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Pregnancy in women with epilepsy : preliminary results of Kerala registry of epilepsy and pregnancy.
Correspondence Address:
Eighty-five women with epilepsy were followed up for reproductive functions under the registry of epilepsy and pregnancy. 32 of them had completed the pregnancy. Their mean age was 26 years and mean seizure frequency was 0.7 during current pregnancy. Nineteen of them (59.4%) had generalized epilepsy. Nine of them were not on any anti epileptic drugs (AED), 23 women were on various AEDs, 19 being on monotherapy. Only 40% of the women were taking folic acid during pregnancy. Pregnancy ended as spontaneous abortion in one patient. Nearly one third required cesarean section. Majority (87.5%) had term babies. Three (10.7%) babies had birth asphyxia. Six babies (21.4%) had low birth weight. Congenital malformations were detected in four cases (12.5%). Malformations included neural tube defects, talipes equinovarus and other minor anomalies. These babies were exposed to sodium valproate, carbamazepine or phenobarbitone. The risk of malformation was significantly greater (p<0.05) when the mother had generalized epilepsy. The odds ratio for risk of malformation was much higher with sodium valproate (6) than that with carbamazepine (1.2) or phenobarbitone (0.8). Majority of women with epilepsy had safe pregnancy and childbirth without any aggravation of epilepsy.
Epilepsy is one of the commonest neurological disorders in our country. Some 30% of the 75,000 women with epilepsy (WWE) in Kerala come under the reproductive age group. The social stigma and negative attitude prevalent in the society make it hard for WWE to integrate well into normal social life. There is considerable concern regarding the safety of pregnancy and health of the baby among these couples. Most of the previous studies indicate that WWE may have a slightly reduced fertility, when compared to others.[1] However, a recent community based study revealed that fertility is not reduced among WWE.[2] They may also face increased risk of complications of pregnancy such as hyperemesis gravidarum, spontaneous abortions, premature labour and assisted delivery or cesarean section.[3] The risk of congenital malformations is increased among the infants born to WWE by two to three times (4%-6%).[4] Most of the data on epilepsy and pregnancy had been compiled through the registries operating in the developed countries. The special situations prevailing in India and other developing countries are not adequately addressed in these studies. The outcome of pregnancy among WWE in developing countries further depends on these factors also. The preliminary results of the registry are presented here.
This study was carried out in the Kerala registry of epilepsy and pregnancy. The protocol of registry is described in Annexure I. Patients got enrolled in the registry at the preconception period or during pregnancy. Terminology according to International League Against Epilepsy (ILAE) was followed in classifying seizures and epileptic syndromes.[5],[6] Patients were followed up according to the consensus protocol developed by a team of doctors consisting of neurologists, gynaecologists, imageologists and experts from genetics and biochemistry departments during a workshop held for this purpose.[7] Clinical and laboratory investigations were carried out at predetermined intervals as laid down in the protocol. 85 WWE were enrolled in the registry between June 1998 and November 1998. Twenty of them (23.5%) reported in the preconception period and 65 (76.5%) during pregnancy. 14 patients were in the first trimester, 16 were in the second trimester and 35 in the third trimester. Follow up was incomplete in four of them and they were excluded from the analysis. The results pertain to the 32 patients, who had completed their current pregnancy. As per the policy of the registry, obstetrical follow up and delivery are conducted at a centre chosen by the patient. We compiled data on deliveries conducted elsewhere. Student's 't' test was performed to ascertain significance of group means. Odds ratio was calculated to estimate the risk of malformation with different AEDs.
