Malformation risks of antiepileptic drugs in pregnancy: A prospective study from the UK Epilepsy and Pregnancy Register
Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, Beth I, et al.;
Commented by , 23 Oct 2005
Background
The comparative teratogenic risk of individual AEDs and their combinations is poorly characterized (ref. 1).
Aim
To compare rates of major congenital malformations (MCM) in the offspring of women with epilepsy in relation to AED exposure during the first trimester of pregnancy.
Methods
- In a U.K.-based registry, health professionals enrolled women with epilepsy before outcome was known. Self-enrolment was also possible. Outcome data were obtained from the patient’s general practitioner 3 months after the expected date of delivery.
- The registry included data for 2468 monotherapy and 718 polytherapy exposures, in addition to 227 pregnancies in untreated women with epilepsy. The most common monotherapies were carbamazepine (900), valproate (715), lamotrigine (647) and phenytoin (82).
Results
- MCM rates were 3.5% (95% CI 1.8-6.8%) for non-AED exposed offspring, 3.7% (3.0-4.5%) for all monotherapies combined, and 6.0% (4.5-8.0%) for polytherapy.
- For monotherapy exposures, MCM rates were 6.2% (4.6-8.2%) for valproate, 2.2% (1.4-3.4%) for carbamazepine, 3.2% (2.1-4.9%) for lamotrigine, and 3.7% (1.3-10.2%) for phenytoin.
- In offspring exposed to monotherapy with carbamazepine, valproate and lamotrigine, MCM rates increased with increasing dosage of all three AEDs.
- CMs after exposure to AED combinations containing valproate were 2-3 times as frequent than in combinations without valproate. MCM rates were 8.8% (3.8-18.9) for the combination of valproate + carbamazepine, and 9.6% (5.7-15.7%) for the combination of valproate + lamotrigine.
Professor Perucca's comments
Several prospective registries are comparing teratogenic risks associated with prenatal AED exposure. This article provides the largest and most comprehensive prospective data set to date (ref. 2).
Some data (e.g, higher MCM rates with valproate than with most other AEDs, and with polytherapy compared with monotherapy) are confirmatory (ref. 3).
At least three recent studies identified higher MCM rates after exposure to valproate than after exposure to carbamazepine (ref. 4; ref. 5) or a pool of other monotherapies (ref. 6).
The lamotrigine data are of special interest. MCM rates did not differ between lamotrigine- and carbamazepine-exposed offspring. Although this does not prove a teratogenic effect of lamotrigine, the significant relationship between lamotrigine dose and MCM rates does suggest a cause-effect relation.
It cannot be excluded, however, that women on high lamotrigine dosages had a more severe seizure disorder which, by itself, could have affected foetal outcome.
In the manufacturer’s registry, MCM frequency after lamotrigine exposure was considered similar to that expected for the general population (ref. 7), but the validity of this interpretation has been questioned (see CNSforum, April 2005 http://www.cnsforum.com/commenteditem/dfa31d51-44fc-457c-8e42-b50c95664d47/default.aspx).
Comparison of MCMs at different dosages of lamotrigine and valproate is interesting. With valproate, MCM frequencies were
- 4.1% (2.3-7.3%) at <600 mg/day
- 6.1% (3.7-9.8%) at 600-1000 mg/day and
- 9.1% (5.8-14.1%) at >1000 mg/day
whereas corresponding figures for lamotrigine were
- 1.3% (0.4-4.7%) at <100 mg/day
- 1.9% (0.8-4.8%) at 100-200 mg/day and
- 5.4% (3.3-8.7%) at >200 mg/day
The observation that the estimated risk with valproate < or = 1000 mg/day was similar to that with lamotrigine > 200 mg/day, if confirmed, would have important implications for management decisions.
While this study is important, it has limitations:
- Allocation to different AEDs and AED dosages was not randomised, an inevitable shortcoming of all studies in this area, but also a potential source of bias
- Although the study was prospective, most critical details were only obtained three months after delivery, when outcome was already known;
- Potentially important confounders such as socio-economic status, smoking and alcohol use were not assessed;
- The observation that offspring not exposed to AEDs had similar MCM rates as those exposed to carbamazepine, phenytoin and lamotrigine raises concerns about ascertainment bias.
How do these findings affect our treatment practices in women of childbearing potential? Keeping seizures under control in pregnancy remains an important goal. In partial epilepsies, carbamazepine appears to be safer than valproate.
In generalized epilepsies, high-dosage lamotrigine may not be safer than < 1000 mg/day valproate.
Further data to guide treatment decisions are needed, including more information on additional concerns related to valproate exposure, particularly the possibility of impaired postnatal intellectual development in the offspring (ref. 8; ref. 9; ref. 10; ref. 11).
References
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