Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Cornell Medicine

Dr. Kandula reports no financial relationships relevant to this field of study.

SYNOPSIS: These authors analyzed data from a long-standing prospective cohort to study changes in prescribing habits and pregnancy outcomes following restriction on the use of valproic acid in women of child-bearing potential. Declining use of valproate and carbamazepine was associated with a decline in teratogenesis.

SOURCE: Tomson T, Battino D, Bonizzoni E, et al; EURAP Study Group. Declining malformation rates with changed antiepileptic drug prescribing: An observational study. Neurology 2019;93:e831-e840.

Since the initial publication of the 2009 American Academy of Neurology practice parameters¹ and NEAD study² (fetal antiepileptic drug exposure and cognitive outcomes), there has been increasing interest in both structural and cognitive teratogenesis with regard to anticonvulsant use. The global impact of both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) efforts to tighten the restrictions on the use of valproic acid has changed clinician prescription patterns with a gradual decline of valproic acid use during pregnancy. This decline has been mirrored across several large-scale pregnancy registries. In this article, the authors focused on analyzing pregnancy outcomes from EURAP (European anti-epileptic pregnancy registry) during the 14-year period (2000-2013) preceding the EMA’s introduction of further restrictions on valproic acid use.

The EURAP registry was established in 1999 and has involved 42 countries. Previously registered patients included pregnancies exposed to anticonvulsants at conception and enrolled within 16 weeks of gestation. Information on demographics, type of epilepsy, seizure frequency, comorbidities, family history of major congenital malformations, and drug treatment previously were obtained in early pregnancy per registry protocol. Follow-up data after each trimester, at birth, and one year after birth were collected by the treating physician and transferred online to a national coordinator in Italy. The authors’ analysis tracks the changes in anticonvulsant use and corresponding teratogenic outcomes for conception between the years 2000 and 2013. Those patients with incomplete medical reports or lost to follow-up were excluded. Intrauterine deaths, abortions, and pregnancies complicated by chromosomal and genetic abnormalities were excluded.

Data regarding seizure classification, family history of major congenital malformation, and folate use (initiated at a minimum dosage of 0.4 mg/d consistently at least three months before conception) were extrapolated and analyzed. Information on obstetrical outcomes and occurrence of convulsions during pregnancy were obtained from reporting physicians. To calculate frequencies of major congenital malformations (MCMs), the numerator was the sum of all live births plus pregnancy losses with confirmed MCMs, while the denominator included live births, pregnancies terminated electively for MCMs, and perinatal deaths.

Pregnancies then were divided into three groups based on the year of conception (2000-2005, 2006-2009, and 2010-2013) to analyze time trends. The first epoch, 2000 through 2005, was selected as the reference prior to the first set of important studies demonstrating increased risks with valproic acid published in 2004 and 2005. A second wave of influential studies providing comparative data on teratogenic effects of valproic acid were subsequently published between 2009 and 2011, hence supporting the split of time periods of 2006-2009 (pre-second-wave publications) and 2010-2013 (post-second-wave publications).

In total, 10,291 pregnancies met the criteria for inclusion in the analysis of treatment changes and seizure control, whereas 9,023 pregnancies met criteria for analysis of teratogenic outcomes.

Overall, the proportion of pregnancies with appropriate folic acid supplementation increased over time, but still remained below 50% throughout the 14-year period. The proportion of pregnancies exposed to anticonvulsant monotherapy was similar across all three periods (80.4-81.6%). However, a notable decline in the use of specific anticonvulsants, such as valproic acid (26% to 6%) and carbamazepine (41% to 13.5%), and an increase in the use of lamotrigine and levetiracetam were noted. The use of valproic acid in combination therapy also decreased markedly from the first to the second and third time periods.

The prevalence of MCMs with any monotherapy exposure decreased from 6.0% during 2000-2005 to 4.4% during 2010-2013. With regard to polytherapy, there was also a comparable reduction of 8.3% to 6.1% during 2000-2005 and 2010-2013, respectively. With regard to specific MCMs, an overall reduction for all subtypes was noted, with the exception of those with renal malformations and for multiple MCMs. There were no clinically significant changes in convulsion rate between the three time periods.

COMMENTARY

Overall, the study demonstrates a declining trend for the prevalence of MCMs over the 14-year time period. Adjustment for changes in anticonvulsant treatment resulted in elimination of the overall trend, suggesting that improved malformation outcomes were directly related to changes in anticonvulsant use and exposure, namely decreased use of both valproic acid and carbamazepine. Other smaller registries, including the Australian registry and United Kingdom and Ireland registry, found an overall reduction in prescribing of both valproic acid and carbamazepine, but no associated clinically significant improvement in teratogenic outcomes. Despite declining use of first-generation anticonvulsants, seizure control remained unchanged, suggesting equivalent efficacy of second-generation anticonvulsants with a better side effect and teratogenic profile. Further large-scale registries with prospective pregnancies are needed to verify the initial promising results of this analysis. In addition, data regarding long-term cognitive teratogenesis also are critical with regard to counseling women of child-bearing age optimally.

REFERENCES

1. 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;12:244-252.
2. 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;73:133-141.