Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated

Joan D Garey¹, Per Damkier^{2

3}, Anthony R Scialli¹, Shari Lusskin⁴, Stephen R Braddock⁵, Laurent Chouchana⁶, Brian Cleary^{7

8}, Elizabeth A Conover⁹, Orna Diav-Citrin^{10

11}, Rachel S Dragovich¹², Facundo Garcia-Bournissen¹³, Ken Hodson¹⁴, Debra Kennedy¹⁵, Steven H Lamm¹⁶, Sharon A Lavigne¹⁷, Sarah G Običan¹⁸, Alice Panchaud^{19

20}, Kirstie Perrotta²¹, Alfred N Romeo²², Svetlana Shechtman¹⁰, Corinna Weber-Schoendorfer²³

Affiliations

¹ Reproductive Toxicology Center, A Non-Profit Foundation, Washington, DC, USA.
² Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³ Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark.
⁴ Departments of Psychiatry and Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁵ Division of Medical Genetics, Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
⁶ Regional Center of Pharmacovigilance, Department of Pharmacology, Cochin Port Royal Hospital, APHP, Paris, France
⁷ The Rotunda Hospital, Dublin, Ireland.
⁸ School of Pharmacy and Biomedical Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
⁹ Division of Clinical Genetics, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
¹⁰ The Israeli Teratology Information Service, Ministry of Health, Jerusalem, Israel.
¹¹ The Hebrew University Hadassah Medical School, Jerusalem, Israel.
¹² Department of Internal Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA.
¹³ Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹⁴ UK Teratology Information Service, Newcastle upon Tyne, UK.
¹⁵ Royal Hospital for Women, Randwick, New South Wales, Australia.
¹⁶ Center for Epidemiology and Maternal-Child Health (CEOH), Washington, DC, USA.
¹⁷ MotherToBaby Connecticut, Division of Medical Genetics, UConn Health, Farmington, Connecticut, USA.
¹⁸ Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
¹⁹ Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland.
²⁰ Service of Pharmacy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²¹ Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
²² MotherToBaby Utah, Utah Department of Health, Salt Lake City, Utah, USA.
²³ Charité - Universitätsmedizin Berlin, Pharmakovigilanzzentrum Embryonaltoxikologie, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany.

PMID: 39189597
DOI: 10.1002/bdr2.2392

Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated

Joan D Garey et al. Birth Defects Res. 2024 Aug.

. 2024 Aug;116(8):e2392.

doi: 10.1002/bdr2.2392.

Authors

Affiliations

¹ Reproductive Toxicology Center, A Non-Profit Foundation, Washington, DC, USA.
² Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³ Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark.
⁴ Departments of Psychiatry and Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁵ Division of Medical Genetics, Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
⁶ Regional Center of Pharmacovigilance, Department of Pharmacology, Cochin Port Royal Hospital, APHP, Paris, France
⁷ The Rotunda Hospital, Dublin, Ireland.
⁸ School of Pharmacy and Biomedical Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
⁹ Division of Clinical Genetics, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
¹⁰ The Israeli Teratology Information Service, Ministry of Health, Jerusalem, Israel.
¹¹ The Hebrew University Hadassah Medical School, Jerusalem, Israel.
¹² Department of Internal Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA.
¹³ Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹⁴ UK Teratology Information Service, Newcastle upon Tyne, UK.
¹⁵ Royal Hospital for Women, Randwick, New South Wales, Australia.
¹⁶ Center for Epidemiology and Maternal-Child Health (CEOH), Washington, DC, USA.
¹⁷ MotherToBaby Connecticut, Division of Medical Genetics, UConn Health, Farmington, Connecticut, USA.
¹⁸ Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
¹⁹ Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland.
²⁰ Service of Pharmacy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²¹ Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
²² MotherToBaby Utah, Utah Department of Health, Salt Lake City, Utah, USA.
²³ Charité - Universitätsmedizin Berlin, Pharmakovigilanzzentrum Embryonaltoxikologie, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany.

PMID: 39189597
DOI: 10.1002/bdr2.2392

Erratum in

Correction to Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently SubstantiatedGarey, J., Damkier, P., Scialli, A., Lusskin, S., Braddock, S., Chouchana, L., Cleary, B., Conover, E., Diav-Citrin, O., Dragovich, R., Garcia-Bournissen, F., Hodson, K., Kennedy, D., Lamm, S., Lavigne, S., Običan, S., Panchaud, A., Perrotta, K., Romeo, A., Shechtman, S. and Weber-Schoendorfer, C. (2024), Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated. Birth Defects Research, 116: e2392. https://doi.org/10.1002/bdr2.2392.
[No authors listed] [No authors listed] Birth Defects Res. 2025 Jan;117(1):e2430. doi: 10.1002/bdr2.2430. Birth Defects Res. 2025. PMID: 39825724 No abstract available.

Abstract

On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate. These new measures recommend patient supervision by a specialist in the management of epilepsy, bipolar disorder, or migraine. In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age. We, members of the European Network of Teratology Information Services (ENTIS) and the Organization of Teratology Information Specialists (OTIS), believe that the EMA and MHRA warnings were premature. We are of the opinion that the underlying scientific data do not convincingly substantiate the inference of a paternally mediated risk from valproate to children, much less to an extent that justifies these far-reaching recommendations.

Keywords: lamotrigine; levetiracetam; neurodevelopmental disorders; paternal valproate; valproate.

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References

1. Brikell, I., L. Ghirardi, B. M. D'Onofrio, et al. 2018. “Familial Liability to Epilepsy and ADHD: A Nationwide Cohort Study.” Biological Psychiatry 83, no. 2: 173–180. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723535/pdf/nihms908395.pdf.
1. Christensen, J., B. B. Trabjerg, and J. W. Dreier. 2024. “Valproate use during spermatogenesis and risk to offspring.” JAMA Netw Open 7, no. 6: e2414709. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/38833248/.
1. EMA. 2024. “Potential Risk of Neurodevelopmental Disorders in Children Born to Men Treated With Valproate Medicines: PRAC Recommends Precautionary Measures.” https://www.ema.europa.eu/en/news/potential‐risk‐neurodevelopmental‐diso....
1. MHRA. 2024. “Valproate (Belvo, Convulex, Depakote, Dyzantil, Epilim, Epilim Chrono or Chronosphere, Episenta, Epival, and Syonell): New Safety and Educational Materials to Support Regulatory Measures in Men and Women Under 55 Years of Age.” https://www.gov.uk/drug‐safety‐update/valproate‐belvo‐convulex‐depakote‐....
1. Nicholich, M. J., and J. F. Gamble. 2011. “What Is the Minimum Risk That Can Be Estimated From an Epidemiology Study?” In Advanced Topics in Environmental Health and air Pollution Case Studies, edited by A. M. Moldoveanu. London, UK: IntechOpen. https://doi.org/10.5772/17023.

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Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated

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Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated

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