Which antiepileptic (anti-seizure) medication is considered safe during pregnancy?

Lamotrigine and Levetiracetam Are the Safest Antiepileptic Drugs During Pregnancy

Lamotrigine and levetiracetam have the lowest teratogenic potential among antiepileptic medications and should be the preferred first-line agents for women with epilepsy during pregnancy. 1

First-Line Antiepileptic Medications

Lamotrigine

• Lamotrigine monotherapy shows no increased risk for major congenital malformations compared to unexposed pregnancies 1, 2
• The initial concern about oral clefts from the North American registry has not been confirmed in subsequent large studies—no cases of oral cleft were found in a prospective cohort of 218 lamotrigine-exposed pregnancies 2
• Neurodevelopmental outcomes are generally reassuring, with no increased risk for autism spectrum disorder (OR 0.97), ADHD (OR 1.14), or language disorders (OR 1.16) 3
• Critical caveat: Lamotrigine requires significant dose increases during pregnancy (typically 30% or more by 4-6 weeks gestation) due to increased clearance, with therapeutic drug monitoring essential to maintain seizure control 1, 4

Levetiracetam

• Levetiracetam demonstrates favorable safety data with no association with major congenital malformations or adverse obstetrical outcomes 1
• A large, well-controlled study showed no increased risks for long-term neurodevelopmental outcomes, psychiatric disorders, epilepsy, seizures, vision/hearing impairments, or growth impairment 5
• Like lamotrigine, levetiracetam clearance increases during pregnancy, requiring dose escalation guided by therapeutic drug monitoring 4
• FDA pregnancy category C, but clinical evidence supports safety 6

Second-Line Option

Oxcarbazepine

• Oxcarbazepine has favorable teratogenic data and can be considered when lamotrigine or levetiracetam are ineffective 1
• Its active metabolite (licarbazepine) also requires monitoring during pregnancy due to decreased concentrations 4

Medications to Avoid

Valproate - CONTRAINDICATED

• Valproate must be avoided during pregnancy due to high teratogenic risk and negative impact on neuropsychological development 5, 1
• Should only be used if a woman cannot achieve seizure freedom with other medications AND cannot become pregnant 1
• If valproate is unavoidable, the patient must be fully informed of risks and receive folate supplementation 1

Other Medications with Unfavorable Profiles

• Topiramate tends to have an unfavorable teratogenic profile 1
• Phenytoin, carbamazepine, and phenobarbital are associated with congenital anomalies and should be avoided when possible 5

Practical Management Algorithm

Pre-Conception (Essential Step)

• Obtain baseline therapeutic drug monitoring with two measurements before pregnancy to establish reference concentrations 4
• Switch to lamotrigine or levetiracetam monotherapy if currently on valproate or other higher-risk medications 1
• Achieve seizure control at the lowest effective dose 5

During Pregnancy

• Increase lamotrigine or levetiracetam dose if concentrations decrease 15-25% from baseline in the presence of seizure risk factors 4
• Mandatory dose adjustment if concentrations decrease >25% from baseline 4
• Monitor drug levels monthly, particularly in second and third trimesters when clearance increases most 4, 7
• Approximately 61% of women require lamotrigine dose increases and 54% require levetiracetam increases during pregnancy 7

Postpartum

• Rapidly reduce doses back to pre-pregnancy levels within the first few weeks after delivery as clearance returns to baseline 4
• Continue monitoring to prevent toxicity from elevated postpartum levels 4

Supplementation

Folic Acid

• Folate supplementation is recommended to reduce risk of major congenital malformations, though optimal dosing remains unclear 1

Vitamin K

• No general recommendation exists for peripartum vitamin K prophylaxis 1

Common Pitfall to Avoid

The most critical error is failing to proactively increase antiepileptic drug doses during pregnancy. Studies show that 40% of women do not have their lamotrigine or levetiracetam doses increased during pregnancy, and only 12.4% receive therapeutic drug monitoring 7. This leads to subtherapeutic levels, breakthrough seizures, and maternal hypoxia—which poses greater fetal risk than the medications themselves 5.