What are the guidelines for using Levetiracetam (Keppra) in pregnancy?

Levetiracetam Use in Pregnancy

Levetiracetam is considered a safe and appropriate antiepileptic drug for use during pregnancy, with a low risk of major congenital malformations when used as monotherapy, and should be used when the potential benefit justifies the potential risk to the fetus. 1

FDA Classification and General Safety

• Levetiracetam is classified as FDA Pregnancy Category C, meaning animal studies have shown adverse effects but there are no adequate well-controlled studies in pregnant women 1
• The FDA label states that levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus 1
• Animal studies showed developmental toxicity at doses similar to or greater than human therapeutic doses, including minor fetal skeletal abnormalities and decreased fetal weights 1

Risk of Major Congenital Malformations

Monotherapy

• The major congenital malformation (MCM) rate with levetiracetam monotherapy is very low at 0.70% (95% CI 0.19%-2.51%), based on 304 pregnancies from the UK and Ireland Epilepsy and Pregnancy Registers 2
• A separate study of 221 pregnancies with first-trimester levetiracetam monotherapy showed no significantly increased risk of major birth defects compared to lamotrigine monotherapy 3
• Another cohort of 30 patients receiving levetiracetam monotherapy showed zero MCMs, comparable to pregnant women who never used antiepileptic drugs 4

Polytherapy

• The MCM rate increases significantly with polytherapy at 5.56% (95% CI 3.54%-8.56%) 2
• The risk varies substantially by combination: levetiracetam with lamotrigine shows lower MCM rates (1.77%; 95% CI 0.49%-6.22%) compared to combinations with valproate (6.90%) or carbamazepine (9.38%) 2
• Important caveat: Dual therapy with levetiracetam and lamotrigine showed an unexpectedly high risk of spontaneous abortion (adjusted hazard ratio = 3.01,95% CI = 1.43-6.33) in one study, requiring further investigation 3

Therapeutic Drug Monitoring and Dose Adjustment

Pharmacokinetic Changes During Pregnancy

• Levetiracetam concentrations decrease significantly throughout pregnancy due to physiologically-based pharmacokinetic changes 5
• Concentration/dose ratios decline during all months of pregnancy in most patients 5
• Only 12.4% of women had any therapeutic drug monitoring (TDM) performed, and 40% did not have dose increases during pregnancy despite recommendations 6

Monitoring Recommendations

• Therapeutic drug monitoring is recommended for all pregnant patients on levetiracetam as concentrations significantly decrease throughout pregnancy 5
• For patients who were not seizure-free in the year before pregnancy: maintain LEV concentration above 65% of preconceptional concentration 5
• For seizure-free patients: maintain LEV concentration at approximately 46% of preconceptional concentration 5
• Low LEV concentrations were significantly associated with increased seizure frequency (p = 0.022) in non-seizure-free patients 5

Dose Adjustment Protocol

• Proactive dose adjustment should occur in the second and third trimesters alongside TDM 6
• Blood samples should be collected monthly through venous puncture or dried blood spot method 5
• Critical postpartum consideration: Doses should be reduced after delivery, as 43.1% of women who had dose escalation during pregnancy did not have doses reduced postpartum, risking toxicity 6

Fetal Outcomes Beyond Malformations

• Male neonates may have significantly lower birth weight after levetiracetam monotherapy compared to lamotrigine monotherapy, requiring further investigation 3
• No significantly increased risk of spontaneous abortion with levetiracetam monotherapy 3
• The combination of levetiracetam and lamotrigine requires careful consideration due to the elevated spontaneous abortion risk 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 1
• Enrollment must be done by patients themselves and provides valuable data on in utero exposure effects 1

Breastfeeding Considerations

• Levetiracetam is excreted in breast milk 1
• A decision should be made whether to discontinue nursing or the drug, considering the importance of the medication to the mother 1

Clinical Algorithm for Use

1. Establish baseline: Obtain preconceptional LEV concentration for reference
2. Assess seizure history: Determine if patient had seizures within 12 months before pregnancy
3. Initiate monthly TDM: Begin in first trimester and continue throughout pregnancy
4. Adjust doses proactively: Increase doses in second and third trimesters to maintain target concentrations (65% for non-seizure-free, 46% for seizure-free patients)
5. Monitor seizure frequency: Document any breakthrough seizures
6. Plan postpartum reduction: Decrease dose after delivery to prevent toxicity
7. Enroll in registry: Register patient in NAAED Pregnancy Registry