AEDs During Pregnancy: The Risks
abstract & commentary
Source: Olafsson E, et al. Pregnancies of women with epilepsy: A population-based study in Iceland. Epilepsia 1998; 39(8):887-892.
Pregnant women with epilepsy are considered to be at higher risk than the general population of an adverse outcome. Previous studies have documented an increased risk of malformations in the offspring of mothers with epilepsy.1 Few studies have determined the proportion of all pregnancies that occur in women with active epilepsy.
Olafsson et al performed a population-based survey in Iceland to identify all women with epilepsy who gave birth during the 19-year period from 1972 through 1990. The average Icelandic population during the study period was 231,000. The number of live births during the 19 years was 82,483 from 81,473 pregnancies. During this period, there were 266 pregnancies to 157 women with active epilepsy, yielding 268 liveborn children—a prevalence of 3.3 pregnancies in women with active epilepsy for every 1000 pregnancies in the population.
The frequency of adverse events during pregnancy in women with epilepsy was similar to that observed among all live births in the population. Perinatal mortality rate and mean birth weight did not differ significantly in the offspring of women with epilepsy compared with the rest of the population. Caesarean section was performed twice as often in epileptic mothers as in the general population.
During delivery, four women had generalized tonic-clonic seizures, including one episode of convulsive status epilepticus. There were 15 major congenital malformations (MCM) in the offspring of epileptic women. The risk of MCM was increased 2.7 fold (5.9 vs 2.2%) in women treated during pregnancy with anti-epileptic drugs (AEDs) over that in the general population. The rate of MCM (4.8%) in the offspring of epileptic mothers not treated with AED was not significantly less than that in treated mothers. There was a significant increase in the number of MCM in the offspring of mothers receiving two AEDs. Certain AEDs (phenobarbital, phenytoin, and sulthiame) were associated with a significantly increased risk for MCM. (See Table 1.) The specific types of MCM and the number and types of AEDs are shown in Table 2.
Information regarding occurrence of seizures was available for 59% of the affected pregnancies. Maternal seizures during pregnancy were associated with a significant increase in MCM (standard morbidity ratio = 3.8). There was no increase in MCM in offspring of mothers who did not have seizures during pregnancy.
| Table 1 | ||||
| MCM and Type of AED Used During Pregnancy | ||||
| Type of AED* | MCM (n=15) | Offspring (n=265)** | % Affected index | Stand. Morbidity (95% CZ) |
| None | 2 | 42 | 4.8 | 2.2 (0.3-8.0) NS |
| CBZ | 1 | 84 | 1.2 | 0.5 (0.1-3.1) NS |
| VPA | 2 | 44 | 4.5 | 2.0 (0.2-7.2) NS |
| PRM | 2 | 31 | 6.5 | 2.9 (0.3-10.3) NS |
| PHT | 7 | 91 | 7.7 | 3.5 (1.4-7.2) |
| PB | 8 | 92 | 8.7 | 4.0 (1.7-7.9) |
| SUL | 2 | 5 | 40.0 | 20.03 (2.4-72.2) |
| DZP | 1 | 2 | 50.0 | 25.0 (0.6-139.2) NS |
| *Abbreviations: CBZ, carbamazepine; VPA, valproate; PRM, primidone; PHT, phenytoin; PB, phenobarbital; SUL, sulthiame (no longer available); DZP, diazepam; NS, not significant. | ||||
| ** Three children for whom drug exposure was not known were excluded. | ||||
| Table 2 | |||
| Type of MCM and AED Exposure During Pregnancy | |||
| MCM |
|
Number of AEDs | Type of AED |
| Cleft lip/palate | 6 |
|
VPA(2), PRM(2), PB(5), PHT(2), SUL(1), DZP(1) |
| Congenital Heart Disease | 3 |
|
PB(2), CBZ(1), PHT(1) |
| Hypospadias | 3 |
|
PHT |
| Anencephaly | 1 |
|
PHT, PB |
| Microcephaly | 1 |
|
PHT, PB |
| Spina Bifida | 1 |
|
PHT, SUL |
Commentary
This study indicates that the rate of complications of pregnancy in epileptic mothers is similar to that of the general population. Maternal seizures and the use of AEDs during pregnancy significantly increase the risk of MCM in the offspring. The surprising findings are that of the currently used AEDs both phenobarbital and phenytoin were associated with an increased risk of MCM. Carbamazepine was associated with the lowest risk of malformations, and, in fact, no MCM were associated with carbamazepine as monotherapy. Valproic acid had an intermediate risk of MCM between that of phenobarbital, phenytoin and carbamazepine. Whether the occurrence of MCM in this study could have been affected by prenatal folic acid administration is not known.
These results underscore the need for counseling of women with epilepsy before they become pregnant. During pregnancy, control of seizures should be the main goal, and it should be achieved using monotherapy if at all possible. Before a planned pregnancy, it seems worthwhile to attempt to substitute carbamazepine for other AEDs.
Reference
1. Dravet C, et al. Epilepsy, antiepileptic drugs, and malformation in children of women with epilepsy: A French prospective cohort study. Neurology 1992; 42(suppl 5):75-82.
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