Lamotrigine and the risk of malformations in pregnancy
Cunnington M, Tennis P, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee;
Commented by , 21 Apr 2005
In this commentary, Professor Perucca comments on two articles on the same topic. One is mentioned in the headline, and the other is the following:
Increased rate of major malformations in offspring exposed to valproate during pregnancy
Wyszynski DF, Nambisan M, Surve T, et al. for the Antiepileptic Drug Pregnancy Registry
Neurology 2005; 64 (6); 961-965
Background
Information on the comparative teratogenicity of antiepileptic drugs (AEDs) is inadequate (ref. 1). Prospective registries have been set to address this issue.
Aim
To assess the risk of major congenital malformations (MCM) associated with exposure to lamotrigine and valproate in the first trimester of pregnancy.
Methods
Data were collected through registries which enrolled pregnancies prospectively, on a voluntarily basis, before outcome was known.
The lamotrigine registry, set up by the drug manufacturer, only enrols pregnancies exposed to lamotrigine worldwide. The Antiepileptic Drug Pregnancy Registry (ref. 2) enrols pregnancies exposed to any AED in the U.S. and Canada.
Results
In the lamotrigine registry, MCM were recorded in 12 of 414 exposures to lamotrigine monotherapy (2.9%, 95% CI: 1.6-5.1%), 11 of 88 exposures to lamotrigine polytherapy including valproate (12.5%; CI: 6.7-21.7%) and 5 of 182 exposures to lamotrigine polytherapy excluding valproate (2.7%, CI: 1.0-6.6%).
In the North American registry, MCM occurred in 16 of 149 valproate exposures (10.7%, CI: 6.3-16.9%). The prevalence of MCM among 1,048 pregnancies exposed to all other AEDs was 2.9% (CI: 2.0-4.1%). ).
Therefore, compared with women taking other AEDs, valproate exposed women had a 4-fold increase in risk of having an offspring with MCM (OR: 4.0; CI: 2.1-7.4; p < 0.001).
Professor Perucca's comments
For several decades, the teratogenicity of AEDs has been investigated in small scale studies, most of which had major methodological shortcomings (ref. 1).
These led to the notion that intake of AEDs during pregnancy increases 2-3-fold the risk of MCM in the offspring. None of these studies had sufficient power to assess reliably risks associated with individual AEDs, except for the identification of a relationship between spina biphida and exposure to valproate and, to a lesser extent, carbamazepine (ref. 3).
The findings commented in this month’s CNS Forum derive from two of the many ongoing multinational registries (ref. 4) and are important because they reinforce existing evidence (ref. 5; ref. 6; ref. 7) that valproate is more harmful than other AEDs. Neither of the two studies is without shortcomings:
- The lamotrigine registry lacks other AED monotherapy controls, does not appear to account for potential confounders, makes no mention of the classification committee being blinded about type of exposure, and provides only erratic follow-up after birth (an important limitation, given that a substantial proportion of MCM are identified in the first year of life). Moreover, the truly prospective nature of registry can be questioned, because it is unclear whether pregnancies without MCM enrolling at an advanced stage of gestation or after ultrasonographic testing were really excluded. Moreover, critical case information was only collected "shortly after the expected date of birth";
- Unlike other registries, which rely on health personnel for enrolment, in the North American Registry women self-enrol by calling a toll-free number, which may create selection bias. It is also unclear whether outcome classification was made blindly to type of exposure, confounders (e.g. history of previous MCM, type of epilepsy) do not appear to have been accounted for, and again no follow-up was done after birth.
Despite these limitations, the signals pointing to valproate as a higher-risk AED are impressive. Results of an additional registry to be published soon (ref. 8) and discussed in an accompanying editorial (ref. 9) also single-out valproate as being more teratogenic than other AEDs. In the latter study, as in some other reports (ref. 10; ref. 11; ref. 12), valproate-associated MCM risk was dose-related.
There is also concern about potential detrimental effects of prenatal valproate exposure on postnatal mental development. These concerns are echoed in a publication (ref. 13) which appeared alongside the two commented articles and, intriguingly, seems to report basically the same cases and the same analysis as an earlier article by the same group (ref. 14) discussed in the epilepsy commentary on CNSforum in November 2004.
As for lamotrigine’s teratogenicity, the data are inconclusive. MCM rates after lamotrigine monotherapy exposures were similar to those after exposure to lamotrigine in combination with other AEDs not including valproate. In the U.K. registry, MCM rates after lamotrigine exposure (2.9%, CI 1.4-4.9%, n=476) and carbamazepine exposure (2.3%, CI 1.5-3.6%, n=776) were very similar (ref. 5).
On the other hand, the claim that MCM rates with lamotrigine are similar to those expected for the general population are unconvincing, because historical controls may not be comparable.
Until more information becomes available, it makes sense, in women of childbearing potential, to consider alternative therapies to valproate. Valproate, however, may still remain the best choice for some patients.
As seizures may harm the fetus and the mother, switching AEDs after conception should be discouraged. More data on risks associated with new generation AEDs are sorely needed (ref. 1; ref. 9).
References
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