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Grand Rounds

Antiepileptic Medications and Risk for Congenital Malformations

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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

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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?

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