Abstract
Background
Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs (AEDs) and increased risk of both physical anomalies and neurodevelopmental impairment. Neurodevelopmental impairment is characterised by either a specific deficit or a constellation of deficits across cognitive, motor and social skills and can be transient or continuous into adulthood. It is of paramount importance that these potential risks are identified, minimised and communicated clearly to women with epilepsy.
Objectives
To assess the effects of prenatal exposure to commonly prescribed AEDs on neurodevelopmental outcomes in the child and to assess the methodological quality of the evidence.
Search methods
We searched the Cochrane Epilepsy Group Specialized Register (May 2014), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 4), MEDLINE (via Ovid) (1946 to May 2014), EMBASE (May 2014), Pharmline (May 2014) and Reprotox (May 2014). No language restrictions were imposed. Conference abstracts from the last five years were reviewed along with reference lists from the included studies.
Selection criteria
Prospective cohort controlled studies, cohort studies set within pregnancy registers and randomised controlled trials were selected for inclusion. Participants were women with epilepsy taking AED treatment; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy.
Data collection and analysis
Three authors (RB, JW and JG) independently selected studies for inclusion. Data extraction and risk of bias assessments were completed by five authors (RB, JW, AS, NA, AJM). The primary outcome was global cognitive functioning. Secondary outcomes included deficits in specific cognitive domains or prevalence of neurodevelopmental disorders. Due to substantial variation in study design and outcome reporting only limited data synthesis was possible.
Main results
Twenty-two prospective cohort studies were included and six registry based studies. Study quality varied. More recent studies tended to be larger and to report individual AED outcomes from blinded assessments, which indicate improved methodological quality.The developmental quotient (DQ) was lower in children exposed to carbamazepine (CBZ) (n = 50) than in children born to women without epilepsy (n = 79); mean difference (MD) of -5.58 (95% confidence interval (CI) -10.83 to -0.34, P = 0.04). The DQ of children exposed to CBZ (n = 163) was also lower compared to children of women with untreated epilepsy (n = 58) (MD -7.22, 95% CI -12.76 to – 1.67, P = 0.01). Further analysis using a random-effects model indicated that these results were due to variability within the studies and that there was no significant association with CBZ. The intelligence quotient (IQ) of older children exposed to CBZ (n = 150) was not lower than that of children born to women without epilepsy (n = 552) (MD -0.03, 95% CI -3.08 to 3.01, P = 0.98). Similarly, children exposed to CBZ (n = 163) were not poorer in terms of IQ in comparison to the children of women with untreated epilepsy (n = 87) (MD 1.84, 95% CI -2.13 to 5.80, P = 0.36). The DQ in children exposed to sodium valproate (VPA) (n = 123) was lower than the DQ in children of women with untreated epilepsy (n = 58) (MD -8.72, 95% -14.31 to -3.14, P = 0.002). The IQ of children exposed to VPA (n = 76) was lower than for children born to women without epilepsy (n = 552) (MD -8.94, 95% CI -11.96 to -5.92, P < 0.00001). Children exposed to VPA (n = 89) also had lower IQ than children born to women with untreated epilepsy (n = 87) (MD -8.17, 95% CI -12.80 to -3.55, P = 0.0005).
