Therapeutic monitoring of antiepileptic drugs during pregnancy and in the postpartum period: is it useful?

As in all patient populations, epilepsy is common in pregnant women. Consequently, approximately 1 in 200 pregnancies is exposed to antiepileptic drugs (AEDs). Although exposure to AEDs in utero has been associated with an increased risk of major fetal malformations, most women with epilepsy require medication throughout pregnancy, since seizures themselves may be potentially harmful not only for the mother but also for the developing fetus. Physiological changes during pregnancy result in a reduction in the serum concentrations of most AEDs, particularly in late pregnancy. Changes in protein binding lead to a greater reduction in total than free (active) drug concentrations. Pharmacokinetic changes in pregnancy show interindividual variability and are not well understood for most newer AEDs. However, recent studies have shown that changes in lamotrigine clearance are particularly marked, with increases in each trimester and a significant fall in plasma concentrations, leading to consequent breakthrough seizures in some women. Concentrations may then rise precipitously after delivery, leading to symptoms of lamotrigine toxicity. Therapeutic drug monitoring could theoretically guide adjustment of AED dosage to achieve good seizure control while minimising fetal exposure, although there are several limitations to such monitoring. Firstly, there are wide interindividual variations in serum drug concentrations, with seizure control often correlating poorly with a given therapeutic range. Secondly, therapeutic ranges have not been well defined for newer AEDs and their measurement is often not always available. Thirdly, for highly protein-bound drugs, although measurement of free drug concentrations may more accurately reflect drug availability during pregnancy than total drug concentrations, assays for this are not always available and may be unreliable. Thus, it may be useful, prior to pregnancy, to establish the total and free drug concentrations required to achieve optimal seizure control in a given individual. Regular monitoring of AEDs has been advocated in each trimester and shortly after delivery, with adjustment of dosage to avoid seizure precipitation during pregnancy or symptoms of toxicity after birth. More frequent monitoring has been recommended for lamotrigine. However, aggressive drug monitoring of any AED has yet to be proven to be effective in improving seizure control or care. Furthermore, higher doses may be associated with a greater potential for teratogenicity and it is not yet known whether longer term adverse effects may be related to in utero exposure in the latter half of pregnancy. There is limited evidence about the relationship of maternal serum drug concentrations and teratogenicity. While there is a theoretical role for therapeutic drug monitoring in improving the risk-to-benefit ratio of AED therapy during pregnancy, there are many practical limitations. Future work is needed to clarify its role in improving seizure control during pregnancy and identifying serum drug concentrations that may be considered safe for fetal exposure.