Is Levepil (levetiracetam) safe to use during pregnancy in women with epilepsy?

Levetiracetam (Levepil) Safety in Pregnancy

Levetiracetam is considered one of the safest antiepileptic drugs for use during pregnancy, with a low major congenital malformation rate of 0.70% in monotherapy, making it a preferred alternative to valproate for women with epilepsy of childbearing age. 1

Evidence for Safety Profile

Malformation Risk

• The UK and Ireland Epilepsy and Pregnancy Registers documented only 2 major congenital malformations among 304 pregnancies exposed to levetiracetam monotherapy (0.70%; 95% CI 0.19%-2.51%), which is substantially lower than many other antiepileptic drugs. 1
• Multiple studies from India confirmed zero major congenital malformations in children born to mothers receiving levetiracetam monotherapy during pregnancy. 2, 3
• When used in polytherapy, the malformation rate increases to 5.56%, but this varies significantly by combination—lowest when combined with lamotrigine (1.77%) versus higher rates with valproate (6.90%) or carbamazepine (9.38%). 1

FDA Classification and Animal Data

• The FDA classifies levetiracetam as Pregnancy Category C, indicating that animal studies showed developmental toxicity at doses similar to or greater than human therapeutic doses, but there are no adequate well-controlled studies in pregnant women. 4
• Animal studies demonstrated increased fetal skeletal abnormalities and retarded offspring growth at doses ≥350 mg/kg/day (approximately equivalent to the maximum recommended human dose), with a developmental no-effect dose of 70 mg/kg/day (0.2 times the MRHD). 4
• Despite animal findings, human data consistently shows a favorable safety profile, making levetiracetam preferable to older antiepileptic drugs like valproate. 1

Critical Management Considerations During Pregnancy

Therapeutic Drug Monitoring

• Levetiracetam concentrations decrease significantly throughout pregnancy due to physiologic pharmacokinetic changes, requiring monthly therapeutic drug monitoring. 5
• For women who were NOT seizure-free in the year before pregnancy, maintain levetiracetam concentration above 65% of preconceptional levels to prevent seizure deterioration. 5
• For seizure-free patients, maintain levetiracetam concentration above 46% of preconceptional levels. 5
• Low levetiracetam concentrations during pregnancy are significantly associated with increased seizure frequency in non-seizure-free patients (p = 0.022). 5

Dosing Adjustments

• Expect to increase levetiracetam doses during pregnancy to maintain therapeutic concentrations, as concentration/dose ratios decrease throughout all months of pregnancy. 5
• Monthly blood sampling (venous puncture or dried blood spot method) should be performed to guide dose adjustments. 5

Comparison to Other Antiepileptic Drugs

Advantages Over Valproate

• Valproate carries a 13.3% major congenital malformation rate and should be avoided in women of childbearing potential. 2
• Levetiracetam monotherapy can be considered a safer alternative to valproate with respect to major congenital malformations. 1

Efficacy Considerations

• While valproate may provide better seizure control than levetiracetam, the substantially higher teratogenic risk makes it inappropriate for use during pregnancy. 2
• The majority of women (61.1%) maintained unchanged or improved seizure control on levetiracetam during pregnancy. 3

Pregnancy Registry Enrollment

• Physicians should recommend that pregnant patients taking levetiracetam enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting www.aedpregnancyregistry.org. 4
• Registry enrollment must be done by patients themselves to provide ongoing safety data. 4

Breastfeeding Considerations

• Levetiracetam is excreted in breast milk, requiring a decision about whether to discontinue nursing or the drug based on the importance of the medication to the mother. 4
• The FDA label notes potential for serious adverse reactions in nursing infants, though specific data on breastfeeding safety is limited. 4

Clinical Algorithm for Use

For women with epilepsy planning pregnancy or who become pregnant:

1. Switch to levetiracetam monotherapy if currently on valproate, phenytoin, or carbamazepine (higher malformation risks). 1, 2
2. Establish baseline preconceptional levetiracetam concentration. 5
3. Implement monthly therapeutic drug monitoring throughout pregnancy. 5
4. Adjust doses to maintain concentration above 65% of baseline (non-seizure-free) or 46% of baseline (seizure-free). 5
5. Enroll patient in pregnancy registry. 4
6. Monitor for seizure frequency changes and adjust accordingly. 5