Influencing clinical practice regarding the use of antiepileptic medications during pregnancy: Modeling the potential impact on the prevalences of spina bifida and cleft palate in the United States

Abstract

Selected antiepileptic drugs (AEDs) increase the risk of birth defects. To assess the impact of influencing AED prescribing practices on spina bifida and cleft palate we searched the literature for estimates of the association between valproic acid or carbamazepine use during pregnancy and these defects and summarized the associations using meta-analyses. We estimated distributions of the prevalence of valproic acid and carbamazepine use among women of childbearing age based on analyses of four data sets. We estimated the attributable fractions and the number of children born with each defect that could be prevented annually in the United States if valproic acid and carbamazepine were not used during pregnancy. The summary odds ratio estimate for the association between valproic acid and spina bifida was 11.9 (95% uncertainty interval (UI): 4.0-21.2); for valproic acid and cleft palate 5.8 (95% UI: 3.3-9.5); for carbamazepine and spina bifida 3.6 (95% UI: 1.3-7.8); and for carbamazepine and cleft palate 2.4 (95% UI: 1.1-4.5) in the United States. Approximately 40 infants (95% UI: 10-100) with spina bifida and 35 infants (95% UI: 10-70) with cleft palate could be born without these defects each year if valproic acid were not used during pregnancy; 5 infants (95% UI: 0-15) with spina bifida and 5 infants (95% UI: 0-15) with cleft palate could be born without these defects each year if carbamazepine were not used during pregnancy. This modeling approach could be extended to other medications to estimate the impact of translating pharmacoepidemiologic data to evidence-based prenatal care practice.

Increasing use of atypical antipsychotics and anticonvulsants during pregnancy

“…Existing research has demonstrated increasing off-label use of atypical antipsychotics and anticonvulsant medications in the U.S. and case control studies suggest that early fetal exposure to anticonvulsants may be associated with increased risk for birth defects. 4–12 …”

“…13–15 At the same time, pregnancy-related exposure to certain antipsychotics, anticonvulsants and/or lithium may place the developing fetus at risk for birth defects and other adverse outcomes. 11,12,16–20 …”

Urgent global opportunities to prevent birth defects

“…The US Food and Drug Administration has made valproic acid a class X drug for migraines, where the risks involved in using valproic acid in pregnant women clearly outweigh potential benefits. Within the USA, it was estimated that w40 cases of spina bifida have occurred due to valproic acid use [90], and about 4 per 1000 prescriptions are still written for valproic acid for nonepilepsy conditions [89]. The March of Dimes Global report on birth defects (2006) indicated that the risk of such exposure is even higher in developing countries where valproic acid use may be uncontrolled and more common compared with more expensive and less teratogenic anticonvulsive drugs [1,91].…”

Challenges in Studying Modifiable Risk Factors for Birth Defects

“…Simulations have been used to estimate the number of cases of specific birth defects that could be prevented with decreased use of teratogenic antiepileptic medications [93]; a reduction in the prevalence of prepregnancy obesity [94]; elimination of periconceptional cigarette smoking [95]; addition of folic acid to birth control pills [96] and folic acid fortification of corn masa flour [97]. …”