What are the reproductive side effects of Keppra (levetiracetam)?

From the Guidelines

Levetiracetam (Keppra) has minimal known reproductive side effects compared to many other antiepileptic medications. For women, it generally does not interfere with hormonal contraception effectiveness and has not been associated with significant menstrual irregularities 1. For men, there is no strong evidence that levetiracetam affects sperm quality, count, or testosterone levels. During pregnancy, levetiracetam is considered one of the safer antiepileptic options with a lower risk of birth defects compared to medications like valproate.

Key Points

• Levetiracetam does not significantly impact hormonal contraception effectiveness in women
• There is no strong evidence of levetiracetam affecting sperm quality, count, or testosterone levels in men
• Levetiracetam is considered a safer option during pregnancy with a lower risk of birth defects
• The North American Antiepileptic Drug Pregnancy Registry reports a malformation rate of approximately 2.4% for levetiracetam monotherapy, which is close to the background rate in the general population
• Levetiracetam crosses into breast milk, but breastfeeding is generally considered compatible with its use Some key considerations for patients taking levetiracetam include:
• Patients should not discontinue levetiracetam without consulting their healthcare provider, as seizure control remains a priority, especially during pregnancy when seizures could pose risks to both mother and fetus
• Any reproductive concerns should be discussed with a neurologist and/or obstetrician to develop an individualized treatment plan
• It is essential to weigh the benefits and risks of levetiracetam use during pregnancy and breastfeeding, considering the potential impact on the mother and the fetus or baby.

From the FDA Drug Label

Impairment Of Fertility No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day (approximately 6 times the maximum recommended human dose on a mg/m2 or exposure basis) Pregnancy Pregnancy Category C In animal studies, levetiracetam produced evidence of developmental toxicity at doses similar to or greater than human therapeutic doses Administration to female rats throughout pregnancy and lactation was associated with increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m2 basis) Treatment of pregnant rabbits during the period of organogenesis resulted in increased embryo fetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥600 mg/kg/day (approximately 4 times MRHD on a mg/m2 basis)

The reproductive side effects of Keppra (levetiracetam) include:

• Developmental toxicity at doses similar to or greater than human therapeutic doses
• Minor fetal skeletal abnormalities and retarded offspring growth in rats at doses ≥350 mg/kg/day
• Increased embryo fetal mortality and minor fetal skeletal abnormalities in rabbits at doses ≥600 mg/kg/day
• No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day 2

From the Research

Reproductive Side Effects of Keppra (Levetiracetam)

• The use of levetiracetam during pregnancy has been studied, and the results suggest that it may be associated with certain reproductive side effects 3, 4.
• A study published in Neurology. Clinical practice found that levetiracetam was preliminarily associated with many birth defects, although more research is needed to investigate this further 3.
• Another study published in Epilepsia found that there was no significantly increased risk of major birth defects or spontaneous abortions after first-trimester exposure to levetiracetam, but dual therapy with levetiracetam and lamotrigine resulted in a significantly increased risk of spontaneous abortion 4.
• The same study found that birth weight of male neonates was significantly lower after levetiracetam monotherapy compared to lamotrigine monotherapy 4.
• A retrospective cohort study published in Neurology found that decreased levetiracetam concentrations during pregnancy were associated with increased seizure frequency in non-seizure-free patients 5.
• The study recommended therapeutic drug monitoring for all pregnant patients on levetiracetam, especially non-seizure-free patients, to keep the concentration above 65% of the preconceptional concentration 5.
• A case report published in Epilepsy & behavior : E&B described a woman with epilepsy treated with levetiracetam who was discouraged from breastfeeding, resulting in clinically significant withdrawal seizures in her newborn 6.
• A review of levetiracetam use in pregnancy published in The Annals of pharmacotherapy found that the clearance of levetiracetam increases during pregnancy, leading to decreased serum levetiracetam concentrations, and recommended that women receive adequate amounts of folic acid and have serum concentrations of levetiracetam determined before conception and during each trimester 7.

Birth Defects and Malformations

• The studies suggest that levetiracetam may be associated with an increased risk of birth defects and malformations, particularly when used in combination with other antiepileptic drugs 3, 4.
• However, the data are limited, and more research is needed to fully understand the reproductive side effects of levetiracetam 3, 4, 7.

Pregnancy and Lactation

• The use of levetiracetam during pregnancy and lactation should be carefully monitored, and women should be informed about the possible risks and benefits 4, 6, 7.
• The studies suggest that levetiracetam may be a suitable antiepileptic drug for use during pregnancy, but more research is needed to fully understand its effects on the fetus and newborn 4, 7.