Jun 8, 2021

Position Statement on the Use of Valproate by Women of Childbearing Potential

Updated June 8, 2021

Background

The American Epilepsy Society (AES) recognizes that research studies and international pregnancy registries have demonstrated that valproate (valproic acid, divalproex sodium) has a substantial risk of causing major congenital malformations (birth defects), lower intelligence quotient (IQ) scores, and other neurodevelopmental disorders, including autism, hearing impairment or loss, and ADHD in children born to mothers taking this medication during pregnancy for any reason.1-14 Increased awareness of valproate-associated safety risks has been cited as a factor in reduced rates of valproate prescription for women of childbearing potential and reduced rates of related teratogenesis. 15-17


FDA Valproate Warnings

The AES endorses the following warnings provided by the United States Food and Drug Administration (FDA) in valproate prescribing information.1-4

  • Women who are pregnant, or who plan to become pregnant, should not be treated with valproate for epilepsy or bipolar disorder unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. Valproate use is contraindicated for prophylaxis of migraine headaches in pregnant women and women of childbearing potential who are not using effective contraception.
  • Because of the risk to the fetus of decreased IQ, other neurodevelopmental disorders, and major congenital malformations, including neural tube defects, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such situations, effective contraception should be used. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as migraine prophylaxis.


Counseling Patients on Valproate Risks

Women of childbearing potential should be counseled regularly regarding the relative risks and benefits of valproate use during pregnancy.6,14,18-21 Given the high rates (>50%) of unplanned pregnancies,22,23 this includes women who are not planning a pregnancy and girls at the onset of puberty; alternative therapeutic options should be considered for these patients.14,15


Related Folic Acid Information

Supplemental folic acid, both prior to conception and during pregnancy, should be routinely recommended for patients using valproate.14,18 Although there is not clear evidence that folic acid reduces the risk of major congenital malformations in the children exposed to valproate, there is evidence that supplemental folic acid can partially lower the risk for decreased IQ and autistic traits in children born to women with epilepsy on anti-epileptic drugs.14,18,24-26


AES Recommendations

The AES encourages broad dissemination to providers of this important information about valproate. AES recommends that before healthcare providers treat any female of childbearing potential with valproate, they must inform the patient of these risks. Supplemental folic acid should be given to all females of childbearing potential.