Patient characteristics and AED therapy : Thirty-two women had completed their pregnancy under this protocol. Their age ranged from 19-38 years (mean 26 years), and parity ranged from 1-4 (mean 1.6). Nineteen (59.38%) of them had generalized epilepsy, 11 (34.37%) had localisation related epilepsy and 2 (6.26%) had other types. The seizure frequency during current pregnancy ranged from 0-8 (mean 0.7). Only 23 (71.9%) of them were taking AED, whereas nine (28.1%) were not on any AED. Nineteen were on monotherapy and 4 (12.5%) were on polytherapy. Nine patients were on phenobarbitone, seven on carbamazepine, six on sodium valproate and five on phenytoin. Regular consumption of folic acid was documented in only 40% patients although majority of them were recommended nutritional supplements including folic acid. None of them had any preconception evaluation or counseling. Pregnancy outcome : There was an increase in seizure frequency in only 4 women (12.5%) whereas there was no change in the seizure frequency in 25 (78.1%). Seizure frequency had decreased among 3 (9.4%) women. Over a quarter of these patients experienced pregnancy induced hypertension (PIH) or preeclampsia. Other complications observed during pregnancy were intrauterine growth retardation (IUGR), post term, placenta previa and hydramnios [Table I]. There was one case of spontaneous abortion. Nineteen (59.4%) women had normal vaginal delivery. Nearly one-third (10) required cesarean section [Table II]. The indication for cesarean section was foetal distress, uterine inertia and failure of induction. There was no episode of postpartum hemorrhage. Foetal outcome : There were 28 (87.5%) term babies, 2 (6%) were post term and 1 (3%) was pre-term. The mean head circumference of the babies was 34.9 cm (range 32-44 cm) and mean birth weight 2.84 kg (range 1.8-4 kg). 6 (21.4%) of the term babies were of low birth weight(<2.5 kg) and 3 (10.7%) had birth asphyxia (apgar 1 mt/5 mts = 2-6/3-7). Congenital malformations : Congenital malformations were detected in 4 babies [Table III]. The anomalies included hydrocephalus, meningomyelocele, spina bifida, Arnold-Chiarri malformation, intracerebral haemorrhage, talipes equinovarus and minor anomalies like asymmetric ears, pectus excavatus. Two of these babies were exposed to sodium valproate, while others to carbamazepine and phenobarbitone respectively. Two babies with malformations died in the immediate neonatal period. The baby with minor malformation Case 4, [Table III] was delivered in a peripheral hospital. The baby was transferred to neurology care when it developed neonatal seizures. An ultrasound examination through anterior fontenella showed intracerebral haemorrhage that was confirmed by CT Scan. This baby was managed with vitamin K injections, anti-convulsants and cerebral anti-oedema measures but died on 30th day. The clinical characteristics of pregnancies with and without malformations in the babies are compared [Table IV], even though the number of pregnancies with foetal anomalie was too small, due to small sample. There was no statistically significant difference in the maternal age, between those who had babies with malformations and those without malformations. There was a statistically significant (p <0.05) increase in frequency of major anomalies among babies exposed to AEDs in general, when compared to those not exposed to AEDs. The odds ratio for occurrence of malformations with various AEDs was as follows: sodium valproate (6), carbamazepine (1.2) and phenobarbitone (0.8). There was no anomaly in patients exposed to phenytoin.
