BACKGROUND AND PURPOSE:

• Most women with epilepsy will continue to take antiepileptic drugs (AEDs) throughout pregnancy based on medical advice and the balance of risks/benefits
• Weston et al. (Cochrane Database Syst Rev, 2016) examined the AED exposure and prevalence of congenital malformations in offspring

METHODS:

• Systematic review and meta-analysis
• Relevant literature included prospective cohort studies, RCTs and registry studies
• Intervention group
  • Women with epilepsy receiving AEDs as monotherapy
• Control groups
  • Women without epilepsy
  • Women with epilepsy not on treatment
• Primary outcome
  • Presence of a major congenital malformation
• Secondary outcome
  • Specific types of major congenital malformation (NTDs, cardiac defects, orofacial clefting/craniofacial anomalies and skeletal or limb malformations)
  • Minor malformations (e.g., low set ears or digital hypoplasia)

RESULTS:

Risk of Malformation

• 50 studies were selected, 31 of which contributed to meta-analysis
• Carbamazepine (CBZ): Increased risk of malformation vs controls
  • Without epilepsy: Risk ratio (RR) 2.01, 95% confidence interval (CI) 1.20 to 3.36
  • Untreated epilepsy: RR 1.50, 95% CI 1.03 to 2.19)
• Phenobarbital (PB): Increased risk of malformation vs control
  • Without epilepsy: RR 2.84, 95% CI 1.57 to 5.13
• Phenytoin (PHT): Increased risk of malformation vs controls
  • Without epilepsy: RR 2.38, 95% CI 1.12 to 5.03
  • Untreated epilepsy: RR 2.40, 95% CI 1.42 to 4.08)
• Topiramate (TPM): Increased risk of malformation vs control
  • Without epilepsy: RR 3.69, 95% CI 1.36 to 10.07
• Valproate (VPA): Increased risk of malformation vs controls
  • Without epilepsy: RR 5.69, 95% CI 3.33 to 9.7
  • Untreated epilepsy: RR 3.13, 95% CI 2.16 to 4.54)
• No increased risk of malformations for the following (limited data for meds with *)
  • Lamotrigine (LTG)
  • *Gabapentin (GBP)
  • *Levetiracetam (LEV)
  • *Oxcarbazepine (OXC)
  • *Primidone (PRM)
  • *Zonisamide (ZNS)

Prevalence of Major Malformations

• CBZ: 4.93% (95% CI 3.84 to 6.16)
• GBP: 1.47% 1.47% (95% CI 0.26 to 3.64)
• LEV: 1.77% 1.77% (95% CI 0.98%-2.79)
• LTG: 2.31% (95% CI 1.87 to 2.78)
• OXC: 2.39% (95% CI 0.85% to 4.68%)
• PB: 7.10% (95% CI 5.36 to 9.08)
• PHT: 6.26% (95% CI 4.37 to 8.47)
• PRM: 8.49% (95% CI 4.13 to 14.22)
• TPM: 4.28% (95% CI 2.65 to 6.29)
• VPA: 10.93% (95% CI 8.91 to 13.13)
• ZNS: 0.28% (95% CI 0.25 to 2.39) / only 1 small study

Comparing AEDs

• VPA: increased risk of malformation compared to
  • CBZ: RR 2.44, 95% CI 2.00 to 2.94
  • GBP: RR 6.21, 95% CI 1.91 to 20.23
  • LEV: RR 5.82, 95% CI 3.13 to 10.81)
  • LTG: RR 3.56, 95% CI 2.77 to 4.58
  • TPM: RR 2.35, 95% CI 1.40 to 3.95
  • OXC: RR 3.71, 95% CI 1.65 to 8.33
  • PB: RR 1.59, 95% CI 1.11 to 2.29
  • PHT: RR 2.00, 95% CI 1.48 to 2.71
  • ZNS: RR 17.13, 95% CI 1.06 to 277.48
• CBZ: increased risk of malformation compared to
  • LEV: RR 1.84, 95% CI 1.03 to 3.29
  • LTG: RR 1.34, 95% CI 1.01 to 1.76
• PB: Increased risk of malformation compared to
  • GBP: RR 8.33, 95% CI 1.04 to 50.00
  • LEV: RR 2.33, 95% CI 1.04 to 5.00
  • LTG: RR 3.13, 95% CI 1.64 to 5.88)
• PHT: Increased risk of malformation compared to
  • LTG: RR 1.89, 95% CI 1.19 to 2.94
• TPM: Increased risk of malformation compared to
  • LEV: RR 2.00, 95% CI 1.03 to 3.85
  • LTG: RR 1.79, 95% CI 1.06 to 2.94

Specific Malformations

• PB exposure was associated with cardiac malformations
• VPA exposure with NTD, cardiac, clefting/craniofacial anomalies, and skeletal and limb malformations
• Risk of malformation was dosage dependent for VPA exposure
• Limited data may have contributed to lack of statistically significant associations with specific malformations in other AEDs

CONCLUSION:

• AEDs are associated with increased risk of congenital malformation in children, with VPA ranking the highest risk and LEV and LTG the lowest
  • Concurs with previous studies and professional guidelines to be cautious using VPA
  • NOTE: Consider higher dose of folic acid (4mg daily) for women on VPA
• Further studies are needed to define specific malformations associated with LEV and LTG
• Few studies provided sufficient data on minor malformations

Learn More – Primary Sources:

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.

Related ObG Topics:

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

Vitamin B3 (Niacin) and its Role in Preventing Birth Defects

Cleft Lip and Palate – Considerations and Discussion Points

NTDs and Pregnancy – Folic Acid Recommendations