While we have sufficient data to support the use of certain anticonvulsants, such as lamotrigine (Lamictal), during pregnancy, there is less data on some of the other newer anticonvulsants, such as oxcarbazepine (Trileptal). This is not a medication commonly used to treat psychiatric illness, and data regarding its efficacy as a mood stabilizer are not robust. Yet, we sometimes see women who have responded well to oxcarbazepine. During pregnancy, we would typically recommend switching to medications with a better reproductive safety profile — for example, lamotrigine — but what happens if this does not work? Is oxcarbazepine a reasonable treatment option during pregnancy? What information do we have on its reproductive safety?
Data from a Cochrane Database Review (2016) indicated that the prevalence of major malformations for children exposed to oxcarbazepine (N = 238) was 2.39%, which did not differ from the prevalence observed in the control groups. While this report provided reassuring data, the sample size was small. Now we have another meta-analysis to guide our decision making from Althar and colleagues (2022).
Systematic Review and Meta-Analysis
This systematic review included 19 cohort studies with a total of over 5 million pregnancies, of which 2450 were exposed to oxcarbazepine (OXC) either as monotherapy or polytherapy. (Text continues after image below.)
Meds and Pregnancy: Oxcarbazepine by Ruta Nonacs, MD PhD – Updated on January 2, 2023
The researchers observed a small, but not statistically significant, increase risk of malformations in children exposed to oxcarbazepine, with an estimated odds ratio (OR) of 1.69 (95% CI, 0.95-2.98) as compared to a control group of unexposed pregnancies (seven studies, n = 625). The finding was diminished further when compared to lamotrigine-exposed children (3 studies, n = 591), where the odds ratio was 1.19 (95% CI, 0.67-2.12). (As lamotrigine has not been associated with increased risk for malformations, using lamotrigine-exposed pregnancies as a control group helps to control for potential confounding factors associated with the disease itself.)
Three studies (n = 770) reported on the association between prenatal oxcarbazepine monotherapy and fetal/perinatal deaths. The researchers calculated a threefold increase in risk of fetal or perinatal death among infants with prenatal exposure to oxcarbazepine (OR 3.33; 95% CI, 1.70-6.51). However, healthy, non-exposed pregnant women were used as a control group in this analysis, which makes it difficult to control for other factors more common in women with epilepsy that might contribute to adverse fetal and neonatal outcomes.
The meta-analysis conducted here has several important limitations. First of all, they note that most of the included studies did not specify the timing of fetal exposure to oxcarbazepine. Because first trimester exposure is the only time of exposure relevant to calculating risk of malformations, the inclusion of cases with exposures only during the second or third trimesters of pregnancy may result in underestimation of risk.
Another limitation is that the meta-analysis included exposures to oxcarbazepine monotherapy and polytherapy. Previous studies have shown higher rates of malformations associated with AED polytherapy, especially regimens including valproic acid. Thus, the inclusion of cases with polytherapy may result in overestimation of risk.
Based on the quality of this meta-analysis and the studies contributing to the analysis, we do not yet have enough data to reassure patients about the reproductive safety of oxcarbazepine. Larger, better quality studies are needed to better estimate the risks associated with prenatal exposure to oxcarbazepine.
These are difficult clinical decisions to make, and there is no “right” or “perfect” answer in these sorts of situations. The ultimate decision requires a consideration of the risks of exposure to a particular medication, but one must also take into consideration personal preferences. The following possible options should be considered.
Would it be possible to find an alternative that is safer, or at least better characterized, with regard to reproductive safety? Lamotrigine rises to the top of that list; it is frequently used during pregnancy, and the most recent studies indicate that lamotrigine exposure during pregnancy has not been associated with an increased risk of malformations. Could an atypical antipsychotic medication be used to reduce risk for relapse?
Would it be possible to stop the oxcarbazepine during the first trimester of pregnancy to reduce the risk of exposure during the most vulnerable time of organ formation? We know from previous studies that women with bipolar disorder who attempt to discontinue treatment with a mood stabilizer during pregnancy experience high rates of relapse, often during the first trimester. In addition, the finding from this study of increased risk of fetal or perinatal death raises concerns, in that exposure to oxcarbazepine later in pregnancy may negatively affect outcomes.
Would it be reasonable to consider maintaining treatment with oxcarbazepine during the course of her pregnancy? There are often settings where the best option for a particular patient may be to consider maintaining treatment with a particular medication in the absence of adequate reproductive safety data.
Ruta Nonacs, MD PhD
Athar F, Ehsan M, Farooq M, Lo KB, Cheema HA, Ahmad S, Naveed A, Umer M. Adverse fetal and neonatal outcomes following in-utero exposure to oxcarbazepine: A systematic review and meta-analysis. Br J Clin Pharmacol. 2022 Aug; 88(8):3600-3609.
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