Carbamazepine in pregnancyBMJ 2010; 341 doi: http://dx.doi.org/10.1136/bmj.c6582 (Published 03 December 2010) Cite this as: BMJ 2010;341:c6582
- Irena Nulman, associate professor of paediatrics, University of Toronto
Epilepsy is the most common neurological disorder seen in pregnant women. It often needs drug treatment, and it causes complications in about 0.25% of all pregnancies. Seizure control is the primary goal when treating a convulsive disorder. Epilepsy itself is not associated with an increased risk of major congenital malformations,1 although some risk cannot be excluded. All first line antiepileptic drugs, such as valproic acid, carbamazepine, and phenytoin, are associated with a twofold to threefold increase in rates of major congenital malformations compared with the general population. In the linked review of observational data (doi:10.1136/bmj.c6581), Jentink and colleagues assessed major congenital malformations associated with the use of carbamazepine in the first trimester of pregnancy⇓.2
The benefits of seizure control during pregnancy should not be underestimated. For many pregnant women, discontinuing antiseizure drugs is not an option. The choice of drug is challenging to patients and doctors because of the conflict between the optimal treatment of the mother and the wellbeing of the fetus. Women should plan their pregnancy, receive evidence based prenatal counselling, and be given the safest antiepileptic drug.
Several factors make the reproductive safety of antiepileptic drugs difficult to assess. It is hard to attribute congenital abnormalities to any single factor because of the interaction between genetic and environmental components and the lack of studies with sufficient power to control for them. Although a randomised controlled trial would provide the most reliable evidence, it would not be ethical. High quality observational studies are therefore the best source of evidence.
Carbamazepine is efficacious in the treatment of a variety of epileptic seizures and is widely accepted as the drug of choice in pregnancy. Large population based studies and registries have reported that rates of major congenital malformation after exposure to carbamazepine are almost the same as those in the general population. The Swedish medical birth registry reported an odds ratio of 1.86 (95% confidence interval 1.42 to 2.44) for having a major congenital malformation in those exposed to antiepileptic drugs.3 Monotherapy with valproic acid compared with carbamazepine gave an odds ratio of 2.51 (1.43 to 4.68). Recently the North American registry found that the prevalence of malformations associated with carbamazepine monotherapy was 2.6%,4 similar to that of the general population (1-3%). The United Kingdom epilepsy and pregnancy register reported an absolute rate of major congenital malformations of 2.2% with carbamazepine, 3.2% with lamotrigine, and 6.2% with valproic acid compared with 3.5% in untreated women with epilepsy.5 On the basis of this report, the American Academy of Neurology and American Epilepsy Society subcommittee concluded that in utero exposure to carbamazepine does not substantially increase the risk of major congenital malformations in offspring.6 The committee reported that there was no association between carbamazepine dose and major congenital malformations rates, but that the drug contributes to the risk of a posterior cleft palate.
Despite their importance, long term neurodevelopmental outcomes have received little attention. A systematic review found insufficient evidence to differentiate between the long term neurodevelopmental outcomes associated with different antiepileptic drugs.7 Two subsequent studies found that valproic acid has a clear, dose dependent, adverse effect on children’s neurodevelopment,8 9 whereas six studies found no impairment of cognitive functions in children exposed to carbamazepine monotherapy.10
Jentink and colleagues reported the results of a review of all published cohort studies and a population based case-control study using the EUROCAT database. They compared carbamazepine monotherapy with five “signals of specific congenital malformations” derived from combined published cohort studies “as cases.” They found no significant association between carbamazepine and cleft palate (odds ratio 1.3, 0.4 to 4.1), diaphragmatic hernia, hypospadias, and total anomalous pulmonary venous return (no exposed cases were found). Only spina bifida was significantly associated with carbamazepine monotherapy (2.6, 1.2 to 5.3), when compared with unexposed controls.2
Jentink and colleagues confirmed that carbamazepine is associated with a specific pattern of malformation: spina bifida. Although the study found a rate of neural tube defects that was 2.6 times higher than the general population rate of 1:1000 births, the absolute risk is still small. This should be clearly communicated to pregnant women and care providers. Importantly, carbamazepine has not yet been found to impair children’s long term neurodevelopment, an outcome that cannot be screened prenatally.
Proper prenatal counselling and the recommendation of folic acid supplements may help to prevent major congenital malformations.11 The screening tests used, which include α fetoprotein in maternal blood and two dimensional or three dimensional ultrasound, are highly sensitive for the prenatal diagnosis of neural tube defects. Detection rates for some of these defects approach 100%.12
Patients should be informed and understand the risks associated with uncontrolled seizures and the teratogenicity of anticonvulsive drugs. Of all the anticonvulsant drugs, carbamazepine is associated with the lowest rate of morphological defects and has not been found to be neurotoxic. Carbamazepine should therefore be considered the drug of choice in pregnancy. Proper seizure control and judicious perinatal counselling and management will produce favourable outcomes in more than 95% of pregnancies.
Cite this as: BMJ 2010;341:c6582
Competing interests: The author has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; IN coauthored a study on neurodevelopment of children exposed in utero to phenytoin and carbamazepine in 1994, which was funded by Novartis.
Provenance and peer review: Commissioned; not externally peer reviewed.