ACETOHEXAMIDE

Fetal Risk Summary

Acetohexamide is a sulfonylurea used for the treatment of adult-onset diabetes mellitus. It is not indicated for the pregnant diabetic. Shepard (1) and Schardein (2) cited a study in which acetohexamide was embryotoxic, but not teratogenic in rats.

When administered near term, acetohexamide crosses the placenta and may persist in the neonatal serum for several days (3). One mother, who took 1 g/day throughout pregnancy, was delivered of an infant whose serum level was 4.4 mg/dL at 10 hours of life (3). Prolonged symptomatic hypoglycemia because of hyperinsulinism lasted for 5 days. A 1971 Reference briefly cited a case of prolonged hypoglycemia and convulsions in a newborn whose mother had taken acetohexamide during pregnancy (4).

Although teratogenic in animals, an increased incidence of congenital defects, other than that expected in diabetes mellitus, has not been found with acetohexamide (see also Chlorpropamide, Tolbutamide) (5,6 and 7). Insulin, however, is still the treatment of choice for this disease. Oral hypoglycemics are not indicated for the pregnant diabetic because they will not provide good control in patients who cannot be controlled by diet alone (8). Moreover, insulin, unlike acetohexamide, does not cross the placenta, and thus eliminates the additional concern that the drug therapy itself is adversely effecting the fetus. Carefully prescribed insulin therapy will provide better control of the mother's blood glucose, thereby preventing the fetal and neonatal complications that occur with this disease. High maternal glucose levels, as may occur in diabetes mellitus, are closely associated with a number of maternal and fetal adverse effects, including fetal structural anomalies, if the hyperglycemia occurs early in gestation. To prevent this toxicity, most experts, including the American College of Obstetricians and Gynecologists, recommend that insulin be used for types I and II diabetes occurring during pregnancy and, if diet therapy alone is not successful, for gestational diabetes (9,10). If acetohexamide is used during pregnancy, therapy should be changed to insulin and acetohexamide discontinued before delivery (the exact time before delivery is unknown) to lessen the possibility of prolonged hypoglycemia in the newborn.

Breast Feeding Summary

It is not known whether acetohexamide is excreted into breast milk. No reports describing its use during lactation, or measuring the amount excreted into milk, have been located. Other antidiabetic sulfonylurea agents are excreted into milk (e.g., see Chlorpropamide and Tolbutamide), and a similar excretion pattern for acetohexamide should be expected. The effect on the nursing infant from exposure to this drug via the milk is unknown, but hypoglycemia is a potential toxicity.

References

1. Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:4.
2. Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY:Marcel Dekker, 1993:417.
3. Kemball ML, McIver C, Milnar RDG, Nourse CH, Schiff D, Tiernan JR. Neonatal hypoglycaemia in infants of diabetic mothers given sulphonylurea drugs in pregnancy. Arch Dis Child 1970;45:696–701.
4. Harris EL. Adverse reactions to oral antidiabetic agents. Br Med J 1971;3:29–30.
5. Malins JM, Cooke AM, Pyke DA, Fitzgerald MG. Sulphonylurea drugs in pregnancy. Br Med J 1964;2:187.
6. Adam PAJ, Schwartz R. Diagnosis and treatment: should oral hypoglycemic agents be used in pediatric and pregnant patients? Pediatrics 1968;42:819–23.
7. Dignan PSJ. Teratogenic risk and counseling in diabetes. Clin Obstet Gynecol 1981;24:149–59.
8. Friend JR. Diabetes. Clin Obstet Gynaecol 1981;8:353–82.
9. American College of Obstetricians and Gynecologists. Diabetes and pregnancy. Technical Bulletin. No. 200. December 1994.
10. Coustan DR. Management of gestational diabetes. Clin Obstet Gynecol 1991;34:558–64.