USE OF CARBAMAZEPINE IN PREGNANCY

Carbamazepine is a dibenzazepine derivative licensed to treat paroxysmal pain of trigeminal neuralgia, and as an antiepileptic and mood stabilising medication. It is also used off-license for the treatment of alcohol withdrawal and diabetic neuropathy.

The available data on carbamazepine use in pregnancy are derived mainly from studies of women with epilepsy. Although it is possible that the underlying maternal illness may have confounded some of the findings reported in these studies, similar risks should be assumed for pregnant women using the drug in the treatment of psychiatric or other disorders.

Carbamazepine monotherapy exposure in pregnancy may increase the risk of infant congenital malformation, with absolute risk estimates ranging from 3.8% to 6.2% (i.e. up to a ~3 times increase above background rates). Neural tube defects have been inconsistently associated with prenatal exposure and various other specific malformations have also been identified in single studies. Minor malformations including nail dysplasia, and facial dysmorphic features such as hypertelorism, nose hypoplasia or broad/flat nasal bridge, upslanting palpebral fissures, epicanthal folds and elongation of the philtrum have also been attributed to carbamazepine exposure in utero.

From the small number of studies currently available there is no evidence of an increased risk of miscarriage, though further studies are required to confirm this. No reliable evidence of an increased rate of stillbirth, premature delivery or small for gestational age infants has been provided; however, an association cannot be excluded as the data are often conflicting. An increased risk of neonatal complications, including neonatal intensive care admission (specifically due to requirement for respiratory care), and adverse effects on infant neurodevelopment, including poorer cognitive and language development and negative behavioural traits, have been reported. The available data are both limited and occasionally conflicting, meaning these associations remain to be confirmed.

Some studies have identified associations between increasing maternal carbamazepine dose and the likelihood of major congenital malformation and neurodevelopmental impairment, with doses of ≥1,000 mg/day being associated with the highest risk of malformation.

In comparison with carbamazepine monotherapy-exposed infants, exposure in polytherapy has been associated with higher rates of major congenital malformation, and in one study, slight intrauterine growth impairment. However, it is likely that the inclusion of sodium valproate in these regimens has contributed to increased malformation rates and effects of the underlying maternal epilepsy on fetal growth cannot be excluded.

Carbamazepine can interfere with folate metabolism. It is currently advised that all women taking carbamazepine who are either planning a pregnancy or who become pregnant should be prescribed high dose folic acid (5mg/day). Women should, however, be counselled that there is no direct evidence that folate supplementation at any dose can protect against neural tube defects and other congenital malformations, or neurodevelopmental problems specifically caused by carbamazepine exposure.

Plasma concentrations of carbamazepine have been shown to decline as pregnancy progresses and regular clinical review of women taking carbamazepine is therefore recommended. The carbamazepine dose may need to be increased on the basis of plasma-drug concentration monitoring or according to clinical response to maintain seizure control, particularly in later pregnancy.

Carbamazepine should only be used during pregnancy where the benefits of treatment are considered to outweigh any potential risks. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.