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- Materials and methods
Purpose: To investigate pregnancy, delivery, and child outcome in an unselected population of women with both treated and untreated epilepsy.
Methods: In the compulsory Medical Birth Registry of Norway, all 2,861 deliveries by women with epilepsy recorded from 1999–2005 were compared to all 369,267 nonepilepsy deliveries in the same period.
Results: The majority (66%, n = 1900) in the epilepsy group did not use antiepileptic drugs (AEDs) during pregnancy. A total of 961 epilepsy-pregnancies were exposed to AEDs. Compared to nonepilepsy controls, AED-exposed infants were more often preterm (p = 0.01), and more often had birth weight <2,500 g (p < 0.001), head circumference <2.5 percentile (p < 0.001), and low Apgar score (p = 0.03). Small-for-gestational-age (SGA) infants (<10 percentile) occurred more frequently in both AED-exposed (p = 0.05) and unexposed (p = 0.02) epilepsy-pregnancies. Frequency of major congenital malformations (MCMs) was 2.8% (n = 81) in the epilepsy group versus 2.5% in controls (p = 0.3). Increased risk for MCMs could be demonstrated only for exposure to valproate (5.6%, p = 0.005) and AED polytherapy (6.1%, p = 0.02). Neonatal spina bifida was not significantly increased, but was a major indication for elective pregnancy termination among women with epilepsy. Cesarean section was performed more often in maternal epilepsy, regardless of AED-exposure (p < 0.001).
Discussion: Adverse pregnancy and birth outcome in women with epilepsy is mainly confined to AED-exposed pregnancies, although some risks are associated also with untreated epilepsy. The risk for congenital malformations was lower than previously reported. This could be due to a shift in AED selection, folic acid supplement, or possibly reflect the true risks in an unselected epilepsy population.
Epilepsy is the most common maternal neurologic disorder requiring medical treatment during pregnancy (Pennell, 2006). Risks associated with medical treatment during pregnancy must be weighed against the risk for fetal or maternal complications due to epileptic seizures (Kalviainen & Tomson, 2006; Meador et al., 2006). Increased frequency of pregnancy complications (preeclampsia, vaginal bleeding) as well as adverse perinatal outcome (low birth weight, prematurity, mortality) and development delay has been reported (Crawford, 2001; Adab et al., 2004; Pennell, 2006), although results have been conflicting (Hiilesmaa et al., 1985; Viinikainen et al., 2006).
Teratogenicity of antiepileptic drugs (AEDs) has been extensively debated. Infants of mothers with epilepsy have a reported two to three fold higher risk for congenital malformations, mainly associated with AED treatment (Holmes et al., 2001; Perucca, 2005). Intrauterine exposure to valproate or to multiple AEDs seems to represent the highest malformation risk (Perucca, 2005; Breen & Davenport, 2006; Pennell, 2006). Dose-dependency has been demonstrated for valproate (Artama et al., 2005; Vajda & Eadie, 2005; Meador et al., 2006) and lamotrigine (Morrow et al., 2006). Some AEDs are associated with specific malformations, that is, spina bifida and cleft lip-palate (Samren et al., 1999; Artama et al., 2005). Risks associated with pregnancy and AEDs will change over the years parallel to a shift regarding preferred drugs. Changes in guidelines for folic acid supplementation during pregnancy could also be important.
Reports on malformation rates are based primarily on retrospective or prospective observational studies in pregnancy registries with an acceptable cohort size that permits systematic data collection. However, such studies often have several methodologic limitations—that is, insufficient sample size, recruitment and assessment bias, retrospective design, limited follow-up length for malformation identification, inadequate definition of major congenital malformations (MCMs), questionable control group, not accounting for elective/spontaneous abortions—and drawing final conclusions regarding causality and effect have been difficult (Perucca, 2005; Pennell, 2006).
The population-based Medical Birth Registry of Norway (MBRN) offers a unique opportunity to examine a complete epilepsy cohort including both women with and without AED treatment. The compulsory, prospective registration of all deliveries, obtained from a population of 4.5 million people during a 7-year period, ensures a large cohort without selection bias. In addition, the material represents a population with homogenous health services during both pregnancy and delivery, ensuring comparable notification of all the study subjects and minimizing the effect of socioeconomic factors.
The aim of this study was to investigate and evaluate pregnancy and birth outcome in an unselected and time-representative epilepsy population, including women with both treated and untreated epilepsy.