References

  1. U.S. Food and Drug Administration. Depakote (divalproex sodium) delayed-release tablets, for oral use. Prescribing Information. Initial U.S. approval 1983, AbbVie, Inc., North Chicago, IL. Revised February 10, 2021. Accessed May 21, 2021.    https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/019680s051lbl.pdf
  2. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/valproate-information
  3. U.S. Food and Drug Administration. Drug Safety Communication: valproate anti-seizure products contraindicated for migraine prevention in pregnant women due to decreased IQ scores in exposed children. May 6, 2013. Accessed March 11, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-valproate-anti-seizure-products-contraindicated-migraine-prevention.
  4. U.S. Food and Drug Administration. Drug Safety Communication: Children born to mothers who took Valproate products while pregnant may have impaired cognitive development. June 30, 2011. Accessed May 24, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-children-born-mothers-who-took-valproate-products-while-pregnant-may
  5. Meador KJ, Reynolds MW, Crean S, Fahrbach K, Probst C. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res. 2008;81(1):1-13. doi: 10.1016/j.eplepsyres.2008.04.022
  6. Harden CL, Meador KJ, Pennell PB, et al. 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. doi:10.1111/j.1528-1167.2009.02129.x
  7. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013;12(3):244-252. doi:10.1016/S1474-4422(12)70323-X
  8. Christensen J, Grønborg TK, Sørensen MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309(16):1696-1703. doi:10.1001/jama.2013.2270
  9. Baker GA, Bromley RL, Briggs M, et al. IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study. Neurology. 2015;84(4):382-390. doi:10.1212/WNL.0000000000001182
  10. Meador KJ. Valproic acid: reducing the risks of prenatal exposure. Lancet Neurol. 2016;15(2):132-133. doi:10.1016/S1474-4422(15)00357-9
  11. Tomson T, Battino D, Perucca E. Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug. Lancet Neurol. 2016;15(2):210-218. doi:10.1016/S1474-4422(15)00314-2
  12. Meador KJ. Fetal Valproate Exposure and Attention-Deficit/Hyperactivity Disorder. JAMA Netw Open. 2019;2(1):e186603. Published 2019 Jan 4. doi:10.1001/jamanetworkopen.2018.6603
  13. Cohen MJ, Meador KJ, May R, et al. Fetal antiepileptic drug exposure and learning and memory functioning at 6 years of age: The NEAD prospective observational study. Epilepsy Behav. 2019;92:154-164. doi:10.1016/j.yebeh.2018.12.031
  14. Tomson T, Battino D, Bromley R, et al. 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. doi:10.1684/epd.2019.1105
  15. Tomson T, Battino D, Bonizzoni E, et al. Declining malformation rates with changed antiepileptic drug prescribing: An observational study. Neurology. 2019;93(9):e831-e840. doi:10.1212/WNL.0000000000008001
  16. Karlsson Lind L, Komen J, Wettermark B, von Euler M, Tomson T. Valproic acid utilization among girls and women in Stockholm: Impact of regulatory restrictions. Epilepsia Open. 2018;3(3):357-363. Published 2018 Jun 13. doi:10.1002/epi4.12228
  17. Puteikis K, Medžiaušaitė I, Mameniškienė R. Valproate utilisation trends among girls and women from 2013 to 2018. Seizure. 2019;70:77-81. doi:10.1016/j.seizure.2019.07.001
  18. Harden C, Lu C. Epilepsy in Pregnancy. Neurol Clin. 2019;37(1):53-62. doi:10.1016/j.ncl.2018.09.008
  19. Spiegel R, Merius H. Principles of Epilepsy Management for Women in Their Reproductive Years. Front Neurol. 2020;11:322. Published 2020 Apr 28. doi:10.3389/fneur.2020.00322
  20. Macfarlane A, Greenhalgh T. Sodium valproate in pregnancy: what are the risks and should we use a shared decision-making approach?. BMC Pregnancy Childbirth. 2018;18(1):200. Published 2018 Jun 1. doi:10.1186/s12884-018-1842-x
  21. Harden CL, Meador KJ, Pennell PB, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73(2):133-141. doi:10.1212/WNL.0b013e3181a6b312
  22. Herzog AG, Mandle HB, Cahill KE, Fowler KM, Hauser WA. Predictors of unintended pregnancy in women with epilepsy. Neurology. 2017;88(8):728-733. doi:10.1212/WNL.0000000000003637
  23. Herzog AG, Mandle HB, MacEachern DB. Prevalence of highly effective contraception use by women with epilepsy. Neurology. 2019;92(24):e2815-e2821. doi:10.1212/WNL.0000000000007581
  24. Harden CL, Pennell PB, Koppel BS, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73(2):142-149. doi:10.1212/WNL.0b013e3181a6b325
  25. Meador KJ, Pennell PB, May RC, et al. Effects of periconceptional folate on cognition in children of women with epilepsy: NEAD study. Neurology. 2020;94(7):e729-e740. doi:10.1212/WNL.0000000000008757
  26. Bjørk M, Riedel B, Spigset O, et al. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero [published correction appears in JAMA Neurol. 2018 Apr 1;75(4):518]. JAMA Neurol. 2018;75(2):160-168. doi:10.1001/jamaneurol.2017.3897

 

 

This update replaces the May 2019 AES Position Statement of the same title and was approved by the AES Treatments Committee June 2, 2021; approved by the AES Council on Clinical Activities June 2, 2021; and approved by the AES Board of Directors June 8, 2021.