In an attempt to define the pathogenesis of congenital malformations in diabetic pregnancy, a number of serum factors were determined in normal and diabetic pregnant rats and correlated to the outcome of gestation with the aid of multivariate linear regression analysis. The animals were from two different lines of Sprague-Dawley rats with documented differences in rates of fetal dysmorphogenesis in diabetic pregnancy. The diabetic rats increased less in body weight than the normal rats, yet displayed increased liver and kidney weights. The serum concentrations of glucose, P-hydroxybutyrate, triglycerides, the branched-chain amino acids, and asparagine, proline, alanine, citrulline, tyrosine, and ornithine were increased by diabetes. In contrast, IGF-I, glutamic acid, glutamine, cystine, and lysine were decreased in the serum of the diabetic pregnant rats. The maternal metabolic imbalance exerted profound effects on embryonic development. Thus, the embryos of the diabetic rats were smaller, had fewer somites, and contained less DNA and protein than the control embryos. In addition, the resorption and malformation rates were increased in the embryos of the diabetic rats. The regression analysis of the data revealed significant interrelationships between adverse embryonic outcome (rates of malformations and resorptions) and the maternal serum concentrations of glucose, triglycerides, P-hydroxybutyrate, branched-I---Diabetic pregnancy is associated with an increased risk of fetal maldevelopment (1-3). The pathogenesis of congenital malformations in the offspring of diabetic mothers is unknown. In previous clinical and experimental studies, strict metabolic control of the mother has been shown to diminish the risk of fetal maldevelopment, especially if the improved control is initiated in early pregnancy (4-7) or before conception (8).chain amino acids, and creatinine. This suggests that the maternal metabolism of the three major classes of nutrients covariates with the embryonic development in diabetic rat pregnancy. The monitoring of only one of these maternal parameters, e.g. the serum glucose concentration, may therefore not adequately predict the developmental status of the offspring. Our results suggest that the pathogenesis of fetal malformations in diabetic pregnancy is multifactorial. Thus, maintaining metabolites from all nutrient classes at a normal level may be important in preventing adverse fetal outcome. Maintenance of normal serum glucose levels alone, however, does not seem to completely protect the fetus from malformations (9). Other disturbed metabolic processes in the mother, reflected by alterations in serum levels of associated metabolites, may therefore have pathogenic roles in the teratogenicity of diabetic pregnancy. In previous studies of an animal model for diabetic pregnancy, w e found increased rates of fetal malformations and resorptions among the offspring of streptozotocin-diabetic rats
