Levetiracetam Use in Pregnancy
Levetiracetam is considered safe for use during pregnancy and is one of the preferred antiepileptic drugs for pregnant women with epilepsy, showing a low risk of major congenital malformations when used as monotherapy.
Safety Profile and Malformation Risk
Levetiracetam monotherapy carries a very low risk of major congenital malformations (MCM), with rates of 0.70% (95% CI 0.19%-2.51%) in a large prospective registry study of 304 pregnancies, which is comparable to the general population risk 1.
The FDA classifies levetiracetam as Pregnancy Category C, noting 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 2.
A retrospective study of 102 pregnancies found no major congenital malformations in patients receiving levetiracetam monotherapy, confirming its safety profile at the same risk level as women who never used antiepileptic drugs 3.
Levetiracetam monotherapy can be considered a safer alternative to valproate for women with epilepsy of childbearing age 1.
Polytherapy Considerations
When levetiracetam is used in combination with other antiepileptic drugs, the MCM risk increases to 5.56% (95% CI 3.54%-8.56%), though this varies significantly by the specific combination used 1.
The combination of levetiracetam with lamotrigine shows lower MCM rates (1.77%; 95% CI 0.49%-6.22%) compared to combinations with valproate (6.90%; 95% CI 1.91%-21.96%) or carbamazepine (9.38%; 95% CI 4.37%-18.98%) 1.
Two major congenital malformations were observed in polytherapy groups in smaller studies, reinforcing that monotherapy is preferable when clinically feasible 3.
Critical Pharmacokinetic Changes During Pregnancy
Levetiracetam serum concentrations decrease significantly throughout pregnancy, requiring therapeutic drug monitoring and dose adjustments to maintain seizure control.
Levetiracetam concentration/dose ratios decrease throughout all months of pregnancy, with the most significant decrease occurring during the first trimester—raw serum concentration drops by 5.76 mg/L compared to pre-pregnancy levels 4.
Apparent clearance increases by 71.08 L/day during the first trimester compared to pre-pregnancy measurements 4.
Approximately 30% of levetiracetam serum levels during pregnancy fall below the laboratory reference range 4.
Therapeutic Drug Monitoring Recommendations
For patients who were NOT seizure-free in the year preceding pregnancy: maintain levetiracetam concentration above 65% of the preconceptional concentration, as low levels are significantly associated with increased seizure frequency (p = 0.022) 5.
For patients who WERE seizure-free in the year preceding pregnancy: maintain levetiracetam concentration above approximately 46% of the preconceptional concentration 5.
Monthly monitoring of serum levetiracetam levels is essential upon planning pregnancy and throughout gestation to maintain therapeutic levels 4.
Non-seizure-free patients require more careful monitoring as they are at higher risk for experiencing increased seizure frequency during pregnancy 5.
Clinical Management Algorithm
Initiate therapeutic drug monitoring before conception to establish baseline levetiracetam levels 5, 4.
Monitor serum levels monthly throughout pregnancy, with particular attention during the first trimester when the most significant decrease occurs 4.
Adjust doses proactively to maintain target concentrations based on seizure history (65% for non-seizure-free patients, 46% for seizure-free patients) 5.
Prioritize monotherapy over polytherapy whenever clinically possible to minimize malformation risk 1, 3.
Important Caveats
The benefit of maintaining seizure control during pregnancy outweighs the theoretical risks of levetiracetam, as uncontrolled seizures pose significant risks to both mother and fetus 2.
Physicians should recommend enrollment in the North American Antiepileptic Drug (NAAED) pregnancy registry (1-888-233-2334) to contribute to ongoing safety data collection 2.
Levetiracetam is excreted in breast milk, and decisions about breastfeeding should weigh the importance of the drug to the mother against potential risks to the nursing infant 2.