Essential Reads: Oxcarbazepine (Trileptal) and Pregnancy

Looking at the data from a Cochrane Database Review published in 2016, there have been a total of four studies which have included data on children exposed to oxcarbazepine monotherapy.  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 these preliminary findings are certainly reassuring, the number of exposed children included in this analysis is very small.  In order to identify a twofold increase in risk for relatively common malformations, such as cardiovascular defects, we need to analyze about 600-800 exposures.  So when it comes to oxcarbazepine, we still have a ways to go.

Oxcarbazepine and Neurodevelopmental Outcomes

In a meta-analysis published in 2017, Veroniki and colleagues looked at the impact of antiepileptic drugs (AEDs) on neurodevelopmental outcomes of infants and children with exposure to AEDs in utero or during breastfeeding.  Their analysis included 29 cohort studies and a total of 5100 children born to women who used antiepileptic drugs during pregnancy or breastfeeding.  

In this analysis, there were 5 cohort studies with a total of 2551 children which examined risk for autism spectrum disorders in AED-exposed children. Compared to children with no exposure to AEDs, children with exposure to oxcarbazepine had an increased risk for autism, with a calculated network meta-analysis (NMA) of 13.51 (95% CI 1.28-221.40).  However, when they compared risk in women with epilepsy who received or did not receive oxcarbazepine, there was no difference between the two groups, suggesting that there may be confounding by indication.  

This meta-analysis did not indicate the number of oxcarbazepine-exposed children included in the analysis.  According to Appendix D, there was only one study (Christensen et al, 2013) which included children exposed to oxcarbazepine. In that article, they included 321 children with exposure to oxcarbazepine. The Christenssen study did not observe an increased risk of autism in children exposed to oxcarbazepine.

In terms of scientific method, I would trust the original work of Christainsen more than the meta-analysis from Veroniki which includes the data from the Christainsen study.  Nonetheless, it is somewhat difficult to ignore the findings from the Veroniki study.  More studies are required to better estimate the neurodevelopmental risks associated with oxcarbazepine exposure.   

Clinical Recommendations

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.  In our discussion, we reviewed the following possible options.

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.  

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

Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M.  Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism.  JAMA. 2013 Apr 24;309(16):1696-703. Free article.

Veroniki AA, Rios P, Cogo E, Straus SE, Finkelstein Y, Kealey R, Reynen E, Soobiah C, Thavorn K, Hutton B, Hemmelgarn BR, Yazdi F, D’Souza J, MacDonald H, Tricco AC.  Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breastfeeding: a systematic review and network meta-analysis.  BMJ Open. 2017 Jul 20;7(7):e017248. 

Weston J, Bromley R, Jackson CF, Adab N, Clayton-Smith J, Greenhalgh J, Hounsome J, McKay AJ, Tudur Smith C, Marson AG.  Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.  Cochrane Database Syst Rev. 2016 Nov 7;11:CD010224. 

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