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A prospective, controlled study of developmental outcome following in utero exposure to phenytoin and carbamazepine monotherapy
160
Reproductive Toxicology
Centre de Renseignements sur les Agents T~ratog~nes (C.R.A.T.) C.H.U. Saint-Antoine, Paris, France The 610 observations of irradiations during pregnancy collected in our TIS, and especially subdiaphragmatic x-ray diagnosis, support the general opinion that low dosages (-< 10 cGy) are not teratogenic. It must be stressed that no specific prenatal diagnosis is required in these circumstances. On the other hand, the estimation of gonadal irradiation might be useful, in some cases of radiologic examinations involving the pelvis, when the number of films and the duration of radioscopy were unusually high.
A prospective, controlled study of developmental outcome following in utero exposure to phenytoin and carbamazepine monotherapy D. Scolnik, I. Nulman, J. Rivet, G. Koren Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada Background: The doubled incidence of major malformations in the offspring of epileptic women could be due to genetic, environmental, or iatrogenic factors. Previous studies attempting to elucidate the role of each have been confounded by patients being on polytherapy, by the lack of appropriate controls, and by failure to account for maternal IQ. Patients and Methods: As part of an on-going study, 27 women on phenytoin and 29 on carbamazepine monotherapy were prospectively recruited during the first trimester of pregnancy from referrals to an antenatal counseling service, neurologists, and a geneticist. Controls were matched for age of mother and child, parity, and gravidity. Children were tested with either Bayley or McCarthy, and Reynell Scales; mothers were tested with Wechsler Scale-Revised (pro-rated), Hollingshead and Parenting Stress Indices, and Toddler Temperament or Behaviour Style Questionnaire. Results: Preliminary examination of the data on the first 27 phenytoin- and 29 carbamazepine-exposed children and on 45 controls suggests that the social status of patient and control groups was similar. IQ of phenytointreated mothers tended to be lower than that of either carbamazepine or control groups, but not significantly so. IQ of children exposed to phenytoin was lower than either carbamazepine or control children (P < 0.05). Seven of the 27 phenytoin-exposed children had an IQ more than 1 standard deviation below the mean, compared to 0 of 29 carbamazepine-exposed children, and 0 of 45 controls (P < 0.02). Comments: Further analysis of data will be performed when results become available on the offspring of a total of 35 patients in each anticonvulsant group and their matched controls. It is possible that differences in maternal IQ may account for some of the differences in children's outcome measures.
Drug usage by women participating in the US NICHD collaborative study on the safety and accuracy of chorionic villus sampling (CVS) E. Pergament, J. Zachary, US N I C H D Collaborative CVS Study Group
Volume 7, Number 2, 1993 Prentice W o m e n ' s Hospital and Maternity Center, Northwestern Memorial Hospital and Medical School, Chicago, Illinois We wish to report on the drug consumption of 4319 women who participated in the National Institute of Health's multicenter study comparing the safety and accuracy of CVS and amniocentesis. This population was characterized by a mean age of 36.9 years, primarily white (94%), a college or postgraduate degree (72%); limited use of tobacco (daily, 7%), and less than one alcohol drink/week (84%). Forty-seven percent reported drug ingestion in the 4 months prior to their last menstrual period or during the 8 to 9 weeks of pregnancy that elapsed to initial intake. Of the women taking drugs, 50% took a single medication, 27% took 2 medications, and 23% reported taking 3 or more medications. At the 16-week follow-up, data are available on 3975 women, of whom 21% report taking drugs at some point since intake. Of these women, 71% report taking 1 medication, 24% report taking 2 medications, and 5% report taking 3 or more medications. Analgesics, antibiotics, and antihistamines constituted over 60% of the drugs ingested. Three percent of the women acknowledged the use of illicit drugs (marijuana, cocaine, LSD). Livebirths occurred in 93% of the pregnancies. Comparison of women participating in this N I C H D study will be made with previous reports, in order to determine any trends and/or changes in the drug consumption patterns of pregnant women over time.
Maternal and fetal ADH and ALDH genotypes: relationship to fetal alcohol syndrome R.A. Martin, K.L. Jones, H. Thomasson, T.K. Li Department of Pediatrics, University of California School of Medicine, La Jolla, California, and Department of Medicine, University of Indiana, Indianapolis, Indiana Alcohol metabolism in humans involves two major steps: alcohol to acetaldehyde via alcohol dehydrogenase (ADH) and acetaldehyde to acetate via aldehyde dehydrogenase (ALDH). These two enzymes exhibit significant genetic polymorphism resulting in pharmacokinetic variability of alcohol metabolism based on enzyme genotype. Using a mouse model for the fetal alcohol syndrome (FAS), Chernoff (1980) showed that the frequency of FAS was directly proportional to the significantly different maternal ADH activity in 3 different genetic strains of mice. The purpose of this study is to determine whether a specific ADH or A L D H genotype is present in mothers of children with FAS. To date we have evaluated 16 children born to 13 chronic alcoholic mothers, all of whom admitted to heavy drinking throughout the first trimester of pregnancy for each child examined. All children born to these mothers were examined by us. Five mothers had children with FAS, and eight mothers had unaffected children. Blood samples from each child and from his or her mother were obtained, and the genotypes for class I ADH and class lI A L D H were determined blindly using standardized gene amplification techniques. For these 13 mothers and their 16 offspring, no particular maternal or fetal A D H / A L D H genotype was associated with occurrence of FAS. Although these data do not rule out the possibility that the
Reproductive Toxicology
Centre de Renseignements sur les Agents T~ratog~nes (C.R.A.T.) C.H.U. Saint-Antoine, Paris, France The 610 observations of irradiations during pregnancy collected in our TIS, and especially subdiaphragmatic x-ray diagnosis, support the general opinion that low dosages (-< 10 cGy) are not teratogenic. It must be stressed that no specific prenatal diagnosis is required in these circumstances. On the other hand, the estimation of gonadal irradiation might be useful, in some cases of radiologic examinations involving the pelvis, when the number of films and the duration of radioscopy were unusually high.
