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      Epilepsy drugs and effects on fetal development: Potential mechanisms

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          Abstract

          Approximately 1% of all pregnancies are in woman with epilepsy. Although, the majority of children born to women with epilepsy are normal, they are at increased risk for malformations. Notably, the teratogenicity of antiepileptic drugs is a well-defined subject. The incidence of major malformations in offspring of mothers with epilepsy who were treated with AEDs is higher than women with untreated epilepsy and in the general population. These malformations include spina bifida, cleft palate, limb reduction defects, cardiac abnormalities, hypospadias, and gastrointestinal atresia. The exact mechanism by which the AEDs mediate abnormalities in the fetus is uncertain. However, there are several hypotheses to explain them. Some of the most important include folate-related actions, ischemia, reactive intermediates (e.g., free radicals), and genetic susceptibility. Thus, understanding the mechanisms of AED-related abnormalities is of vital importance for the care of epileptic women and their offspring.

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          Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register.

          J. Morrow, A. Russell, E Guthrie … (2006)
          To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs). Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first three months of life was the main outcome measure. Full outcome data were collected on 3607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI), 3.6% to 5.0%). The MCM rate was higher for polytherapy (6.0%) (n = 770) than for monotherapy (3.7%) (n = 2598) (crude odds ratio (OR) = 1.63 (p = 0.010), adjusted OR = 1.83 (p = 0.002)). The MCM rate for women with epilepsy who had not taken AEDs during pregnancy (n = 239) was 3.5% (1.8% to 6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI, 4.6% to 8.2%) than only to carbamazepine (2.2% (1.4% to 3.4%) (OR = 2.78 (p<0.001); adjusted OR = 2.97 (p<0.001)). There were fewer MCMs for pregnancies exposed only to lamotrigine than only to valproate. A positive dose response for MCMs was found for lamotrigine (p = 0.006). Polytherapy combinations containing valproate carried a higher risk of MCM than combinations not containing valproate (OR = 2.49 (1.31 to 4.70)). Only 4.2% of live births to women with epilepsy had an MCM. The MCM rate for polytherapy exposure was greater than for monotherapy exposure. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM.
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            Folic acid antagonists during pregnancy and the risk of birth defects.

            Douglas A. Mitchell, A. Walker, Martha M. Werler … (2000)
            Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinary tract defects in their infants. We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations. We compared data on exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors and to certain antiepileptic drugs for 3870 infants with cardiovascular defects, 1962 infants with oral clefts, and 1100 infants with urinary tract defects with data for 8387 control infants with malformations the risk of which is not reduced after vitamin supplementation. Mothers were interviewed within six months after delivery about their medication use. The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors during the second or third month after the last menstrual period, as compared with infants whose mothers had no such exposure, were 3.4 (95 percent confidence interval, 1.8 to 6.4) and 2.6 (95 percent confidence interval, 1.1 to 6.1), respectively. The relative risks of cardiovascular defects, oral clefts, and urinary tract defects after maternal exposure to antiepileptic drugs were 2.2 (95 percent confidence interval, 1.4 to 3.5), 2.5 (95 percent confidence interval, 1.5 to 4.2), and 2.5 (95 percent confidence interval, 1.2 to 5.0), respectively. Use of multivitamin supplements containing folic acid diminished the adverse effects of dihydrofolate reductase inhibitors, but not that of antiepileptic drugs. Folic acid antagonists, which include such common drugs as trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbital, and primidone, may increase the risk not only of neural-tube defects, but also of cardiovascular defects, oral clefts, and urinary tract defects. The folic acid component of multivitamins may reduce the risks of these defects.
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              The teratogenicity of anticonvulsant drugs.

              S Khoshbin, E Harvey, K. I. Huntington … (2001)
              The frequency of major malformations, growth retardation, and hypoplasia of the midface and fingers, known as the anticonvulsant embryopathy, is increased in infants exposed to anticonvulsant drugs in utero. However, whether the abnormalities are caused by the maternal epilepsy itself or by exposure to anticonvulsant drugs is not known. We screened 128,049 pregnant women at delivery to identify three groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The infants were examined systematically for the presence of major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size. The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7). The frequency was also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1). The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of those abnormalities than the control infants. A distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Res Med Sci
                Journal ID (iso-abbrev): J Res Med Sci
                Journal ID (publisher-id): JRMS
                Title: Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences
                Publisher: Medknow Publications & Media Pvt Ltd (India )
                ISSN (Print): 1735-1995
                ISSN (Electronic): 1735-7136
                Publication date (Print): September 2012
                Volume: 17
                Issue: 9
                Pages: 876-881
                Affiliations
                [1 ]Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Iran
                [2 ]Pharmaceutical Sciences Research Center, Mashhad University of medical Sciences, Iran
                [3 ]Medical Toxicology Research Center, Mashhad University of Medical Sciences, Iran
                Author notes
                Address for correspondence: Dr. Seyed Adel Moallem, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box 91775-1365, Mashhad, Iran. E-mail: moallem@ 123456mums.ac.ir
                Article
                Publisher ID: JRMS-17-876
                PMC ID: 3697215
                PubMed ID: 23826017
                SO-VID: 19ef9c3e-7f27-4610-ab63-9f23ecb0635c
                Copyright © Copyright: © Journal of Research in Medical Sciences
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 07 January 2012
                Date revision received : 24 July 2012
                Date accepted : 29 July 2012
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Medicine
                Keywords: anti-epileptic drugs,epilepsy,pregnancy,teratogen
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: anti-epileptic drugs, epilepsy, pregnancy, teratogen

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