There has been controversy as to whether epilepsy itself or anticonvulsant mediation is teratogenic. Whichever factor is the teratogen, previous studies show the relative risk of damage is about 2 to 3 for exposed infants in comparison to unexposed infants. by using a systematic assessment with """"""""blind"""""""" examiners, we have developed in the 01 to 03 years an effective method for comparing anticonvulsant-exposed to epilepsy history (no drug) to unexposed infants. In the 01 to 03 years we have compared many outcomes; the frequency of one or more of five (microcephaly, growth retardation, major malformation, the """"""""anticonvulsant face"""""""" and fingernail hypoplasia) was 35.2% among 108 monotherapy drug-exposed, 50% among 24 polytherapy drug-exposed, 17.5% among 99 epilepsy history (no drugs) and 11.2% among 375 unexposed """"""""control"""""""" infants. The Rate Ratios comparing monotherapy drug-exposed to unexposed were significant for a higher frequency of major malformations, """"""""the face"""""""" and fingernail hypoplasia. No significant differences have been identified between epilepsy history and unexposed, but the same size is not yet adequate to be definitive. Power calculations show the value of having the systematic evaluation for subtle physical features; by using this approach we will have power of .99 to identify among 78 phenobarbital only exposed infants the three-fold higher frequency of all five outcomes identified to date (35.2% v. 11.2%). Preliminary tabulations of serum levels during pregnancy show that women whose infants had one of the five abnormal outcomes had significant differences in mean blood levels of anticonvulsants in some, but no all, trimesters. In the 04 to 06 years continued enrollment of all drug-exposed, seizure history and unexposed infants will be carried out at five Boston area hospitals. Parent-child correlations will be made to assess the true frequency of microcephaly. Face photographs of drug- exposed and unexposed infants will be digitized and analyzed to determine the morphometric differences in those infants considered to have the """"""""anticonvulsant face"""""""". We will correlate the phenotypic feature of the anticonvulsant-exposed infants with the drug levels in each trimester of pregnancy and the level of activity of enzymes involved in the metabolism of anti-convulsants, epoxide hydratase and glutathione S-transferase and peroxidase, in placental villus tissue and amniocyte cultures. A deficiency of one or more of these enzymes has been postulated to be the cause of the teratogenicity of anticonvulsants.
| Harvey, Elizabeth A; Coull, Brent A; Holmes, Lewis B (2003) Anticonvulsant teratogenesis 5: observer bias in a cohort study. Birth Defects Res A Clin Mol Teratol 67:452-6 |
| Holmes, L B (2002) The teratogenicity of anticonvulsant drugs: a progress report. J Med Genet 39:245-7 |
| Holmes, L B; Harvey, E A; Coull, B A et al. (2001) The teratogenicity of anticonvulsant drugs. N Engl J Med 344:1132-8 |
| Carlin, J B; Ryan, L M; Harvey, E A et al. (2000) Anticonvulsant teratogenesis 4: inter-rater agreement in assessing minor physical features related to anticonvulsant therapy. Teratology 62:406-12 |
| Holmes, L B; Harvey, E A; Brown, K S et al. (1994) Anticonvulsant teratogenesis: I. A study design for newborn infants. Teratology 49:202-7 |
| Raymond, G V; Holmes, L B (1994) Head circumferences standards in neonates. J Child Neurol 9:63-6 |
