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Pregnancy, epilepsy and antiepileptic drugs.
P. Satishchandra, S. Sinha Department of Neurology National Institute of Mental Health and Neurosciences Bangalore, India. Women with epilepsy have some legitimate questions and worries regarding the effect of epilepsy and use of anti epileptic drugs (AEDs) upon their pregnancies and their unborn babies. The concerns are : i) increased seizure frequency during pregnancy, ii) risk of birth defects, iii) risk associated with breastfeeding, iv) psychomotor retardation in off springs and v) foetal deaths. Due to better social adjustment and awareness, more number of women with epilepsy are getting married and bearing children.1,2 It is also universally accepted that AEDs must be continued through out pregnancy because uncontrolled seizures during pregnancy may cause more harm if not treated adequately. Therefore, it is important to put the teratogenic potential of AEDs in proper perspective. The article by Thomas et al in this issue attempts to highlight some of the above problems of women with epilepsy from Kerala registry. They have reported follow up data of 32 women with epilepsy who delivered babies. Among them, 23 were on treatment with various AEDs.[3] The report of 'foetal hydantoin syndrome' was first published in 1960s. Since there many aspects of drug toxicity in foetus have been reported[2],[4],[5] viz : a) infants of mothers with epilepsy are at greater risk of developing congenital malformations than general population, b) foetal malformations among infants born to mothers with epilepsy and AEDs during pregnancy are higher than among infants of epileptic mothers not exposed to AEDs in-utero, c) mean serum AED level is higher in mothers of infants with malformation, d) infants of mothers on polytherapy have higher rates of malformations. A prospective case control study is the best way to determine the risks and factors responsible for increased risks. The method used by Thomas et al though prospective - unfortunately lacks control group, has non-random use of AEDs and consists of heterogeneous types of epilepsy. One must have information segregated by seizure types along with the proper number of subjects required to attain adequate statistical power and control to determine the potential influence of a specific type of seizure or epilepsy syndrome that may itself pose risk of adverse outcome independent of the AEDs administered.4 It is said that fertility of women with epilepsy is 85% when compared to the general population. The complications like pregnancy induced hypertension (28.1%), intrauterine growth retardation (18.8%), reported by Thomas et al mainly are in accordance with that reported in literature.[2] Most women have a normal vaginal delivery. A relatively lower incidence (60%) of normal vaginal delivery in the study from Kerala could be because of small sample. Regular and periodic antenatal check up with a good ultra sound examination for foetal well-being / malformations and/or alpha feto protein (AFP) levels should be done and the practitioner must choose a course that prevents seizures and minimizes foetal exposure to AEDs.[5] The background risk of malformations is approximately 1-3%, which increases to 7% with monotherapy and to 15% with polytherapy.2 In a study, it has been found that overall malformation risk is 9.7% in infants of epileptic mothers compared to 4.8% in controls.1,6 It is believed that in prospective studies the incidence of anomalies is more than that reported in retrospective studies as the minor anomalies are overlooked in the later. Thomas et al3 in this issue report a rather high incidence of teratogenecity of 12.5% (4/32). All the patients were on monotherapy with different drugs. Surprisingly the teratogenicity of sodium valproate i.e. neural tube defects (NTD) is 33% (2/6) in this study which is much higher than other reports in literature (1 to 1.5%). This, however, should not send a wrong message to patients and physicians. The reasons could be very small sample size in this preliminary report from Kerala and further studies with larger sample and comparison with controls may be required before a final conclusion can be drawn. All AEDs cross placenta and attain sufficient pharmacological active levels in embryo. The mechanisms of teratogenecity are still not clear but may be because of formation of epoxide and/or oxide metabolites and of cytotoxic free radicals. Though there is no conclusive evidence for a differential overall risk of teratogenicity of various AEDs, it is generally believed that sodium valproate carries probably a higher risk especially with regards to neural tube defects.[7] Rosa et al reported that NTD is slightly more with valproate (1.47%) than carbamazepine (1.0%).[8] However, there are some reports that valproate/carbamazepine along with other AEDs in utero have decreased incidence of NTDs! The reason however is not clearly understood.[1] There is no conclusive evidence for or against the safety of newer AEDs till now. Kondo et al from Japan have reported that among 20 patients on zonisamide (18 on polytherapy and 2 on monotherapy) used in pregnancy, one had atrial septal defect.[9] Valproate induced impaired embryonic folate metabolism was studied by Wegener et al.[10] Serum folate levels, less than 4 mg/dl have been found to be associated with increased risk of anomalies.[10] An MRC study from UK found that 4mg/day of folate from pre-conception, to women who have given birth to an infant with NTDs, was associated with 72% protection. Thomas et al[3] found that only 40% of women with risk were on folate supplement. It appears that we should have some definitive guidelines in India for prescribing folate during pregnancy in order to prevent these anomalies. If major anomalies are detected, medical termination (MTP) should be recommended. A protocol, as prepared by Keral registry, may be a good idea to follow. The problems addressed here are important to our patients and us. The difficulties in mounting a definitive prospective study are daunting. A detailed preconception counseling of women with epilepsy with a multidisciplinary approach and a good periodic antenatal check up is required. Definitive steps for folate supplementation are required.[5] The suggested guidelines include - i) all women of childbearing age with epilepsy, should be (during preconception) counseled that the incidence of malformation in infants of mothers with epilepsy who are treated with AEDs is two or three times that of the infants of mothers without epilepsy, ii) children of mothers with epilepsy treated or untreated with AEDs tend to have more minor anomalies than do children of father with epilepsy or general population, iii) we do not know which of four major AEDs (phenobarbitone, phenytoin, car-bamazepine and sodium valproate) is least teratogenic. Under therapeutic conditions, valproate may be regarded as considerably teratogenic while all other AEDs as weakly teratogenic, iv) if AED therapy cannot be avoided, the first drug of choice for the seizure type and/or epilepsy syndrome should be used as monotherapy in lowest minimal effective dose, v) folate supplementation is a must, vi) intense search for birth defects must be done during regular follow up and interventions (if required) during pregnancy and labour. Though there is small but significant risk, more than 90% of women with epilepsy on AEDs during pregnancy will deliver normal child without any form of birth defects.[11]
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