BACKGROUND AND PURPOSE:

• Antiepileptic drugs (AEDs) are used for other indications beyond epilepsy (e.g., mood disorders, pain management, migraine etc.)
• In the US, AED use during pregnancy is considerable: 21.9 per 1000 pregnancies
• Blotière et al. (Neurology, 2019) investigated the association between exposure to 10 different antiepileptic drugs during the first 2 months of pregnancy and the risk of 23 major congenital malformations

METHODS:

• Nationwide cohort study (2011-2015)
  • French National Health Insurance claims
  • Databases used previously for large-scale pharmacoepidemiologic studies
• Study population
  • Pregnancies ≥20 weeks
  • Excluded pregnancies associated with increased risk of birth defects
  • Children could not be lost to follow up for at least first year of life
• Definition of exposure to AED
  • Medication dispensed between 1 month before and 2 months after the beginning of pregnancy
  • Control group was pregnant women with no reimbursement for AEDs
• Major congenital malformations were identified up to 12 months after birth
  • Exceptions: 24 months for microcephaly, hypospadias, and epispadias
• Data analysis
  • Odds ratio (aOR) adjusted for potential confounders when at least 5 cases were identified, otherwise crude OR used
  • Confounders adjusted for included relevant diagnoses (e.g., mood disorder, diabetes, epilepsy etc.)
  • Preconception folic acid supplementation was taken in to account and defined as at least 1 dispensing between 1 month before pregnancy and 3 months after the start of pregnancy

RESULTS:

• 1,886,825 pregnancies included
• Valproic acid was associated with multiple major congenital malformations
  • Spina bifida aOR 19.4 (95% CI, 8.6-43.5)
  • VSD aOR 4.0 (95% CI, 2.1-7.8) | ASD aOR 9.0 (95% CI, 5.4-15.0)
  • Pulmonary valve atresia OR 27.8 (95% CI, 3.3-102.5)
  • Hypoplastic left heart syndrome OR 19.6 (95% CI, 2.4-71.7)
  • Cleft palate OR, 5.4 (95% CI, 1.1-15.8)
  • Anorectal atresia OR 11.7 (95% CI, 2.4-34.4)
  • Hypospadias aOR 4.8 (95% CI, 2.4-9.8)
• Topiramate was associated
  • Cleft lip with or without cleft palate: OR 6.8 (95% CI, 1.4 to 20.0)
• Clonazepam
  • Microcephaly: OR 10.2 (95% CI, 2.1-30.0)
• Phenobarbital
  • VSD: OR 10.5 (95% CI, 1.3-39.3)
• Pregabalin
  • Coarctation of aorta: OR 5.8 (95% CI, 1.6-14.9)
• No significant association was found for
  • Lamotrigine | Levetiracetam | Carbamazepine | Oxcarbazepine | Gabapentin

CONCLUSION:

• Valproic acid is teratogenic and should be avoided during or before pregnancy
• Topiramate was associated with clefting
• Phenobarbital, pregabalin and clonazepam were also associated with birth defects, although case numbers were small and therefore susceptible to confounding

Learn More – Primary Sources:

Risks of 23 specific malformations associated with prenatal exposure to 10 antiepileptic drugs

Related ObG Topics:

NTDs and Pregnancy – Folic Acid Recommendations

Antiepileptic Drugs: What is the Impact on Risk for Birth Defects

Does Folic Acid Impact Language Delay in Offspring of Mothers on Antiepileptic Medications?

Adverse Perinatal Outcomes and Epilepsy: Is it the Disorder or the Treatment?