Evaluation of pregnancy outcomes after maternal first trimester exposure to levetiracetam

• Conditions: Q89.9; O03; Congenital malformation, unspecified; Spontaneous abortion

• Registration Number: DRKS00017140
• Lead Sponsor: Pharmakovigilanzzentrum Embryonaltoxikologie Charité-Universitätsmedizin

Brief Summary

OBJECTIVE: Levetiracetam is increasingly used in pregnant women with epilepsy. Although teratogenic effects have not been observed so far, data on the risks of spontaneous abortion and major birth defects are still limited, especially for the frequently used dual therapy of levetiracetam and lamotrigine. Our primary aim was to analyze rates of major birth defects and spontaneous abortion after maternal levetiracetam treatment. METHODS: This was a cohort study based on pregnancies recorded by the Embryotox Center from 2000 to 2017. Outcomes of prospectively ascertained pregnancies with first trimester levetiracetam monotherapy (n = 221) were compared to pregnancies with lamotrigine monotherapy for epilepsy (n = 469). In addition, all pregnancies with levetiracetam (n = 364) exposure during the first trimester were analyzed in comparison to a nonexposed cohort (n = 729). Pregnancies with the most frequently used combination therapy comprising levetiracetam and lamotrigine (n = 80) were evaluated separately. RESULTS: There was no significantly increased risk of major birth defects or of spontaneous abortions after first trimester exposure to levetiracetam. Birth weight of male neonates was significantly lower after levetiracetam monotherapy compared to lamotrigine monotherapy. Dual therapy with levetiracetam and lamotrigine resulted in a significantly increased risk of spontaneous abortion (adjusted hazard ratio = 3.01, 95% confidence interval [CI] = 1.43-6.33) and a nonsignificant effect estimate for major birth defects (7.7%, n = 5/65, adjusted odds ratio = 1.47, 95% CI = .48-4.47) compared to a nonexposed cohort. SIGNIFICANCE: Our study confirms the use of levetiracetam as a suitable antiepileptic drug in pregnancy. The lower birth weight of male neonates after maternal levetiracetam monotherapy and the unexpectedly high risk of spontaneous abortion and birth defects after dual therapy with levetiracetam and lamotrigine require further investigation.

Detailed Description

Not available

Study Timeline

• Study Start: 2019-05-02
• Study Completion: 2020-12-31
• Results First Posted: 2023-11-28
• Last Update Posted: 19 August 2024

Recruitment & Eligibility

• Status: Complete
• Sex: Female
• Target Recruitment: 364

Inclusion Criteria

For both cohorts: Enrollment of pregnancies, of which neither the outcome nor pathological results of prenatal diagnostics are known at the first contact. An analysis of these prospectively ascertained pregnancies can therefore be used for risk quantification of the defined endpoints.

Exclusion Criteria

Exclusion Criteria comparison cohort: cases with levetiracetam exposure during pregnancy.

Exclusion criteria (applies for the exposed and comparison groups): therapy of maternal malignancies during pregnancy and cases with maternal exposure considered as potent teratogens or fetotoxicants: i.e. valproate, topiramate and carbamazepine as well as acenocoumarol, ACE-inhibitors and AT1-antagonists (exposure in 2nd and 3rd trimester), lenalidomide, methotrexate, mycophenolate, phenobarbital, phenprocoumon, phenytoin, retinoids (acitretin, adapalen, isotretinoin, tazaroten, tretinoin), thalidomide and warfarin.

Study & Design

• Study Type: observational
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Risk quantification of congenital major birth defects after maternal exposure to levetiracetam during first trimester in comparison to a non-exposed control cohort. Is there an increased rate of spontaneous abortions after maternal exposure to levetiracetam during first trimester in comparison to a non-exposed control cohort?<br><br>First ascertainment of data takes places in early pregnancy with informed consent of the patients when outcome or pathological prenatal diagnosis is unknown. Approximately eight weeks after the estimated date of birth a structured questionnaire is send to collect data about the pregnancy outcome.<br>

Secondary Outcome Measures

Name	Time	Method
To estimate the risk of low birth weight, gestational age at delivery (preterm birth) and pregnancy complications (i.e. preeclampsia, gestational diabetes, stillbirth). Descriptive evaluation of dose adjustment during pregnancy.<br><br>To describe the risk of major congenital malformation or spontaneous abortions after first trimester exposure to levetiracetam combined with e.g. lamotrigine or other antiepileptic drugs.<br><br>In case of significantly increased risks of major congenital birth defects or spontaneous abortions in the exposed cohort, a subsequent sensitivity analysis will be performed using a disease comparison group to account for a possible influence of the underlying treatment indication ‘epilepsy’.<br>The subgroup of pregnancies exposed only to levetiracetam (monotherapy, indication epilepsy) will be compared with a group of women with epilepsy who received a lamotrigine monotherapy.