New-generation antiepileptic drugs during pregnancy and the risk of attention-deficit hyperactivity disorder A scoping review

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Christine Vaccaro
Ahmad Shakeri
Emily Czaplinski
Sherif Eltonsy


Adverse effects, Antiepileptic drugs, Attention Deficit Disorder with Hyperactivity, Epilepsy, Maternal Exposure, Scoping Review


The use of maternal antiepileptic drug (AED) during pregnancy is associated with an increased risk of cognitive adverse effects among the offspring. As new-generation AEDs continue to enter the market, evidence on their safety during pregnancy is limited yet necessary. To date, there are no published reviews summarizing the evidence of new-generation AED exposure in utero and the development of attention deficit-hyperactivity disorder (ADHD) in the offspring. The objective of this scoping review is to summa-rize the available evidence on the risk of ADHD after maternal exposure to new-generation AEDs during pregnancy. We searched EMBASE and MEDLINE for articles published from January 1988 to April 2020. New-generation AEDs were considered if marketed after 1988. ADHD was defined as attention-deficit hyperac-tivity disorder, hyperkinetic disorder, hyperkinesis, or conduct disorder. Of the total articles screened (n = 805), eight publications were finally included (seven cohort studies and one systematic review). Across the studies, the sample size of pregnant women exposed to AEDs ranged from 1 to 1383. Monotherapy was examined in six studies (mostly lamotrigine), while only two studies examined polytherapy. The included studies reported a range of adjusted relative risks, from 0.84 [0.59– 1.19] to 1.63 [0.41–6.06]. Lamotrigine monotherapy holds the largest body of evidence, concluding that no significant risk of ADHD exists among the offspring. However, the available evidence is considered scarce and has several method-ological limitations. Disentangling the effect of AEDs from epilepsy itself and examining polytherapies are challenges that merit additional investigations. Further comparative safety studies with longer follow-up periods and large sample sizes are needed to accurately quantify the true impact of new-generation AED exposure during pregnancy and ADHD in children.

