [PMID: 31814202].
- Bjork, M.; Riedel, B.; Spigset, O.; Veiby, G.; Kolstad, E.; Daltveit, A.K.; Gilhus, N.E. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. JAMA Neurol, 2018, 75(2), 160-168. [http://dx.doi.org/10.1001/jamaneurol.2017.3897] [PMID: 29279889].
- Epilepsies: diagnosis and management-NICE Clinical guideline. 2012, https://nice.org.uk/guidance/cg137/resources/epilepsies-diagnosis-and-management-35109515407813. (Accessed: Jul 27, 2020)
- Committee on Practice, B.-O. Practice Bulletin No. 187: Neural Tube Defects. Obstet Gynecol, 2017, 130(6), e279-e290. [http://dx.doi.org/10.1097/AOG.0000000000002412] [PMID: 29189693].
- MRC VITAMIN STUDY RESEARCH GROUP. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 338;131-137
- Tomson, T.; Battino, D.; Bromley, R.; Kochen, S.; Meador, K.; Pennell, P.; Thomas, S.V. Management of epilepsy in pregnancy: a report from the International League Against Epilepsy Task Force on Women and Pregnancy. Epileptic Disord, 2019, 21(6), 497-517. [http://dx.doi.org/10.1684/epd.2019.1105] [PMID: 31782407].
- Pennell, P.B.; Thomas, M. Management of epilepsy during preconception, pregnancy, and the postpartum period. Schachter, S.C., Lockwood, C.J.(Eds.); UpToDate, Inc.; 2020, https://uptodate.com/contents/management-of-epilepsy-during-preconception-pregnancy-and-the-postpartum-period. (Accessed: Jul 25, 2020)