EURAP is an international registry for antiepileptic drugs and pregnancy.  At its inception in 1999, it included only European countries but EURAP has grown and now includes 42 countries from Europe, Australia, Asia, South America. Thus far, they have enrolled over 24,000 pregnancies.  This is obviously an important resource with regard to assessing the reproductive safety of antiepileptic drugs (AEDs).

Tomson and colleagues analyzed data from a longitudinal, prospective cohort study as part of the EURAP international registry.  The study included 7355 women who were exposed to antiepileptic drug monotherapy at conception who were prospectively identified from 42 countries contributing to EURAP. Follow-up data were collected after each trimester, at birth, and 1 year after birth.

Risk of major congenital malformations was assessed at one year after birth in the offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate).

Among the 7355 pregnancies exposed to one of the eight antiepileptic drugs, the prevalence of major congenital malformations was:

  • 142 (10·3%) of 1381 for valproate,
  • 19 (6·5%) of 294 for phenobarbital,
  • 8 (6·4%) of 125 for phenytoin,
  • 107 (5·5%) of 1957 for carbamazepine,
  • 6 (3·9%) of 152 for topiramate,
  • 10 (3·0%) of 333 for oxcarbazepine,
  • 74 (2·9%) of 2514 for lamotrigine,
  • 17 (2·8%) of 599 for levetiracetam.

Given the large number of women included in the analysis, the researchers were also able to examine the effect of dose on risk for congenital malformation.  They observed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate.  Although previous studies have seen greater risk with doses of valproate above 1000 mg, the current study found that even with valproate at doses less than 650 mg/day, there was a significant increase in risk of malformations as compared to infants exposed to levetiracetam (odds ratio [OR] 2·43).   The risk for major malformations was the highest (25.2%) in women on high dose valproate (above 1450 mg/day).

For carbamazepine, the risk for major malformations was 4.5% in children exposed to less than 700 mg/day and rose to 7.2% in children exposed to doses above 700 mg/day (up to 2400 mg/day).

The researchers also observed a statistically significant, but much less dramatic, increase in risk according to dose for lamotrigine. The risk of major malformations was 2.5% in infants exposed to less than 325 mg/day and 4.3% in children exposed to doses of lamotrigine above 325 mg/day (up to 1300 mg/day).

As seen in previous reports, Tomson and colleagues found that folic acid supplementation did not reduce the risk of major congenital malformations in pregnancies exposed to antiepileptic drugs. However, it should be noted that other studies have demonstrated that periconceptional use of folic acid use is associated with improved cognitive outcomes and lower risk of autistic traits in children with prenatal exposure to to AEDs.

No Dose of Valproate is Safe

The data presented here is consistent with previous data for the most part.  With regard to medications we commonly use to treat psychiatric illness, valproate and carbamazepine carry the greatest risk for congenital malformations, whereas lamotrigine carries the lowest risk.  What is most surprising is the magnitude of the risk in offspring exposed to valproate. The risk of malformations was about 6.3% in children exposed to lower doses (less than 650 mg/day) and rose to 25.2% at higher doses (above 1450 mg/day).  These findings lend further and even stronger support to guidelines recommending the avoidance of valproate in reproductive age women.

More Data on Oxcarbazepine (Trileptal) and Topiramate (Topamax)

A Cochrane Database Review published last year included four studies and a total of 238 children exposed to oxcarbazepine monotherapy during pregnancy.  The prevalence of major malformations for children exposed to oxcarbazepine was 2.39%, which is similar to that observed in this study: 3·0% in a total of 333 infants.  This brings the total of exposed infants with documented outcomes up to 571.  It is also interesting to note that while oxcarbazepine derived from and is structurally similar to carbamazepine (Tegretol), the risk appears to be much lower with oxcarbazepine. They differ by only one molecule; however, the risk is very different.   

This study also contributes data on the outcomes of 152 infants exposed to topiramate monotherapy. Compared to lamotrigine (at < 325 mg/day), this represents a 1.6-fold increase in risk of major malformations.  

No data was provided on some of the new AEDs, including gabapentin (Neurontin).

Should Lamotrigine Dose Be Adjusted?

According to this study, the risk of malformations is slightly higher in infants exposed to higher doses of lamotrigine.  The risk of major malformations was 2.5% in infants exposed to less than 325 mg/day and 4.3% in children exposed to doses of lamotrigine above 325 mg/day.  While this is statistically significant and thus noteworthy, the magnitude of the increase in risk is small. Furthermore, it should be noted that the dose range in the high dose group is higher than we typically use in patients with mood disorders, ranging up to 1300 mg.

Lamotrigine levels do shift during pregnancy.  Estrogen increases the clearance of lamotrigine by inducing the liver enzymes involved in its metabolism. Thus, more rapid metabolism results in lower, and possibly subtherapeutic, levels of lamotrigine. As estrogen levels gradually rise over the course of pregnancy, lamotrigine levels may drop by as much as 50%.  As there is substantial variability in lamotrigine clearance between individuals, some women may experience a large drop in lamotrigine blood levels during pregnancy while others may experience a more modest decline.  In the setting of falling levels, some women may experience clinical destabilization.

For the management of seizures, it is typically recommended that a reference lamotrigine plasma concentration should be determined before pregnancy or as early in pregnancy as possible. After conception, it is recommended that plasma concentrations of lamotrigine should be measured every 4 weeks throughout pregnancy and the dose increased as needed to maintain levels.

While our group typically does not increase the dose of lamotrigine in response to blood levels in the absence of mood symptoms, there was a recent report from Clark and colleagues which recommended adjusting lamotrigine dosing according to blood levels.  In a response to this article, Sharma and colleagues questioned this approach, as there was no evidence in this small case series to indicate that lower blood levels of lamotrigine were associated with relapse.  The current article suggests that we use the lowest possible effective dosage of lamotrigine during pregnancy.

In an accompanying article, Dr. Page Pennell focuses on selecting AEDs with low risk and maintaining the lowest effective dose: “When an antiepileptic drug is prescribed for a reproductive-aged woman, whether for epilepsy, bipolar disorder, migraine, or chronic pain, consideration should be given to whether the antiepileptic drug type and dose chosen have a measured, low risk for major congenital malformations in comparison with treatment alternatives. Clinicians should consider whether the antiepileptic dose can be lowered further while maintaining disease control. For example, after discontinuation of oestrogen-containing contraceptives, the dose of glucuronidated antiepileptic drugs (lamotrigine, valproate, and oxcarbazepine) can usually be reduced to maintain the same target concentration.”

Ruta Nonacs, MD PhD

 

Clark CT, Klein AM, Perel JM, Helsel J, Wisner KL.  Lamotrigine dosing for pregnant patients with bipolar disorder.  Am J Psychiatry. 2013 Nov 1;170(11):1240-7.

Pennell, PB. Prescribing antiepileptic drugs to women of reproductive age. Lancet Neurol. (2018)

Tomson, TorbjörnFaravelli, Francesca et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. (2018)

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. Review.