September 17, 2024

expert reaction to systematic review claiming that there is reassuring evidence that paternal exposure to antiseizure medication doesn’t pose major risk to offspring

A systematic review published in the Journal of Neurology Neurosurgery and Psychiatry looks at antiseizure medication and its risk to offspring. 

Professor Reecha Sofat, University of Liverpool and Associate Director at the BHF Data Science Centre at Health Data Research UK, said:

“First, the evidence base on which the decision that has been taken in men is small. However, from a medicines regulation perspective, signal of harm which is associated with a risk of health problems in offspring has to be taken seriously. Such advice is taken with a great deal of consideration and consultation. The risks that might be associated with withdrawing valproate need to be monitored, and accompanying advice has built in safe guards that allow for the continuation of valproate in men  where this is deemed to be appropriate. For men that never start valproate because of these concerns and their symptoms are well controlled on another drug, then there are no problems. 

“Second, as the press release says, the data from the systematic review are also are limited. It is not clear from the press release, how many father-offspring pairs made up the total, and if the data from the primary papers was reliably reported. More details of the analyses are required, eg the biases that are operating so the conclusions that have been drawn can be understood.

“Third, there is now the potential of being able to link routine health records of children to their parents to more comprehensively understand the effects of drugs taken at the time of conception and/ or during pregnancy on birth outcomes and longer term children’s outcomes. This is an area that requires research which can be enhanced by using data science approach which can in turn  inform experimental approaches to discern the exact mechanisms of any harms.” 

Dr Bassel H.Al Wattar, Associate Professor of Reproductive Medicine, Medical Director – Clinical Trials Unit – Anglia Ruskin University, said:

Does the press release accurately reflect the science? 

“This systematic review offers a narrative analysis of 10 observational studies that evaluated the association between parental exposure to anti-epileptic medication and neonatal exposure. The authors did not perform any new synthesis of data (meta-analysis or pooling of data across studies) and therefore, there is limited new knowledge presented in this article. The conclusion is slightly exaggerated, giving a sense of reassurance, while in fact, the studies summaries are simply not reporting harm. Therefore, caution is warranted when interpreting the findings of this review. 

Is this good quality research?  Are the conclusions backed up by solid data? 
“Most of the included 10 studies suffered from significant methodological limitations. The research is presenting insight on association rather than causality. Therefore, the findings should be interpreted with more caution. 

How does this work fit with the existing evidence?
“The evidence to date support more impact on offspring associated with maternal exposure to anti-epileptic drugs particularly around the first trimester of pregnancy, however, there are more reassuring findings about the safety of certain anti-epileptic drugs and the need to control maternal epilepsy to optimise the health of both mum and baby as detailed in the recent guideline by the RCOG on pregnancy care for women with epilepsy. Robust information about paternal exposure and its impact remains limited and more research is needed. 

Have the authors accounted for confounders?  Are there important limitations to be aware of?
“No, the authors offer a simplistic narrative review of existing studies with no robust assessment of key confounders such as male factor infertility, recurrent miscarriage, duration of treatment, severity of epilepsy, smoking, etc… A more detailed analysis is needed before offering such reassuring conclusion. 

What are the implications in the real world?  Is there any overspeculation?  
“Couples with epilepsy (maternal or paternal) require additional fertility support and detailed pre-conception counselling to help them achieve a health pregnancy. The results of this research are helpful to inform preconception care counselling.”

‘Paternal exposure to antiseizure medications and offspring outcomes: a systematic review’ by Eliza Honybun et al. was published in The Journal of Neurology Neurosurgery and Psychiatry at 23:30 hours UK time (BST) Tuesday 17 September 2024. 

DOI: 10.1136/jnnp-2024-334077

Declared interests

Prof Sofat: I sit on the Pharmacovigilance Expert Advisory Group at the Commission of Human Medicines which advises the MHRA. 

Dr Wattar: No conflicts.