In terms of drug comparisons, in younger children there was no significant difference in the DQ of children exposed to CBZ (n = 210) versus VPA (n=160) (MD 4.16, 95% CI -0.21 to 8.54, P = 0.06). However, the IQ of children exposed to VPA (n = 112) was significantly lower than for those exposed to CBZ (n = 191) (MD 8.69, 95% CI 5.51 to 11.87, P < 0.00001). The IQ of children exposed to CBZ (n = 78) versus lamotrigine (LTG) (n = 84) was not significantly different (MD -1.62, 95% CI -5.44 to 2.21, P = 0.41). There was no significant difference in the DQ of children exposed to CBZ (n = 172) versus phenytoin (PHT) (n = 87) (MD 3.02, 95% CI -2.41 to 8.46, P = 0.28). The IQ abilities of children exposed to CBZ (n = 75) were not different from the abilities of children exposed to PHT (n = 45) (MD -3.30, 95% CI -7.91 to 1.30, P = 0.16). IQ was significantly lower for children exposed to VPA (n = 74) versus LTG (n = 84) (MD -10.80, 95% CI -14.42 to -7.17, P < 0.00001). DQ was higher in children exposed to PHT (n = 80) versus VPA (n = 108) (MD 7.04, 95% CI 0.44 to 13.65, P = 0.04). Similarly IQ was higher in children exposed to PHT (n = 45) versus VPA (n = 61) (MD 9.25, 95% CI 4.78 to 13.72, P < 0.0001). A dose effect for VPA was reported in six studies, with higher doses (800 to 1000 mg daily or above) associated with a poorer cognitive outcome in the child. We identified no convincing evidence of a dose effect for CBZ, PHT or LTG. Studies not included in the meta-analysis were reported narratively, the majority of which supported the findings of the meta-analyses.
Authors’ conclusions
The most important finding is the reduction in IQ in the VPA exposed group, which are sufficient to affect education and occupational outcomes in later life. However, for some women VPA is the most effective drug at controlling seizures. Informed treatment decisions require detailed counselling about these risks at treatment initiation and at pre-conceptual counselling. We have insufficient data about newer AEDs, some of which are commonly prescribed, and further research is required. Most women with epilepsy should continue their medication during pregnancy as uncontrolled seizures also carries a maternal risk.
Plain language summary
Treatment for epilepsy in pregnant women and the development of the child
Background
For most women who have epilepsy it is important for their health that they continue their medication during pregnancy. Over the last 25 years research has shown that children exposed to these medications in the womb can be at a higher risk of having a birth defect or poorer level of development.
Research question
This review aimed to understand whether exposure to antiepileptic drugs (AEDs) during pregnancy is linked to poorer levels of ability for skills such as IQ, language and memory (neurodevelopment).
Characteristics of the studies
The review included 28 studies. Participants were women with epilepsy taking commonly used AEDs who were compared to either women without epilepsy or women who had epilepsy but who were not treated with AEDs. Comparisons were also made between children exposed to different AEDs in the womb. The evidence presented in this review was up to date to May 2014.
Results
– The evidence for younger children exposed to carbamazepine (CBZ) in the womb was conflicting, however this was likely to be due to differences in the way that these studies were carried out. In older children those exposed to CBZ were not poorer in their IQ than children who were not exposed. No link was found between the dose of CBZ and child ability.
– Both younger and older children exposed in the womb to sodium valproate (VPA) showed poorer cognitive development in comparison to children not exposed and children exposed to other AEDs. A link between dose of VPA and child ability was found in six studies; with higher doses of the drug linked to a lower IQ ability in the child. The level of this difference was likely to increase the risk of poorer educational levels.
– Children exposed to CBZ in the womb did not differ in their skills from children exposed to lamotrigine (LTG), however very few studies investigated this. There were also no differences between children exposed to phenytoin (PHT) in the womb and those exposed to CBZ or those exposed to LTG.
– There were very limited data on newer medications such as LTG, levetiracetam or topiramate.
Quality of the studies
The quality of how studies were designed varied. The more recently completed studies tended to have higher quality ratings, which suggests more reliable evidence.
Conclusions
This review found that children exposed to VPA in the womb were at an increased risk of poorer neurodevelopment scores both in infancy and when school aged. The majority of evidence indicates that exposure in the womb to CBZ is not associated with poorer neurodevelopment. Data were not available for all AEDs that are in use or for all aspects of child neurodevelopment. This means decision making for women and their doctors is difficult. Further research is needed so that women and their doctors can make decisions based on research evidence about which medication is right for them in their childbearing years.
