This study demonstrates significant increases in total LTG Cl and free LTG Cl between nonpregnant baseline and all trimesters of pregnancy, and between the first trimester and the latter trimesters of pregnancy. The mean total LTG Cl increased by 94% and the free LTG Cl increased by 89% in the third trimester above the nonpregnant baseline. The magnitude of alteration in total LTG Cl is in the middle of the range of previous reports with smaller patient sample sets.10–13
Substantial interindividual variability in the degree of enhanced Cl has been noted previously11–13
and may contribute to the differences reported. Interestingly, this larger study noted a racial difference, with white patients showing higher LTG Cl rates. The previous studies may have had a different racial mix. Pharmacogenetic variability of UGT1A4 and possibly UGT1A3 polymorphisms35
likely contributes to baseline LTG Cl rates and the degree of enhanced Cl during pregnancy.
Our analysis of the effectiveness of TDM with total LTG concentrations during pregnancy demonstrates improved seizure control compared with previous reports of LTG use during pregnancy.8,10,12
Although 39% of women had an increase in any type of seizure above preconception baseline during pregnancy, 33% actually had a decrease in seizures, and 28% experienced no change. These rates are more consistent with what has been reported for all women with epilepsy on a variety of AED regimens.
The finding of an association between RTC was most robust in the second trimester (14 to 28 weeks), when the largest percentage of patients experienced increased seizures. Our detailed statistical analysis indicates that an RTC < 0.65 in the second trimester is a reliable predictor of seizure worsening. Thus, this data-driven threshold index of a 65% ratio to target LTG concentration should be used for introducing a dosage adjustment for women with epilepsy on LTG during pregnancy. Given that free LTG concentration measurements are not readily available in the clinical setting, measurement of total LTG is adequate for predicting seizure worsening.
Although the RTC does require a simple calculation with consideration of a patient’s target concentration, it is necessary to account for individual differences. The target concentration for each patient is the ideal concentration at which seizures are well controlled without adverse effects. This varies between patients according to epilepsy syndrome, seizure types, and disease severity. Ideally, this target concentration should be established for each woman before pregnancy, but if no preconception baseline is obtained, the practitioner can estimate her target concentration based on these factors.
The return to nonpregnant baseline of total and free LTG Cl rates occurred very quickly and within the first month postpartum (). More than one quarter of the epilepsy patients did experience postpartum toxicity, which was more likely to occur if the postpartum taper was not performed. The risk of postpartum toxicity must be balanced against the necessary adjustments in LTG dose to maintain seizure control during pregnancy, and an empiric postpartum taper is an effective approach to reduce toxicity.
The lack of an association between the amount of LTG dose administered and newborn outcomes suggests that TDM with adjustment of LTG doses during pregnancy may not adversely affect newborn health. However, this study was not powered to detect an increased risk of congenital malformations and the findings need to be considered in light of a report from the UK Epilepsy and Pregnancy Register of a dose-related risk for LTG in the first trimester and major congenital malformations.7
However, a logistic regression analysis of the International Lamotrigine Pregnancy Registry data showed no difference in the risk for major malformations as a function of dose.4
Additionally, this study did not assess long-term neurocognitive outcomes. Whether the clinical utility of TDM of LTG during pregnancy can be extended to bipolar patients is unclear and under investigation.
This study provides characterization and quantification of the changes in total and free LTG Cl across pregnancy and incorporates this novel data into a TDM approach that can provide the foundation for treatment guidelines to prevent increased seizure frequency and improve maternal and fetal health. Future studies should include formal population pharmacokinetic modeling of the alterations in LTG throughout the course of pregnancy and postpartum stages, individual genotyping of UGT1A4/UGT1A3 polymorphisms, exploration of racial differences, and larger sample sets to more thoroughly assess maternal and fetal outcomes, including long-term neurodevelopment.