Risk Of Major Congenital Malformations Research Articles

The International Lamotrigine Pregnancy Registry Update for the Epilepsy Foundation

The International Registry, established in 1992, forms part of an epidemiologic safety program monitoring pregnancy outcomes in women exposed to lamotrigine (LTG). This primarily prospective observational study aims to assess the risk of all major malformations associated with first trimester exposure to LTG monotherapy. Data on LTG polytherapy and patterns of specific malformation types also are reviewed. Physicians from around the world (31 countries) report exposure to LTG during pregnancy (therapy type, dose, and treatment duration) and subsequent outcomes to the registry on a voluntary basis. Details of how to enroll patients are available at http://www.inveresk.com/activereg/activereg.asp. Prospective reporting early in pregnancy is encouraged to increase the accuracy of treatment history and to avoid the bias associated with retrospective reporting. Physicians are then approached close to the expected delivery date to confirm treatment and epilepsy history during pregnancy and to ascertain the health of the infant. Major congenital malformations (MCMs) are almost always ascertained at birth or during the hospital stay by the attending physician. Malformations are classified according to the Centers for Disease Control (CDC) criteria, and the reports are reviewed by an independent pediatrician. The percentage of MCMs is calculated for prospective first trimester LTG monotherapy and polytherapy exposures separately. Chromosomal abnormalities are not included in the numerator, as these are unlikely to be related to AED exposure during pregnancy. Retrospective cases are excluded from risk estimates but are reviewed to determine any patterns of malformation types. Conclusions are developed by a scientific advisory committee. Between September 30, 1992, and March 31, 2004, 12 MCMs were observed among 414 monotherapy exposures, giving a risk of 2.9%[12 of 414; 95% confidence interval (CI), 1.6–5.1%]. This compares with risks of 2 to 3% in the general population (1) [as estimated through the Metropolitan Atlanta Congenital Defects Program (MACDP), which also uses CDC malformation classification criteria] and 3.3 to 4.5% in cohorts of women with epilepsy exposed to AED monotherapy reported in the literature (2-4). The Lamotrigine Registry currently has the power to detect a 1.79- to 2.00-fold increase in the risk of MCMs, assuming a baseline of 2 to 3%, as estimated from the MACDP. The observed risk among 88 LTG and valproate (VPA) polytherapy exposures was 12.5% (11 of 88; 95% CI, 6.7–21.7%) and was 2.7% (five of 182; 95% CI, 1.0–6.6%) among 182 exposures to LTG polytherapy without VPA. No consistent pattern of malformation types was observed among monotherapy or polytherapy exposures. The Lamotrigine Registry represents substantial data on one of the newer AEDs. The risk of MCMs after LTG monotherapy exposure appears to be similar to that in the general population, although the sample size is insufficient to allow definitive conclusions. The higher frequency of major malformations after LTG-VPA polytherapy exposure was consistent with that in publications on VPA monotherapy, although the registry is not powered to determine the individual contribution of each medication. Continued registration of exposed pregnancies will enhance the statistical power of the study and the data available for physicians to assess the benefit–risk ratio of LTG use in pregnancy.

Major malformations in offspring of women with epilepsy.

The offspring of women with epilepsy are at an increased risk of major congenital malformations, but the impact of the various contributing factors remains unresolved. In 1980 through 1998, the authors prospectively followed up 970 pregnancies in women with epilepsy at a single maternity clinic. Of their 979 offspring, 740 were exposed to maternal antiepileptic drugs (AED) during the first trimester of pregnancy and 239 were not exposed. Maternal AED levels and serum folate concentrations were measured at the end of the first trimester. Logistic regression analysis was applied to identify factors associated with the occurrence of major malformations in the fetuses and newborns. Major malformations were detected in 28 fetuses (3.8%) exposed to maternal AED and in 2 (0.8%) not exposed (p = 0.02). After logistic regression analysis, the occurrence of major malformations was independently associated with use of carbamazepine (adjusted OR 2.5; 95% CI 1.0 to 6.0), use of valproate (4.1; 1.6 to 11), use of oxcarbazepine (10.8; 1.1 to 106), low serum folate concentration (5.8; 1.3 to 27), and low maternal level of education (3.0; 1.3 to 6.8). Major malformations were not associated with seizures during the first trimester (0.6; 0.1 to 2.9). Major malformations in the offspring of mothers with epilepsy are associated with use of AED during early pregnancy, and also with low serum folate concentrations and a low level of education.

