TOLAZAMIDE

Fetal Risk Summary

Tolazamide is a sulfonylurea used for the treatment of adult-onset diabetes mellitus. It is not indicated for the pregnant diabetic.

No reports describing the placental transfer of tolazamide have been located. The molecular weight (about 311) suggests, however, that transfer to the fetus probably occurs (see Chlorpropamide).

A 1991 report described the outcomes of pregnancies in 21 non-insulin-dependent diabetic women who were treated with oral hypoglycemic agents (17 sulfonylureas, 3 biguanides, and 1 unknown type) during the 1st trimester (1). The duration of exposure ranged from 3 to 28 weeks, but all patients were changed to insulin therapy at the first prenatal visit. Forty non-insulin-dependent diabetic women matched for age, race, parity, and glycemic control served as a control group. Eleven (52%) of the exposed infants had major or minor congenital malformations compared with six (15%) of the controls. Moreover, ear defects, a malformation that is observed, but uncommonly, in diabetic embryopathy, occurred in six of the exposed infants and in none of the controls (1). One of the infants with an ear defect (thickened curved pinnae and malformed superior helices) was exposed in utero to tolazamide during the first 12 weeks of gestation. Sixteen live births occurred in the exposed group compared with 36 in controls. The groups did not differ in the incidence of hypoglycemia at birth (53% vs. 53%), but three of the exposed newborns had severe hypoglycemia lasting 2, 4, and 7 days even though the mothers had not used oral hypoglycemics (none of the three was exposed to tolazamide) close to delivery. The authors attributed this to irreversible b-cell hyperplasia that may have been increased by exposure to oral hypoglycemics (1). Hyperbilirubinemia was noted in 10 (67%) of 15 exposed newborns compared with 13 (36%) controls (p<0.04), and polycythemia and hyperviscosity requiring partial exchange transfusions were observed in 4 (27%) of 15 exposed vs. 1 (3.0%) control (p<0.03) (1 exposed infant was not included in these data because the infant was delivered after completion of the study).

In summary, although the use of tolazamide during human gestation does not appear to be related to structural anomalies, insulin 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 (2). Moreover, insulin, unlike tolazamide, does not cross the placenta and, thus, eliminates the additional concern that the drug therapy is adversely affecting 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 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 (3,4). If tolazamide is used during pregnancy, therapy should be changed to insulin and tolazamide 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 tolazamide is excreted in milk. No reports of its use during human lactation, or measuring the amount excreted into milk, have been located. The molecular weight (about 311), however, is low enough that excretion in milk should be expected (see also Chlorpropamide). The effects of tolazamide in milk on the nursing infant are unknown, but hypoglycemia is a potential toxicity.

References

1. Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to oral hypoglycaemic drugs. Lancet 1991;338:866–9.
2. Friend JR. Diabetes. Clin Obstet Gynaecol 1981;8:353–82.
3. American College of Obstetricians and Gynecologists. Diabetes and pregnancy. Technical Bulletin. No. 200. December 1994.
4. Coustan DR. Management of gestational diabetes. Clin Obstet Gynecol 1991;34:558–64.