- Top of page
- Materials and methods
Our study demonstrated a low malformation risk of only 4.9% for ACMs and 2.8% for MCMs in maternal epilepsy, similar to the rates in the general population. However, women with epilepsy experienced more pregnancy complications and adverse perinatal outcomes. This was mainly confined to pregnancies associated with AED treatment, although cesarean section and SGA infants were also associated with untreated epilepsy. Occurrence of genital malformations and Down syndrome were specifically increased in the untreated epilepsy group. Interactive effects between genetic factors, socioeconomic factors, maternal disease effect (seizures, underlying etiology), and exposure to AEDs probably explain the higher rate of adverse outcomes in maternal epilepsy.
The overall risk for congenital malformations was not significantly increased in the epilepsy group, and the malformation rates in different AED exposures were low compared to most earlier reports (Artama et al., 2005; Perucca, 2005; Vajda & Eadie, 2005; Wyszynski et al., 2005; Morrow et al., 2006). Valproate- and polytherapy-treated patients were the only groups with an increased risk. In addition, previous studies have shown the highest risks in such pregnancies (Rosa, 1991; Samren et al., 1999; Wide et al., 2004; Morrow et al., 2006). Infants of women with untreated epilepsy had malformation rates very similar to the control group, and this was also true in AED-exposed pregnancies when valproate-treated patients were excluded. Lamotrigine exposure had malformation rates similar to the control group, in line with previous reports (Sabers et al., 2004; Cunnington & Tennis, 2005; Vajda et al., 2006).
We report the malformation rate in an unselected and complete epilepsy population, in contrast to most previous studies, which have reported risks in hospital-based populations or registries with voluntary recruitment. Our cohort included also the women with uncomplicated and inactive epilepsy, and, therefore, at lower risk. The AED-exposed group was treated with a wide range of different AEDs, but the majority of these patients used carbamazepine, valproate, or lamotrigine, and mainly as monotherapy. A shift toward a higher rate of monotherapy and a change toward a less teratogenic AED selection may have contributed to the low malformation risk. The effect of epileptic seizures could not be addressed. A similar study on the Norwegian cohort from 1973 reported a malformation rate twice as high in women with epilepsy compared to the control group (Bjerkedal & Bahna, 1973).
Earlier scientific reports have shown that folic acid reduces malformations in the general population, but this has not been demonstrated for AED-exposed pregnancies. In the present study, folic acid supplementation was higher in AED-treated pregnancies, especially when treated with valproate or polytherapy. Such pregnancies most likely also have a higher malformation risk. Confounding by indication due to potential treatment-selection bias, therefore, made it difficult to assess possible protective effects of folic acid. Folic acid supplementation in high-risk pregnancies may have added to the low malformation rate in our study. However, more than 60% of AED-exposed women did not use folic acid prior to conception, in line with another report on folic acid supplementation during pregnancy in Norway (Nilsen et al., 2006). To prevent neural tube defects, folic acid must be initiated periconceptionally (Czeizel & Dudas, 1992; Botto et al., 2005; Kampman, 2007), and additional efforts to improve folic acid supplementation in women with epilepsy should be undertaken. Only two newborn infants with spina bifida were identified in the epilepsy cohort, but the majority of elective pregnancy terminations among women with epilepsy were performed because of this condition. If spina bifida is diagnosed primarily by prenatal screening procedures, and the majority aborted, it is essential that such information is accounted for when malformations are investigated in pregnancy registries.
Statistical power to demonstrate risk for specific malformations can be difficult to obtain due to small sample size (Pennell, 2006). The risk for cleft lip/palate malformations was not increased in the epilepsy group, regardless of AED exposure. In particular, there were no cleft lip/palate malformations in pregnancies exposed to lamotrigine (Dolk et al., 2008; Holmes et al., 2008). Down syndrome was a common cause for elective abortions in epilepsy pregnancies, and was found at a significantly increased rate in deliveries by women with untreated epilepsy. Infants with untreated mothers also had significantly more genital malformations. To our knowledge, a predisposition for such chromosomal and genital defects has not earlier been reported in women with epilepsy. Advanced maternal age is by far the most important identified risk factor associated with Down syndrome (Gaulden, 1992). However, additional environmental and genetic risk factors are involved. Toxic effects such as exposure to AEDs, ovarian dysfunction linked to hormonal imbalance, and genetic alterations related to low folate status, may predispose women with epilepsy to chromosomal defects (Sherman et al., 2007). Such predisposition could also be associated with epileptic syndrome or etiology, seizure characteristics, or other genetic vulnerability.
