Possible Neurodevelopmental Risks in Children of Fathers Treated With Valproate Drugs

The oral drug valproic acid (generics only) was approved by the Food and Drug Administration (FDA) in 1978 to treat certain types of seizures (sudden, uncontrolled bursts of electrical activity in the brain that can cause convulsions).[1] The similar drug divalproex (DEPAKOTE and generics) was approved in 1983 by the FDA to treat seizures as well.[2] These are commonly known as valproate drugs.

In the November 2018 issue of Worst Pills, Best Pills News we warned our readers that children born to mothers who took valproate drugs during pregnancy have higher risks of reduced intelligence and birth defects, such as spina bifida (a congenital condition that affects the development of the spine and spinal cord), than children whose mothers received other antiseizure drugs during pregnancy.[3]

Findings from a new post-marketing study suggest an increased risk of neurodevelopmental disorders (mental or developmental problems that begin in early childhood) in children of fathers treated with valproate drugs during the three months prior to conception (the time taken for new sperm to be formed). Therefore, international regulators have revised the labeling of valproate drugs to warn the public about this risk. As of September 2024, no similar action has been taken by the FDA.

Post-marketing study and recommended precautions

The European Medicines Agency (EMA) required the makers of valproate drugs to conduct a post-marketing study to evaluate the neurodevelopmental risks in children born to men treated with these drugs. In response, valproate drugmakers conducted a retrospective study using population-based data from Denmark, Norway and Sweden.

A detailed report by an EMA safety committee (hereafter, the committee) that reviewed iterations of results from the post-marketing study suggest an increased risk of neurodevelopmental disorders (including autism spectrum disorder) in children born to men treated with valproate drugs (as their only antiseizure drug) during the three months prior to conception compared with those born to men treated with other antiseizure drugs (also when used as their only antiseizure drug).[4] The alternative drugs were lamotrigine (LAMICTAL and generics) and levetiracetam (KEPPRA, SPRITAM and generics), which are considered first-line antiseizure drugs.

Specifically, approximately 5 in 100 children (from birth until 11 years old) born to fathers treated with valproate drugs around conception were diagnosed with a neurodevelopmental disorder, compared with 3 in 100 children whose fathers received an alternative antiseizure drug.

Notably, an analysis published in June 2024 in JAMA Network Open by Dr. Jakob Christensen and colleagues did not replicate the increased risk of neurodevelopmental disorders reported by the committee. However, the analysis was limited to Danish population-based data and used a different design (including a different definition of neurodevelopmental disorders) than that of the post-marketing study described by the committee.[5] Based on an early draft of the analysis shared by the authors, the committee was not clear on whether that analysis was “sufficiently powered to detect differences between the different treatment groups.”

The committee also considered data from other sources and consulted various experts before concluding that the available data were sufficient to recommend precautionary labeling changes recommending against the use of valproate drugs in male patients. See the Text Box below for a summary of the recommended labeling changes, which have been implemented in at least Australia and New Zealand.[6],[7]

The committee also recommended that a patient guide should be provided to male patients using valproate drugs and related educational materials provided to clinicians.

EMA Committee’s Key Recommended Labeling Changes for Valproate Drugs Regarding Their Use in Males[8]

• • It is recommended that valproate drugs be initiated and supervised by an experienced specialist.
  • Treatment should be regularly reviewed by a specialist to evaluate whether a valproate drug remains the most suitable treatment for the patient.
  • Patients should be informed about the potential risk of neurodevelopmental disorders in their offspring. The need to consider effective contraception during valproate treatment and for three months after stopping these drugs should be discussed with these patients (contraception should be used by female partners as well).
  • Patients should be advised not to donate sperm during treatment and for at least three months after treatment discontinuation.

What You Can Do

If you are of childbearing age, try to avoid treatment with valproate drugs, regardless of your gender, unless other drugs fail to adequately control your condition or cause unacceptable adverse effects. If you must take these drugs, both you and your partner should use effective contraception while using valproate drugs and for three months after stopping these drugs. See additional advice for male patients in the Text Box above.

Do not stop taking valproate drugs or any other antiseizure drugs without consulting your clinician because sudden cessation of these drugs can trigger seizures.

Although maternal intake of a daily folic acid supplement at least one month before pregnancy until the end of the first trimester of pregnancy can help to reduce the risk of birth defects,[9] it is unlikely to reduce the risk of problems caused by use of valproate drugs by either parent.[10]

References

[1] ANI Pharmaceuticals, Inc. Label: valproic acid (generic only). October 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=2314af65-b928-42a9-91eb-6372909ab4f5&type=display. Accessed September 3, 2024.

[2] AbbVie Inc. Label: divalproex (DEPAKOTE). March 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018723s068lbl.pdf. Accessed September 6, 2024.

[3] Valproic acid and divalproex: high risk of birth defects. Worst Pills, Best Pills News. November 2018. https://www.worstpills.org/newsletters/view/1232. Accessed September 3, 2024.

[4] Pharmacovigilance Risk Assessment Committee (PRAC). European Medicines Agency. PRAC non-interventional imposed PASS final study report assessment report. Valproate and related substances (sodium valproate, valproic acid, valproate semisodium, valpromide, valproate magnesium). 2024. https://www.ema.europa.eu/en/documents/other/valproate-prac-non-interventional-imposed-pass-final-study-report-assessment-report-emea-h-n-psr-j-0043_en.pdf. Accessed September 4, 2024.

[5] Christensen J, Trabjerg BB, Dreier JW. Valproate use during spermatogenesis and risk to offspring. JAMA Netw Open. 2024;7(6):e2414709

[6] Arrotex Pharmaceuticals Pty. Ltd. Australian product information: Apo-sodium valproate. May 2024. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2024-PI-01839-1&d=20240826172310101. Accessed September 4, 2024.

[7] Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics. New Zealand data sheet: valproate (Epilim). August 2024. https://medsafe.govt.nz/profs/datasheet/e/Epilimtabsyrliqiv.pdf. Accessed September 4, 2024.

[8] Pharmacovigilance Risk Assessment Committee (PRAC). European Medicines Agency. PRAC non-interventional imposed PASS final study report assessment report. Valproate and related substances (sodium valproate, valproic acid, valproate semisodium, valpromide, valproate magnesium). 2024. https://www.ema.europa.eu/en/documents/other/valproate-prac-non-interventional-imposed-pass-final-study-report-assessment-report-emea-h-n-psr-j-0043_en.pdf. Accessed September 4, 2024.

[9] Recommendation reaffirmed for folic acid supplementation to prevent birth defects. Worst Pills, Best Pills News. February 2024. https://www.worstpills.org/newsletters/view/1581. Accessed September 4, 2024.

[10] Ireland’s Health Service Executive. Valproate. October 6, 2020. https://www.hse.ie/eng/about/who/cspd/medicines-management/patient-information/valproate/. Accessed September 4, 2024.