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      Efectos teratogénicos de la carbamazepina Translated title: Teratogenic effects of carbamazepine.

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          Abstract

          Se realizó un estudio epidemiológico perspectivo sobre los efectos teratogénicos de la carbamazepina, en el servicio de Neurología y Neurocirugía del hospital provincial "Vladimir I. Lenin" de Holguín, durante los años 1992-1998. Se seleccionaron las gestantes epilépticas tratadas con régimen de monoterapia o politerapia. Se constituyó un grupo control con gestantes no epilépticas, procedentes de la consulta de Teratología Clínica del Centro provincial de Genética. Se comprobó que todas las gestantes recibieron tratamiento periconcepcional con 1 mg/d de ácido fólico y seguimiento ulterior de 5 mg, hasta las 20 sem, cuando continuaron con suplemento vitamínico de prenatal. Se halló que la calidad reproductiva fue desfavorable en la historia obstétrica precedente, con alto índice de abortos provocados, espontáneos, incidencia de rivanol por malformaciones congénitas y mortalidad fetal tardía. En las gestaciones propósitos, se obtuvieron tasas de 7,4 % para los abortos espontáneos en ambos regímenes terapéuticos y de 3,7 %, respectivamente para las interrupciones de malformaciones congénitas por el método de rivanol, que se correspondieron con cardiopatías congénitas complejas. No hubo muertes fetales tardías. El grupo control no tuvo fracasos gestacionales. La somatometría al nacer estuvo dentro de límites normales, aunque la circunferencia cefálica alcanzó valor de 32,6 cm, para el grupo de politerapia. La carbamazepina, en régimen terapéutico de monoterapia y politerapia alcanzó la misma expresión teratogénica, provocó abortos espontáneos y cardiopatías congénitas complejas, mientras en régimen de politerapia afectó el desarrollo de la circunferencia cefálica y, en menor grado, el valor del peso y la talla.

          Translated abstract

          A perspective epidemiological study on the teratogenic effects of carbamazepine was carried out in the Neurology and Neurosurgery Department of “Vladimir Ilich Lenin” provincial hospital in Holguín from 1992 to 1998. Epileptic pregnant women treated with monotherapy or combined therapy were selected for the study. Also a control group of non-epileptic pregnant women from the clinical teratology service of the provincial center of genetics participated in it. It was demonstrated that all the pregnant women received periconceptional treatment at a dose of 1 mg of folic acid per day and further follow-up with 5 mg up to the 20th week of gestation when they continued to receive prenatal vitamin supplement. It was found that the reproductive quality was negative in the previous obstetric history of these women because of a high rate of induced abortions, miscarriages, incidence of rivanol in pregnancy terminations because of congenital malformations and late fetal mortality. In the studied pregnancies, rates of 7.4% for miscarriages under both therapeutical regimes and of 3,7% for pregnancy terminations by the rivanol method due to congenital malformations were recorded. The malformations were complex congenital cardiopathies. There was no late fetal death. The control group did not present gestational failures. Somatometry at birth was within standard limits, but the head circunference reached 32,6 cm in the neonates of the group of women under combined therapy. Carbamazepine administered in monotherapy or combined therapy had the same teratogenic expression, caused miscarriages and complex congenital cardiopathies whereas when it was administred in combined therapy, it affected the development of head circunference and in lesser extent, the weight and size figures.

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          Congenital malformations due to antiepileptic drugs.

          To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.
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            Pattern of malformations in the children of women treated with carbamazepine during pregnancy.

            In an attempt to determine whether and to what extent carbamazepine is teratogenic, we evaluated eight children whom we identified retrospectively as having had prenatal exposure to carbamazepine alone or in combination with a variety of anticonvulsants other than phenytoin. In addition, in a prospective study, we documented the outcome of the pregnancies of 72 women who contacted us early in pregnancy because they were concerned about the potential teratogenicity of carbamazepine. A pattern of malformation, the principal features of which are minor craniofacial defects and fingernail hypoplasia, and of developmental delay was identified in the eight children retrospectively ascertained to have been exposed to carbamazepine in utero; this pattern was subsequently confirmed through the evaluation of 48 children born alive to the women in the prospective study. That carbamazepine itself is teratogenic is indicated by the incidence of craniofacial defects (11 percent), fingernail hypoplasia (26 percent), and developmental delay (20 percent) in the 35 live-born children of the women in the prospective study who were exposed prenatally to carbamazepine alone. The similarity between the children exposed prenatally to carbamazepine and those with the fetal hydantoin syndrome is probably related to the fact that both drugs are metabolized through the arene oxide pathway and raises the possibility that it is the epoxide intermediate rather than the specific drug itself that is the teratogenic agent.
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              Guidelines for the care of women with epilepsy.

              Antiepileptic drug (AED) selection in women of reproductive age should consider efficacy, tolerability, interactions with contraceptive medications, and teratogenicity. Women planning a pregnancy should be counseled regarding the need for compliance with therapy and the risk for birth defects. All women with epilepsy who are of childbearing potential should receive folate supplementation. Vitamin K supplementation is recommended during the final month of pregnancy. Withdrawal of AED therapy in seizure-free women can be considered before conception. Women who require AED therapy should receive AED monotherapy rather than polytherapy when at all possible. Medication changes post conception do not significantly reduce the risk for major fetal malformations and may compromise seizure control. Breastfeeding is generally safe for women taking AEDs. Menstrual disorders, reproductive endocrine disorders, ovulatory dysfunction, and infertility appear to be relatively common in women with epilepsy.
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                Author and article information

                Journal
                gin
                Revista Cubana de Obstetricia y Ginecología
                Rev Cubana Obstet Ginecol
                Editorial Ciencias Médicas (Ciudad de la Habana, , Cuba )
                0138-600X
                1561-3062
                December 2001
                : 27
                : 3
                : 241-246
                Affiliations
                [01] Holguín orgnameFacultad de Ciencias Médicas Mariana Grajales Coello Cuba
                Article
                S0138-600X2001000300012 S0138-600X(01)02700312
                fd9fec68-a597-4cd6-916a-0a2f2863b97e

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 11 May 2001
                : 02 October 2001
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 17, Pages: 6
                Product

                SciELO Cuba

                Self URI: Texto completo solamente en formato PDF (ES)
                Categories
                OBSTETRICIA

                CARBAMAZEPINA,EPILEPSIA,COMPLICACIONES DEL EMBARAZO,ANOMALIAS INDUCIDAS POR DROGAS,QUIMIOTERA PIA COMBINADA,CARBAMAZEPINE,EPILEPSY,PREGNANCY COMPLICATIONS,ABNORMALITIES,DRUG- INDUCED,DRUG THERAPY, COMBINATION

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