There was a higher frequency of SGA infants in both AED-exposed and unexposed epilepsy pregnancies, indicating a suboptimal intrauterine growth environment in both groups (Pallotto & Kilbride, 2006). However, occurrence of small head circumference, low birth weight, and prematurity were most strongly related to use of AEDs, suggesting an interaction between maternal disease and drug treatment. Diagnosed placental disorders were not increased in the epilepsy group. Earlier reports indicate both growth restriction and shorter pregnancy length in maternal epilepsy (Bjerkedal & Bahna, 1973; Yerby et al., 1985; Mastroiacovo et al., 1988; Meador et al., 2006). Underlying causes have not been identified, and AED effects on placenta function have not been shown (Eeg-Olofsson et al., 1990). The mechanisms affecting fetal growth and malformation risk most probably are different, as valproate treatment had the highest malformation risk, but was similar to the control group regarding risk for all other adverse perinatal outcomes. In contrast, lamotrigine and carbamazepine were safe regarding risk for fetal malformations, but were associated with an increased frequency of other adverse birth outcomes.
Infants in the epilepsy group had a higher frequency of low Apgar score and were more often transferred to pediatric wards after delivery, especially in AED-treated women. This, as well as the higher rate of emergency cesarean section, indicates more fetal stress during delivery. Low Apgar score, growth restriction, and low birth weight are indicators for childhood and adult morbidity (Moster et al., 2002; O’Keeffe et al., 2003; Jelliffe-Pawlowski & Hansen, 2004; Pallotto & Kilbride, 2006; Vrachnis et al., 2006). Attention toward such neonatal markers and possible long-term effects for children born to mothers with epilepsy, is an important challenge.
Perinatal mortality and stillbirths were not increased in the epilepsy group, regardless of AED exposure. Some earlier reports have suggested higher mortality in infants born to mothers with epilepsy (Bjerkedal & Bahna, 1973; Hiilesmaa et al., 1985; Meador et al., 2006). Two infants were diagnosed with neonatal intracranial hemorrhage in the epilepsy group, both in pregnancies without AED treatment. Inadequate maternal seizure control has been associated with this serious complication (Sherer et al., 1998; LaJoie & Moshe, 2004). Because MBRN contains incomplete information on epileptic seizures during pregnancy and delivery, effects of maternal seizures on pregnancy and birth outcome could not be investigated.
AEDs were associated with more vaginal bleeding during late pregnancy and delivery, in line with previous studies (Bjerkedal & Bahna, 1973; Pennell, 2004; Pilo et al., 2006), and may partly be explained by the reported higher rate of hypotonic uterine activity during labor. Alterations in vitamin K metabolism may also be a causal factor (Crawford, 2001; Pilo et al., 2006), possibly associated with use of enzyme-inducing AEDs (Kaaja et al., 2002). Exposure to AEDs was also associated with an increased risk for preeclampsia (Bjerkedal & Bahna, 1973; Yerby et al., 1985; Pilo et al., 2006). Whether this risk is caused by use of AEDs, or is related to genetic or socioeconomic factors, remains unclear.
This registry-based study has the major strength of including all deliveries in Norway (Irgens, 2002). Notification of maternal epilepsy is based on compulsory information from the attending physician and midwife, and includes treated as well as untreated epilepsy. The reported maternal epilepsy in 0.8% of deliveries indicates good diagnostic sensitivity. Earlier reports on MBRN have also demonstrated high diagnostic validity regarding maternal diseases (Skomsvoll et al., 2002; Hoff et al., 2007). Because a large proportion of the epilepsy group was untreated, potential underreporting of AED treatment is a concern. However, risk for adverse effects of AEDs is well known to Norwegian healthcare workers, and information on both epilepsy and use of AEDs is compulsory in the registry. A recent study in which data from MBRN were linked to the Norwegian Prescription Database, reports a similar proportion of AED treatment during pregnancy in women with epilepsy, strongly supporting the validity of our data (Engeland A, Bjørge T, Daltveit AK, Vollset SE, Furu K, unpublished manuscript). Folic acid supplementation in the untreated group was reported to be similar to controls, supporting the real absence of AEDs. Most likely, the large proportion of untreated epilepsy reflects an unselected population cohort and indicates that pregnancy is more common among women with untreated and probably less active epilepsy, representing the healthiest individuals within the epilepsy population. Distribution of maternal epilepsy within geographic regions in Norway demonstrated acceptable variation of treated versus untreated pregnancies and a consistently low proportion of AED treatment during pregnancy (results not shown). Unfortunately, this study lacks information on socioeconomic status, and AED dose and blood levels. In addition, the lack of data on maternal head circumference might represent a limitation in the interpretation of child head circumference.
In conclusion, the low malformation rate reported in this study may reflect a large group with untreated and less active epilepsy, a shift in AED selection, and folic acid supplementation, and represents the true risk in an unselected epilepsy population. However, a diagnosis of epilepsy still implies a significantly increased maternal risk during pregnancy and delivery, and for the child.