The fetus of the pregnant diabetic woman is exposed to hyperglycemia frequently accompanied by ketoacidosis. Previous studies have demonstrated that beta-hydroxybutyrate, a major ketone body, crosses the ovine placenta in significant amounts, leading to significant reductions in fetal PaO2 and increased fetal heart rate. In the present study the pregnant ewe was used to evaluate the maternal and fetal cardiovascular and metabolic responses to hyperketonemia in the presence of hyperglycemia and to determine if the combined diabetic insults were more detrimental to the fetus than hyperketonemia alone. A glucose priming dose of 25 gm was administered in the maternal femoral vein followed by a continuous glucose infusion of 200 mg/min to achieve steady maternal plasma glucose levels of 180 mg/dl. Once glucose levels were stable, beta-hydroxybutyrate was infused for 2 hours at a rate of 0.39 mmol/100 ml of uterine blood flow into both left and right uterine arteries. Infusion of glucose alone did not significantly alter fetal cardiovascular and blood gas parameters but did increase the fetal glucose level from 17 +/- 4 to 58 +/- 8 mg/dl. The simultaneous infusion of beta-hydroxybutyrate and glucose produced significant decreases in fetal PaO2 and oxygen content as were reported for hyperketonemia alone and significant time-related increases in fetal lactate levels and fetal heart rate. These data suggest that hyperketonemia in the pregnant ewe leads to quantitatively similar changes in oxygenation in both normoglycemic and hyperglycemic fetuses. These observations may in part help explain the increased perinatal mortality in the pregnant woman with uncontrolled diabetes.