Do antiepileptic drugs (AEDs) affect male sperm count and fertility?

Antiepileptic Drugs and Male Sperm Count

Antiepileptic drugs (AEDs) do adversely affect male sperm parameters, with carbamazepine, valproate, oxcarbazepine, and levetiracetam all demonstrating significant negative impacts on sperm morphology, motility, and count, though these effects do not appear to increase birth defects or adverse pregnancy outcomes when men father children while on these medications.

Evidence of AED Effects on Sperm Parameters

Carbamazepine (CBZ)

• Carbamazepine causes multiple sperm abnormalities including reduced motility, abnormal morphology, and decreased sperm concentration 1, 2.
• The FDA drug label specifically warns of "rare reports of impaired male fertility and/or abnormal spermatogenesis" with carbamazepine, noting testicular atrophy in animal studies 3.
• Men taking carbamazepine show significantly higher frequencies of morphologically abnormal sperm compared to controls, with poor sperm motility 1.
• One case report documented complete asthenozoospermia (no motile sperm) in a patient on 400 mg/day carbamazepine, which reversed dramatically within one month of switching to phenytoin, resulting in 65% motility and subsequent conception 4.
• Erectile dysfunction is significantly more common in men taking carbamazepine, with 17.33 times higher odds compared to controls 2.

Valproate (VPA)

• Valproate is associated with abnormal sperm morphology, poor motility, and reduced testicular volume in men with abnormal sperm 1.
• Men on valproate show high frequencies of any sperm abnormality, particularly tail abnormalities 1, 5.
• Valproate-treated patients gain significantly more weight than those on carbamazepine, and after correcting for BMI, the testicular size/BMI ratio is lower 5.

Oxcarbazepine (OXC)

• Oxcarbazepine increases the frequency of morphologically abnormal sperm compared to controls 1.

Levetiracetam (LEV)

• Levetiracetam monotherapy significantly decreases total sperm count, percentage of normal morphology, and functional sperm count without altering sex hormone levels 6.
• There is a moderate correlation between daily levetiracetam dose and reduction in functional sperm count 6.

Clinical Implications for Fertility

Reassurance About Offspring Outcomes

• Despite these sperm abnormalities, current evidence shows no increased risk of birth defects or adverse pregnancy outcomes when men father children while taking AEDs 7.
• The 2025 EULAR guidelines state that treatment with methotrexate ≤25 mg/week, leflunomide, and mycophenolate "has not demonstrated a clinically relevant impact on offspring outcome and can be continued in male patients trying to conceive" 7.
• This principle applies to AEDs as well—the sperm abnormalities do not translate to teratogenic risk 7.

Counseling Approach

• Clinicians should counsel men with epilepsy about potential reversible effects on sperm parameters while reassuring them about offspring safety 7.
• The AUA/ASRM guidelines recommend that "clinicians may discuss risk factors (ie, lifestyle, medication usage, environmental exposures) associated with male infertility" and note that "current data on the majority of risk factors are limited" 7.
• If fertility concerns arise, consider semen analysis to document baseline parameters before initiating AED therapy 7.

Management Strategy

When to Evaluate

• Obtain semen analysis if the couple has been attempting conception for 12 months without success, or if there are clinical concerns about fertility 7.
• Hormonal evaluation including FSH and testosterone should be obtained for men with impaired libido, erectile dysfunction, or oligozoospermia 7.

Treatment Decisions

• Do not discontinue or switch AEDs solely based on theoretical fertility concerns if seizures are well-controlled, as the risk of seizure recurrence outweighs the reversible sperm parameter changes 7.
• If sperm abnormalities are documented and the couple is pursuing fertility, consider assisted reproductive technologies (ART) rather than medication changes that could compromise seizure control 7.
• The exception is cyclophosphamide, which causes dose-related permanent infertility and requires fertility preservation counseling before initiation 7.

Important Caveats

• Weight gain from AEDs (particularly valproate, carbamazepine, vigabatrin, and gabapentin) may indirectly affect fertility through metabolic effects 7.
• Epilepsy itself may contribute to reproductive dysfunction independent of medication effects 7.
• The effects on sperm parameters appear to be reversible upon medication discontinuation, as demonstrated in the carbamazepine case report 4.