The longer term outcome of children born to mothers with epilepsy
Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, Coyle H, et al.;
Commented by , 22 Nov 2004
Background
Antiepileptic drugs are known to be associated with an increased risk of of major birth defects when taken during pregnancy. Their potential impact on postnatal intellectual development, however, has been little investigated.
Aim
To assess the prevalence of cognitive delay and possibly associated dysmorphic features in children exposed to AEDs in utero.
Methods
Retrospective assessment of children aged 6 to 16 years born from mothers with epilepsy.
Information was obtained from maternal interviews and hospital records. Children were assessed with the WISC-III scale (Wechsler). Dysmorphisms were assessed blindly from photographs.
Results
Verbal IQ was significantly lower in children exposed to valproate monotherapy (83.6, 95% CI 78.2-89.0, n=41) than in non-exposed children (90.9, 95% CI 87.2-94.6, n=80) and children exposed to monotherapy with carbamazepine (94.1, 95% CI 89.6-98.5, n=52) and phenytoin (98.5, 95% CI 90.6-106.4, n=21).
At multiple regression analysis, factors significantly associated with a lower verbal IQ were a history of valproate exposure in utero, frequent tonic-clonic seizures and a low maternal IQ.
There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate.
Performance and full scale IQs did not differ between non-exposed childreen and children exposed in utero to individual AEDs.
Professor Perucca's comments
This study claims that prenatal exposure to valproate may lead to an increased incidence of cognitive impairment and dysmorphic features in childhood. It also provides, for the first time, evidence that tonic clonic seizures during pregnancy may affect adversely intellectual development in the offspring.
An earlier report from the same group, possibly based partly on the same population, had suggested that children exposed in utero to valproate are at increased risk of experiencing additional educational needs (ref. 1).
These findings raise major concerns and within days of publication they received wide attention by media, including TV stations (ref. 2 ) and the lay press. Oversimplistic interpretation of these findings, however, could do major damage to patients.
Indeed, the study raises more questions than it answers:
- The survey was retrospective, women were recruited from epilepsy clinics (a population more likely to have severe epilepsy), and only 40% accepted to participate in the study. Therefore, selection bias could have seriously affected the data;
- The study groups were small, and only 8 valproate-treated children had a severely reduced verbal IQ;
- The authors report no information on gestational age at birth of the children, their Apgar scores, and their morbidities. Paternal IQ was not assessed. Ethnic group of the parents and marital status were also not reported. Each of these factors could have a major impact on verbal IQ, and confound the findings if their distribution differed across groups;
- Many more valproate-treated mothers had idiopathic generalized epilepsies than mothers in the other groups;
- The possibility of bias/confounders is suggested by other observations: unexposed controls had a lower than expected verbal IQ; children exposed to polytherapies with valproate did not show reduced verbal IQ, and children exposed to carbamazepine and phenytoin had considerably higher verbal IQs than non-exposed controls.
Despite these inconsistencies, the evidence implicating valproate is suggestive, particularly as there was a negative correlation between verbal IQ and valproate dose in the first trimester.
Children of mothers taking 800 mg valproate or less did not have a reduced verbal IQ. Prior to this report, a small prospective study from Finland found a lower verbal IQ in children exposed in utero to valproate and to polytherapy compared with non-exposed children or children exposed to carbamazepine (ref. 3).
An independent effect of valproate, however, could not be confirmed in the Finnish study because results were confounded by low maternal education and polytherapy.
Well designed prospective studies are needed to confirm or refute these findings. In the meantime, women with epilepsy should not be advised to withdraw valproate during their pregnancy, because the risks of doing so clearly outweigh any doubtful benefits.
For women who need to start AED therapy, given existing evidence that valproate may carry a higher teratogenic risk than other AEDs (ref. 4), it seems prudent to avoid the first-line use of valproate when at least equally effective therapies exist.
Equieffective therapies, however, may not be available in some generalised epilepsies (ref. 5). This raises difficult therapeutic dilemmas, especially since seizures themselves can be harmful for the mother and the fetus.
References
1. Adab N, Jacoby A, Smith D, Chadwick D. Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2001;70:15-21 (Note: Free full text available)
2. BBC News 14 October 2004: Epilepsy drug "lowers baby IQs"
3. Gaily E, Kantola-Sorsa E, Hiilesmaa V, Isoaho M, Matila R, et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology. 2004;62:28-32
4. Tomson T, Perucca E and Battino D. Navigating toward fetal and maternal health: The challenge of treating epilepsy in pregnancy. Epilepsia 2004;45:1171-5
5. The Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of epilepsy in adults. Edinburgh 1997