The gender issues and medical aspects of epilepsy and pregnancy are gaining more focussed attention. Majority of WWE had normal outcome of pregnancy in our study. Only one patient (3%) had a spontaneous abortion which is less than that in the community. This is much less than that observed in our earlier retrospective analysis.[8] Another cohort of WWE, followed under a registry, had 9.4% rate of spontaneous abortion.[9] One of the reasons for this low estimate of spontaneous abortion in our series may be that nearly half of the patients were enrolled in the registry only in the third trimester. The complications of pregnancy, observed in our series is similar to that reported earlier.9,10 However, the frequency of pregnancy induced hypertension and pre-eclampsia is much higher in our series which could partly be due to the geographical preponderance. PIH and PET are multifactorial complications of pregnancy that show much geographical variation in frequency and severity. It is commoner among lower socio-economic group. The head circumferences of the newborns were within normal limits for the community. One fifth of the term babies had low birth weight (<2.5 kg), which indicates some degree of intrauterine growth retardation. The most important finding in this study is the occurrence of major malformations in a relatively high proportion (12.5%) of pregnancies. This frequency is comparable to that described in other prospective studies.[11],[12],[13] It is generally accepted that the incidence of congenital malformations in pregnancies among WWE is higher than that in general population. The incidence of malformations is comparatively higher in prospective studies (10 - 12%) than in retrospective studies were incidence of 2-6% has been reported.14 A retrospective study from our center also had shown a lower (4%) frequency of birth defects.[8] It appears that risk of malformations in WWE is more than what was previously estimated. We had examined several maternal clinical characteristics for possible association with foetal anomalies. There was no statistically significant difference in the maternal age between those who had babies with malformations and those without malformations. Other maternal characteristics such as age, parity and frequency of seizures during pregnancy did not have any significant correlation with congenital anomalies in our cohort. This is in contrast to the observation from Italian registry where the mothers who had babies with malformations had higher age.[9] Frequent seizures during pregnancy had been associated with adverse foetal outcome in earlier studies. However, we could not establish any such relationship. This may be because our patients had very few seizures during pregnancy (mean seizure frequency was 0.7) [Table IV]. In our study, the only clinical factors associated with birth anomalies were the type of maternal epilepsy and use of AED. There was statistically significant increased in incidence of malformations associated with generalized epilepsy. statistically significant. Reports from Berlin also have shown increased incidence of birth defects associated with generalized epilepsy in mothers.[16] In our study there was a clear correlation between the risk of neural tube defects and the exposure to sodium valproate or carbamazepine. Two of the six (33.3%) infants exposed to sodium valproate and one of the seven (14.3%) exposed to carbamazepine showed neural tube defects. The odds ratio was maximum (6) for sodium valproate. These observations are in agreement with other studies from elsewhere.[17],[18],[19],[20],[21] Polytherapy had been identified as one of the risk factors for malformations in earlier studies.22,23 We did not find such a correlation. This could be because there were very few patients (12.5%) on polytherapy. Another major observation in this study is the inconsistency in the prescription and use of folic acid during pregnancy. There was very poor compliance in this aspect as only 40% patients were found to be taking folic acid on a regular basis. The situation in developed countries is better (64%-78%) although it falls short of ideal situation.[24] Medical Research Council study in UK has shown that folic acid supplementation of 4 mg before conception prevented nearly thee quarters of neural tube defects in nonepileptic women.[25] There appears to be no uniform prescription policy regarding folic acid during pregnancy among WWE. One of these babies with minor anomalies developed intracerebral bleed and died on 30th day. This baby was delivered in a peripheral center and was not protected by vitamin K. There is much debate as to the usefulness of administering vitamin K to the mother in the immediate pre parturition period to prevent hemorrhagic disease of newborn.[23] The American Academy of Neurology in its practice parameters have recently recommended Vitamin K (10 mg per day) in the last month of pregnancy or parenteral Vitamin K1 as soon as labor sets in.[26] The study has brought out many of the lacunae in the care of WWE during pregnancy. Special situations prevailing in India and other developing countries do have a bearing on their outcome as observed in this study. The consumption of folic acid during pregnancy was less among WWE in our cohort. They had increased frequency of PIH/PET, and low birth weight babies. The frequency of cesarean sections was more in our cohort. These preliminary results indicate that major malformations occur in about 10% of cases and the risk appears to be higher with sodium valproate. The medical care of WWE in pregnancy need an integrated multidisciplinary approach. In fact the planning should begin much ahead of conception. A detailed preconception counseling should address all aspects of pharmacotherapy and obstetrical issues. The AED therapy need to be carefully evaluated and folic acid should be administered regularly. Pregnancy should be followed up with regular review and screening for serious congenital anomalies.
The authors gratefully acknowledge the financial support from the Department of Science, Technology and Environment, Government of Kerala to the Kerala registry of epilepsy and pregnancy.
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