Lack of Teratogenic Effect of Brief Maternal Insulin-Induced Hypoglycemia in Rats During Late Neurulation

We have previously shown that 1 h of maternal insulin-induced hypoglycemia is teratogenic to rat embryos during the initial stages of neurulation, when they are dependent on uninterrupted glycolysis (day 9.5–9.7 of development). To determine whether this vulnerability persists in later stages of neural tube and cardiac development, we infused insulin into 16 conscious pregnant rats for 1 h beginning after embryos had developed the capacity for aerobic glucose metabolism (day 10.6 of development). Half of the pregnant animals were allowed to become hypoglycemic (44 ± 2 mg/dl) during the insulin infusions. The other half received glucose infusions to maintain normoglycemia (130 ± 3 mg/dl). Normal plasma glucose levels were maintained in all animals after the insulin infusions. Embryos were examined on day 11.5 of development. At that time, 1 of 111 embryos from the normoglycemic group and 1 of 109 embryos from the hypoglycemic group were grossly malformed (P > .5). Means of embryo crown-rump length (4.15 ± 0.03 vs. 4.14 ± 0.03 mm), somite number (29.7 ± 0.1 vs. 29.8 ± 0.2), and total protein content (320 ± 5 vs. 326 ± 6 μg) were also similar in the two groups (P > .5). Thus, we could not detect an embryotoxic effect of 1 h of maternal insulin-induced hypoglycemia beginning at day 10.6 of development. This finding is in contrast to our prior demonstration that a similar period of hypoglycemia occurring earlier in neurulation (day 9.7) caused growth retardation and developmental anomalies in embryos. Our results indicate that the teratogenic effects of brief maternal insulin-induced hypoglycemia in vivo do not extend past early organogenesis in rats. Based on these findings and on clinical data indicating that maternal hypoglycemia is not teratogenic during later portions of the first trimester, we suggest that efforts to determine whether maternal insulin-induced hypoglycemia is teratogenic in humans should focus on the first 3 wk of intrauterine development.