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Invited Commentary
Pharmacy and Clinical Pharmacology
January 4, 2019

Fetal Valproate Exposure and Attention-Deficit/Hyperactivity Disorder

Author Affiliations
  • 1Stanford Neuroscience Health Center, Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California
JAMA Netw Open. 2019;2(1):e186603. doi:10.1001/jamanetworkopen.2018.6603

Attention-deficit/hyperactivity disorder (ADHD) is a common disorder in children and adolescents. It has multiple etiologies, but one underlying mechanism appears to be fetal exposure to certain drugs, which can be associated with behavioral teratogenic effects such as an increased risk of ADHD. One of the most commonly prescribed teratogenic drug classes during pregnancy is anticonvulsant medications, which are required owing to the risks posed by seizures to both the mother and child.1 In particular, fetal valproate exposure has been implicated as a risk for ADHD, but a recent meta-analysis of 5 published studies did not find a statistically significant increased risk of ADHD from valproate.2

Christensen et al3 examined the risk of ADHD from fetal valproate exposure using a population-based cohort study of children comprising all singleton births (913 302) in Denmark from 1997 through 2011, who were subsequently followed up through 2015. The investigators identified all children with ADHD via diagnosis in the Danish Psychiatric Central Register or by redeemed prescriptions for ADHD medications. Children who had fetal valproate exposure had a 48% risk of ADHD compared with unexposed children. When the analysis was restricted to children of women with epilepsy, the risk was 39%. When restricted to children of women without epilepsy, the risk was 89% for valproate-exposed children, but this was not statistically significant owing to small sample size.

Strengths of the study include the large population-based sample, lack of attrition, confirmed ADHD diagnosis combined with drug prescriptions for ADHD, and control for multiple potentially confounding factors such as maternal diagnosis of psychiatric disease, epilepsy, or diabetes; maternal age; maternal smoking; and child’s sex, parity, year of birth, and presence of other disorders such as congenital malformations. Limitations of the study include the observational nature, no assessment of seizures or of drug concentrations in the blood, and lack of control for all other fetal medication exposures, including prescription, recreational, and abused drugs (eg, alcohol).

The discrepancy between the present study and the prior meta-analysis might be due to the meta-analysis using different analytical approaches and examining studies with smaller sample sizes, higher attrition rates, shorter follow-ups, and cohort differences. Nevertheless, the findings by Christensen et al3 are consistent with multiple studies demonstrating adverse neurodevelopmental effects associated with fetal valproate exposure.

The risks of fetal valproate exposure include a 9% to 10% risk of major congenital malformations (highest risk among antiseizure medications),4-6 reduced IQ (reduced by 7-10 points compared with several commonly used antiseizure medications),7 a dose-dependent reduction not only for IQ but also across multiple cognitive domains (ie, language, nonverbal abilities, memory, and executive functions),7 and increased behavioral problems (eg, 4.42% absolute risk of autism spectrum disorder).8 Christensen et al3 now show that valproate was associated with an increased risk for ADHD.

The increased risks from fetal valproate exposure of major congenital malformations and neurodevelopmental problems including ADHD as well as other cognitive and behavioral problems should be communicated to women of childbearing potential who are prescribed valproate for epilepsy or other conditions. The counseling about valproate’s risks to women of childbearing potential should occur not only well before pregnancy but also at any time a prescription for valproate is written for a woman of childbearing potential since approximately half of pregnancies are unplanned. There are a limited number of women for whom valproate may be the best choice, but this should not be prescribed without appropriate informed consent.

Although fetal valproate exposure clearly poses a greater risk for both anatomical and behavioral teratogenesis than several other antiseizure medications, there remains a great need for further research as the teratogenic risks of many antiseizure medications remain uncertain.1 Given the potential lifelong consequences of fetal medication exposures, new approaches should be used to determine these risks more expediently. Considerations should include a national reporting system for congenital malformations, routine preclinical testing of all new antiseizure medications for neurodevelopmental effects, monitoring of antiseizure medication prescription practices for women of childbearing age to determine whether emerging knowledge is being appropriately applied, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms of anatomical and behavioral teratogenesis from antiseizure medications.1

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Article Information

Published: January 4, 2019. doi:10.1001/jamanetworkopen.2018.6603

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Meador KJ. JAMA Network Open.

Corresponding Author: Kimford J. Meador, MD, Stanford Neuroscience Health Center, Department of Neurology & Neurological Sciences, Stanford University School of Medicine, 213 Quarry Rd, MC 5979, Palo Alto, CA 94304-5979 (kmeador@stanford.edu).

Conflict of Interest Disclosures: Dr Meador reported receiving research support from the National Institutes of Health and Sunovion Pharmaceuticals, and travel support from UCB Pharma. The Epilepsy Study Consortium pays Dr Meador’s university for his research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals.

References
1.
Meador  KJ, Loring  DW.  Developmental effects of antiepileptic drugs and the need for improved regulations.  Neurology. 2016;86(3):297-306. doi:10.1212/WNL.0000000000002119PubMedGoogle ScholarCrossref
2.
Veroniki  AA, Rios  P, Cogo  E,  et al.  Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis.  BMJ Open. 2017;7(7):e017248. doi:10.1136/bmjopen-2017-017248PubMedGoogle ScholarCrossref
3.
Christensen  J, Pedersen  LH, Sun  Y, Dreier  JW, Brikell  I, Dalsgaard  S.  Association of prenatal exposure to valproate and other antiepileptic drugs with risk for attention-deficit/hyperactivity disorder in offspring.  JAMA Netw Open. 2019;2(1):e186606. doi:10.1001/jamanetworkopen.2018.6606Google Scholar
4.
Tomson  T, Battino  D, Bonizzoni  E,  et al; EURAP Study Group.  Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry.  Lancet Neurol. 2018;17(6):530-538. doi:10.1016/S1474-4422(18)30107-8PubMedGoogle ScholarCrossref
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Hernández-Díaz  S, Smith  CR, Shen  A,  et al; North American AED Pregnancy Registry.  Comparative safety of antiepileptic drugs during pregnancy.  Neurology. 2012;78(21):1692-1699. doi:10.1212/WNL.0b013e3182574f39PubMedGoogle ScholarCrossref
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North American AED (Antiepileptic Drug) Pregnancy Registry. Update on monotherapy findings. http://www.aedpregnancyregistry.org/wp-content/uploads/2016-newsletter-Winter-2016.pdf. Accessed November 17, 2018.
7.
Meador  KJ, Baker  GA, Browning  N,  et al; NEAD Study Group.  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-XPubMedGoogle ScholarCrossref
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.2013.2270PubMedGoogle ScholarCrossref
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