Elizabeth A. Harvey

The Teratogenicity of Anticonvulsant Drugs

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

The effects of prenatal exposure to phenytoin and other anticonvulsants on intellectual function at 4 to 8 years of age.

Twenty phenytoin exposed children between 48 and 99 months of age had an evaluation of behavior and intelligence by a single examiner who was unaware of exposure status. The controls were 98 children identified at birth as having three or more minor anomalies. None of the children evaluated were mentally retarded. In both, a case-by-case comparison and a comparison of the two entire groups, the phenytoin-exposed children had significantly lower scores for both Performance IQ (PIQ), Full Scale IQ (FSIQ), and Visual Motor Integration Test (VMIT). Similar abnormalities have been found in studies of animals exposed to phenytoin in utero. These results suggest that the teratogenic effects of phenytoin may include an effect on cognitive function.

Anticonvulsant teratogenesis 4: Inter-rater agreement in assessing minor physical features related to anticonvulsant therapy

BACKGROUND We report on inter-rater agreement in the assessment of newborn infants with respect to a range of minor physical features in a cohort study of the fetal effects of maternal anticonvulsant use during pregnancy. METHODS Infants from three groups (exposed to anticonvulsants, seizure history but no medication exposure, and unexposed controls) were examined by both a pediatrician/teratologist, who was blinded with respect to the mothers exposure status, and an unblinded research assistant. Agreement on assessments for selected anomalies associated with anticonvulsant therapy was measured by kappa-statistics, as well as by more sensitive log-linear modeling techniques, which allow examination of possible covariate effects on the strength of agreement. Although the physician and research assistant agreed on a high proportion of cases (80-90%), kappa values were modest (0.2-0. 5), partly because of the low prevalence of the anomalies considered. To explore how agreement varies within subgroups, we used recently developed methods for studying agreement based on log-linear models. RESULTS Log-linear modeling indicated that there was substantial variation in pattern of agreement between different individual research assistants but that other factors (e.g., exposure category, sex, and birthweight) did not appear to be related to agreement. Our results suggest that research assistants with more experience showed the highest degree of agreement with the physicians. CONCLUSIONS Our results have implications for both clinical practice and epidemiologic research and underline the importance of thorough training of staff in the definitions to be used and also the need for multiple independent assessments of these subtle anomalies.

Human skeletal development and feeding behavior: the impact on oxygen isotopes

There is substantial room for isotopic analysis to address questions regarding human migration and interaction with the landscape. Oxygen isotopes in vertebrate tissues, which are generally thought to reflect water source, are derived from a combination of water, food and air isotopic values put through the physiology and intermediary metabolism of the animal. We highlight two additional issues in applying oxygen isotopic analysis to humans: the unique developmental regime of skeletal elements and the impact of cooking on food.