Anti-epileptic drugs in pregnancy: current safety and other issues

Women with epilepsy of child-bearing years have their own considerations, which must be taken into account if management of their epilepsy is to be optimised. The main issues to consider include the effects of: female hormones on seizure control, anti-epileptic drugs (AEDs) on hormonal methods of contraception, epilepsy and AEDs on fertility, epilepsy and AEDs on pregnancy itself, pregnancy on AEDs and seizure control and epilepsy, seizures and AEDs on the developing embryo/fetus. Whereas previous studies have concentrated on the increased risk of major congenital malformations from prenatal AED exposure, the effects on cognitive and behavioural development are increasingly being explored. This article looks at the evidence currently available for all of the above issues, taking into account the increased number of AEDs which are now available.

Issues in the Treatment of Epilepsy

Issues in the Treatment of Epilepsy

Pregnancies of women with epilepsy: a population-based study in Iceland.

Women with epilepsy who become pregnant are commonly considered to be at high risk for complications during pregnancy or delivery. The offspring are also considered to have increased risk of perinatal mortality, congenital malformations, and maturational delay. Because few of these studies are population based, potential bias exists because of selection. We performed a historical population-based cohort study in Iceland to determine the prevalence of epilepsy among pregnant women, to identify pregnancy and delivery complications in women with epilepsy, and to determine the outcome of their pregnancies as compared with that in the general population of Iceland. We identified all women with active epilepsy who gave birth during a 19-year period in Iceland. In this population, 3.3 in 1,000 pregnancies involve mothers with active epilepsy. The frequency of adverse events (AE) during pregnancy in the women with epilepsy is similar to that observed among all live births in the population, but cesarean section was performed twice as frequently as in the general population. Perinatal mortality rate and mean birth weight are not significantly different in the offspring of women with epilepsy as compared with rest of the population. The risk of major congenital malformations (MGM) is increased 2.7-fold over that expected when a mother is treated with antiepileptic drugs (AEDs) during a pregnancy. Our study indicates that the rate of complications of pregnancy in mothers with active epilepsy is low and similar to that of the general population with epilepsy. Use of AEDs by the mother during pregnancy significantly increases the risk of MGM in the offspring.

Teratogenic Effects of Antiepileptic Drugs

Data from 5 prospective European studies totaling 1,221 children exposed to antiepileptic drugs (AED) during pregnancy and 158 children of unexposed control pregnancies were analyzed to quantify the risk of major congenital malformations (MCM) and are reported from University Medical Centers in Rotterdam and Heemstede, The Netherlands; Berlin and Magdeburg, Germany; and Helsinki, Finland.

Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy.

To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2-4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers using > 1,000 mg VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed < or =600 mg VPA/day (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 mg/day and < or =600 mg/day. This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.

Safety of Pregnancy After Discontinuation of Isotretinoin

Isotretinoin (13-cis-retinoic acid, Accutane) increases the risk of major congenital malformations in infants exposed to isotretinoin during pregnancy. However, there have been no epidemiologic reports to date on the effect of a subsequent pregnancy after discontinuation of isotretinoin. This article describes our analysis of pregnancy case reports from patients in whom conception occurred after isotretinoin treatment had been discontinued. Based on the 88 prospectively ascertained cases, the incidence rate of both spontaneous and missed abortions from all pregnancies was 9.1% (eight patients), and the incidence rate of congenital malformation among the live births was 5.0% (four patients). The incidence rates for both these outcomes were not significantly different from the rates reported for women of reproductive age in the general population. In addition, the malformations reported were not characteristic of retinoic acid-induced congenital anomalies.

Early fetal growth delay detected by ultrasound marks increased risk of congenital malformation in diabetic pregnancy.

Ninety-nine insulin-dependent diabetic women with regular menstrual histories were examined by ultrasonic scanning in the seventh to 14th weeks of pregnancy. As judged by the crown-rump length 38 fetuses were smaller than normal. The term early growth delay is suggested for this phenomenon. Nine fetuses had major congenital malformations, and seven of them were smaller than normal in early pregnancy (p less than 0.02). The risk of fetal malformation in diabetic pregnancy increases with the severity of the diabetes. Early fetal growth delay is apparently another risk marker, in this series indicating a risk of 18% (7/38). The combination of severe maternal diabetes (White's classes D and F) and early growth delay yielded a risk of major congenital malformation of 27% (6/22). These observations suggest a common mechanism behind early growth delay and induction of abnormal embryogenesis (and maybe even fetal death). The mechanism is unknown but probably influenced by the quality of regulation of diabetes.