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1. Borthen I, Eide MG, Veiby G, et al. Complications during pregnancy in women with epilepsy: Population-based cohort study. BJOG An Int J Obstet Gynaecol 2009;116(13):1736–42. https://
2. Brosh K, Matok I, Sheine E, et al. Teratogenic determinants of first- trimester exposure to antiepileptic medications. J Popul Ther Clin Pharmacol 2011; 18(1):e89–98.
3. Patel SI, Pennell PB. Management of epi-lepsy during pregnancy: An update. Ther Adv Neurol Disord 2016;9(2):118–29. https://doi. org/10.1177/1756285615623934
4. 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 out-comes. Neurology 2009; 73(2):133–41. https://doi. org/10.1212/WNL.0b013e3181a6b312
5. 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):1237–46. https://doi. org/10.1111/j.1528-1167.2009.02129.x
6. Samrén EB, Van Duijn CM, Koch S, et al. Maternal use of antiepileptic drugs and the risk of major con-genital malformations: A joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia 1997;38(9):981–90.
7. 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.
8. Tomson T, Battino D. Teratogenic effects of antiepileptic medications. Neurol Clin 2009; 27(4):993– 1002.
9. Tomson T, Battino D, Bonizzoni E, et al. 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. https://doi. org/10.1016/S1474-4422(18)30107-8
10. Meador KJ, Loring DW. Risks of in utero exposure to valproate. JAMA 2013; 309(16):1730–31. https://
11. Kilic D, Pedersen H, Kjaersgaard MIS, et al. Birth outcomes after prenatal exposure to antiepileptic drugs—A population-based study. Epilepsia 2014; 55(11):1714–21.
12. Razaz N, Tomson T, Wikström A-K, Cnattingius S. Association between pregnancy and perinatal outcomes among women with epilepsy. JAMA Neurol 2017;74(8):983. jamaneurol.2017.1310
13. Veroniki AA, Cogo E, Rios P, et al. Comparative safety of anti-epileptic drugs during pregnancy: A systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med 2017;15(1):95. s12916-017-0845-1
14. Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: An analysis of data from the EURAP
epilepsy and pregnancy registry. Lancet Neurol 2011;10(7):609–17.
15. Bromley R, Weston J, Adab N, et al. Treatment for epilepsy in pregnancy: Neurodevelopmental out-comes in the child. Cochrane Database Syst Rev 2014;2014(10): CD010236. 14651858.CD010236.pub2
16. Pennell PB. Too complicated or so simple: AED type and AED dose matter for pregnancy. Epilepsy Curr 2012;12(2):63–5.
17. Hill DS, Wlodarczyk BJ, Palacios AM, Finnell RH. Teratogenic effects of antiepileptic drugs. Expert Rev Neurother 2010;10(6):943–59. https://doi. org/10.1586/ern.10.57
18. Gedzelman E, Meador KJ. Antiepileptic drugs in women with epilepsy during pregnancy. Ther Adv Drug Saf 2012;3(2):71–87. https://doi. org/10.1177/2042098611433192
19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 (5th ed.). Washington, DC: American Psychiatric Publishing; 2013. books.9780890425596
20. Tarver J, Daley D, Sayal K. Attention-deficit hyperactivity disorder (ADHD): An updated review of the essential facts. Child Care Health Dev 2014;40(6):762–74.
21. National Collaborating Centre for Mental Health (UK). Attention deficit hyperactivity disorder: Diagnosis and management of ADHD in children, young people and adults. Vol 2009. (Alden Press, ed.). Leicester, UK: The British Psychological Society & The Royal College of Psychiatrists; 2009.
22. Ougrin D, Chatterton S, Banarsee R. Attention deficit hyperactivity disorder (ADHD): Review for primary care clinicians. London J Prim Care (Abingdon) 2010;3(1):45–51. 0/17571472.2010.11493296
23. Polanczyk G, De Lima MS, Horta BL, et al. The worldwide prevalence of ADHD: A systematic review and metaregression analysis. Am J Psychiatry 2007;164(6):942–8. https://doi. org/10.1176/ajp.2007.164.6.942
24. Cortese S, Coghill D. Twenty years of research on attention-deficit/hyperactivity disorder (ADHD): Looking back, looking forward. Evid Based Ment Health 2018;21(4):173–6. ebmental-2018-300050
25. Bromley RL, Mawer GE, Briggs M, et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry 2013;84(6):637–43.
26. Arksey H, O’Malley L. Scoping studies: Towards a methodological framework. Int J Soc Res Methodol Theory Pract 2005;8(1):19–32. https://
27. Tricco AC, Lillie E, Zarin W, et al. PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation. Ann Intern Med 2018;169(7):467– 73.
28. Eltonsy S, Kettani FZ, Blais L. Beta2-agonists use during pregnancy and perinatal outcomes: A systematic review. Respir Med 2014;108(1):9–33.
29. Bramer WM, Giustini D, De Jong GB, et al. De-duplication of database search results for systematic reviews in endnote. J Med Libr Assoc 2016;104(3): 240–3.
30. Christensen J, Pedersen L, Sun Y, et al. 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. jamanetworkopen.2018.6606
31. Miškov S, Gjergja Juraški R, Mikula I, et al. The croatian model of integrative prospective management of epilepsy and pregnancy. ACTA Clin Croat 2016;55(4):535–48. acc.2016.55.04.02
32. Charlton RA, McGrogan A, Snowball J, et al. Sensitivity of the UK clinical practice research datalink to detect neurodevelopmental effects of medicine exposure in Utero: Comparative analysis of an antiepileptic drug-exposed cohort. Drug Saf 2017;40(5):387–97. s40264-017-0506-5
33. Cohen MJ, Meador KJ, Browning N, et al. Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years. Epilepsy Behav 2013;29(2):308–15. https://doi. org/10.1016/j.yebeh.2013.08.001
34. Huber-Mollema Y, Oort FJ, Lindhout D, Rodenburg R. Behavioral problems in children of mothers with epilepsy prenatally exposed to val-proate, carbamazepine, lamotrigine, or levetiracetam monotherapy. Epilepsia 2019;60(6):1069–82.
35. Dean JCS, Hailey H, Moore SJ, et al. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J Med Genet 2002;39(4):251–9. jmg.39.4.251
36. Camm AJ, Fox KAA. Strengths and weak-nesses of “real-world” studies involving non-vitamin K antagonist oral anticoagulants. Open Hear 2018;5(1):e000788. openhrt-2018-000788
37. Stephen LJ, Brodie MJ. Antiepileptic drug monotherapy versus polytherapy: Pursuing seizure freedom and tolerability in adults. Curr Opin Neurol 2012;25(2):164–72. WCO.0b013e328350ba68
38. Cnossen MC, van Essen TA, Ceyisakar IE, et al. Adjusting for confounding by indication in observational studies: A case study in traumatic brain injury. Clin Epidemiol 2018;10:841–52. https://doi. org/10.2147/CLEP.S154500
39. Bebarta V, Luyten D, Heard K. Emergency medicine animal research: Does use of randomization and blinding affect the results? Acad Emerg Med 2003;10(6):684–7. https://doi. org/10.1111/j.1553-2712.2003.tb00056.x