A prospective, controlled study of developmental outcome following in utero exposure to phenytoin and carbamazepine monotherapy D. Scolnik, I. Nulman, J. Rivet, G. Koren Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada Background: The doubled incidence of major malformations in the offspring of epileptic women could be due to genetic, environmental, or iatrogenic factors. Previous studies attempting to elucidate the role of each have been confounded by patients being on polytherapy, by the lack of appropriate controls, and by failure to account for maternal IQ. Patients and Methods: As part of an on-going study, 27 women on phenytoin and 29 on carbamazepine monotherapy were prospectively recruited during the first trimester of pregnancy from referrals to an antenatal counseling service, neurologists, and a geneticist. Controls were matched for age of mother and child, parity, and gravidity. Children were tested with either Bayley or McCarthy, and Reynell Scales; mothers were tested with Wechsler Scale-Revised (pro-rated), Hollingshead and Parenting Stress Indices, and Toddler Temperament or Behaviour Style Questionnaire. Results: Preliminary examination of the data on the first 27 phenytoin- and 29 carbamazepine-exposed children and on 45 controls suggests that the social status of patient and control groups was similar. IQ of phenytointreated mothers tended to be lower than that of either carbamazepine or control groups, but not significantly so. IQ of children exposed to phenytoin was lower than either carbamazepine or control children (P < 0.05). Seven of the 27 phenytoin-exposed children had an IQ more than 1 standard deviation below the mean, compared to 0 of 29 carbamazepine-exposed children, and 0 of 45 controls (P < 0.02). Comments: Further analysis of data will be performed when results become available on the offspring of a total of 35 patients in each anticonvulsant group and their matched controls. It is possible that differences in maternal IQ may account for some of the differences in children's outcome measures.
Drug usage by women participating in the US NICHD collaborative study on the safety and accuracy of chorionic villus sampling (CVS) E. Pergament, J. Zachary, US N I C H D Collaborative CVS Study Group
Volume 7, Number 2, 1993 Prentice W o m e n ' s Hospital and Maternity Center, Northwestern Memorial Hospital and Medical School, Chicago, Illinois We wish to report on the drug consumption of 4319 women who participated in the National Institute of Health's multicenter study comparing the safety and accuracy of CVS and amniocentesis. This population was characterized by a mean age of 36.9 years, primarily white (94%), a college or postgraduate degree (72%); limited use of tobacco (daily, 7%), and less than one alcohol drink/week (84%). Forty-seven percent reported drug ingestion in the 4 months prior to their last menstrual period or during the 8 to 9 weeks of pregnancy that elapsed to initial intake. Of the women taking drugs, 50% took a single medication, 27% took 2 medications, and 23% reported taking 3 or more medications. At the 16-week follow-up, data are available on 3975 women, of whom 21% report taking drugs at some point since intake. Of these women, 71% report taking 1 medication, 24% report taking 2 medications, and 5% report taking 3 or more medications. Analgesics, antibiotics, and antihistamines constituted over 60% of the drugs ingested. Three percent of the women acknowledged the use of illicit drugs (marijuana, cocaine, LSD). Livebirths occurred in 93% of the pregnancies. Comparison of women participating in this N I C H D study will be made with previous reports, in order to determine any trends and/or changes in the drug consumption patterns of pregnant women over time.
Maternal and fetal ADH and ALDH genotypes: relationship to fetal alcohol syndrome R.A. Martin, K.L. Jones, H. Thomasson, T.K. Li Department of Pediatrics, University of California School of Medicine, La Jolla, California, and Department of Medicine, University of Indiana, Indianapolis, Indiana Alcohol metabolism in humans involves two major steps: alcohol to acetaldehyde via alcohol dehydrogenase (ADH) and acetaldehyde to acetate via aldehyde dehydrogenase (ALDH). These two enzymes exhibit significant genetic polymorphism resulting in pharmacokinetic variability of alcohol metabolism based on enzyme genotype. Using a mouse model for the fetal alcohol syndrome (FAS), Chernoff (1980) showed that the frequency of FAS was directly proportional to the significantly different maternal ADH activity in 3 different genetic strains of mice. The purpose of this study is to determine whether a specific ADH or A L D H genotype is present in mothers of children with FAS. To date we have evaluated 16 children born to 13 chronic alcoholic mothers, all of whom admitted to heavy drinking throughout the first trimester of pregnancy for each child examined. All children born to these mothers were examined by us. Five mothers had children with FAS, and eight mothers had unaffected children. Blood samples from each child and from his or her mother were obtained, and the genotypes for class I ADH and class lI A L D H were determined blindly using standardized gene amplification techniques. For these 13 mothers and their 16 offspring, no particular maternal or fetal A D H / A L D H genotype was associated with occurrence of FAS. Although these data do not rule out the possibility that the