Assessing anti-epileptic drug risk in pregnancy: are new methods as reliable as traditional ones?
These are the findings from an Epilepsy Research UK (ERUK) grant, which was awarded to Dr Rachel Charlton, at the University of Bath, in 2014.
For women with epilepsy pregnancy requires very careful planning, because exposure to some anti-epileptic drugs (AEDs) in the womb, valproate in particular, has been linked to an increased chance of birth defects, behavioural problems and delayed cognitive development.
Traditional methods for assessing the risk of behavioural and developmental issues in unborn babies (i.e. face-to-face interviews) require a lot of work and they are very expensive. In recent years, databases that contain routinely-collected electronic medical records have been increasingly used for research; however, whilst this approach offers many advantages, including lower cost and access to larger numbers of exposed children, it is not clear whether it is a reliable way of detecting developmental and behavioural problems. This is important to know, because if the risks of exposure to an AED in the womb are overestimated via a database, the drug may not be recommended by doctors when it is in fact safe. Conversely, if the risks are underestimated, doctors may recommend an AED that could inadvertently cause harm.
Here, Dr Charlton and colleagues aimed to compare the two methods, looking at the risk of specific neurodevelopmental disorders – autism, attention deficit hyperactivity disorder (ADHD) and dyspraxia (coordination difficulties) – associated with different types of AED exposure in the womb.
The researchers used an electronic database, called the Clinical Practice Research Datalink, to collect anonymised information about 7,066 mother-child pairs. Pairs were classified into three groups: 1) in which the mother had epilepsy and received AED treatment during pregnancy (546) 2) in which the mother had epilepsy but did not receive AED treatment during pregnancy (472) and 3) in which the mother did not have epilepsy and had not taken an AED (6,048).
The investigators used the data to identify all of the children in each group who had developed a neurodevelopmental disorder, and they were then able to calculate risk estimates. Risk in the ‘AED-treated group’ was broken down according to the different AEDs/combinations of AEDs taken by the mothers. Finally, the scientists compared their results with those obtained in an earlier UK study that used traditional methods.
Both studies found an increased risk of neurodevelopmental disorders in children born to women with epilepsy than in those born to women without epilepsy; however the database study produced risk estimates that were much lower. Moreover, the risk found amongst the children born to women without epilepsy was lower than that seen in the general population.
In the database study, neurodevelopmental disorders were found in a small number of children born to women with epilepsy who appeared not to have taken any medication during pregnancy. However, on closer examination, it was discovered that these women may still have been coming off their AEDs in the early stages of pregnancy. To look at the impact of this, the team adjusted the groups so that the ‘treated’ mothers also included women who had taken AEDs in the six months before pregnancy.
In both studies, the risk of neurodevelopmental disorders differed between AED exposure groups. Although the database study showed a higher risk with valproate monotherapy (valproate taken alone), it was a) a lot lower than that seen in the traditional study and b) not statistically significant, even when the exposure groups were modified to include the six months before pregnancy. This means that, according to recognised statistical rules, the chance that the finding could have occurred by chance was too high for it to be conclusive. Valproate polytherapy (taken with other AEDs), however, was associated with a significantly increased risk of neurodevelopmental disorders, although this risk was slightly lower than that reported in the traditional study.
These results suggest that neurodevelopmental disorders in children exposed to AEDs before birth are under-recorded in the Clinical Practice Research Datalink. This in turn means that some databases might not be as reliable as traditional methods for assessing the risks associated with AED exposure in the womb. Future research must take the findings of this study into consideration, so that women with epilepsy can be offered the most accurate pregnancy advice possible.
Earlier this year, the Medicines and Healthcare Products Regulatory Authority (MHRA) issued important new guidance about the risks of valproate in pregnancy. Click here to find out more.
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