Tolbutamide in Pregnancy and Breastfeeding

Risk Factor: CM
Class: Hormones / Antidiabetic agents

Contents of this page:
Fetal Risk Summary
Breast Feeding Summary
Questions and Answers

Fetal Risk Summary

Tolbutamide is a sulfonylurea used for the treatment of adult-onset diabetes mellitus. It is not the treatment of choice for the pregnant diabetic patient.

Shepard reviewed four studies that had reported teratogenicity in mice and rats, but not in rabbits (1). In a study using early-somite mouse embryos in whole embryo culture, tolbutamide produced malformations and growth retardation at concentrations similar to therapeutic levels in humans (2). The defects were not a result of hypoglycemia. In a similar experiment, but using tolbutamide concentrations 24 times the human therapeutic level, investigators concluded that tolbutamide had a direct embryotoxic effect on the rat embryos (3).

When administered near term, the drug crosses the placenta (4,5). Neonatal serum levels are higher than corresponding maternal concentrations. In one infant whose mother took 500 mg/day, serum levels at 27 hours were 7.2 mg/dL (maternal 2.7 mg/dL) (5).

In an abstract (6), and later in a full report (7), the in vitro placental transfer, using a single-cotyledon human placenta, of four oral hypoglycemic agents was described. As expected, molecular weight was the most significant factor for drug transfer, with dissociation constant (pKa) and lipid solubility providing significant additive effect. The cumulative percent placental transfer at 3 hours of the four agents and their approximate molecular weight (shown in parenthesis) were tolbutamide (270) 21.5%, chlorpropamide (277) 11.0%, glipizide (446) 6.6%, and glyburide (494) 3.9%.

Although teratogenic in animals, an increased incidence of congenital defects, other than those expected in diabetes mellitus, has not been found with tolbutamide in a number of studies (8,9,10,11,12,13,14,15,16,17 and 18). Four malformed infants have been attributed to tolbutamide but the relationship is unclear (5,19,20 and 21): Hand and foot anomalies, finger and toe syndactyly, external ear defect, atresia of external auditory canal, gastrointestinal, heart, and renal anomalies (19) Grossly malformed (20) Severe talipes, absent left toe (21) Right-sided preauricular skin tag, accessory right thumb, thrombocytopenia (nadir 19,000/mm3 on 4th day) (5) The neonatal thrombocytopenia, persisting for about 2 weeks, was thought to have been induced by tolbutamide (5).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 4 newborns had been exposed to tolbutamide during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (25%) major birth defect was observed (none expected), but specific information on the defect is not available. No anomalies were observed in six categories of defects (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb-reduction defects, and hypospadias.

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 (22). 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. None of the infants with defects were exposed to tolbutamide. 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 tolbutamide) close to delivery. The authors attributed this to irreversible b-cell hyperplasia that may have been increased by exposure to oral hypoglycemics. 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) (22).

A case of prolonged hypoglycemia in a premature infant whose mother was treated with tolbutamide for gestational diabetes was reported in 1998 (23). The mother was treated with tolbutamide starting from 23 weeks' gestation until deliver at 34 weeks. The male infant's weight and length were 3200 g and 49 cm, respectively, both values above 1 standard deviation of the mean for gestational age. Hypoglycemia was diagnosed 1 hour after birth and IV 20% glucose was required for the first 3 days of life. Subcutaneous octreotide was also administered for first 9 days of life. Serum tolbutamide concentrations decreased from 38 g/mL (140.6 mol/L) at 3 hours after birth to 2 g/mL (7.4 mol/L) at 90 hours. The decline in serum concentration showed zero-order kinetics with an initial half-life of 46 hours that declined to 6 hours. The change in tolbutamide elimination suggested immaturity of hepatic elimination during the first 2 days of life (23). The infant displayed normal psychomotor development without seizures and normal glucose values at 3 months of age.

In summary, although the use of tolbutamide 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 (24). Moreover, insulin, unlike tolbutamide, does not cross the placenta and, thus, eliminates the additional concern that the drug therapy itself is adversely affecting the fetus. Because tolbutamide crossed the placenta, prolonged hypoglycemia occurred in a premature infant. 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 (25,26). If tolbutamide is used during pregnancy, therapy should be changed to insulin and tolbutamide discontinued before delivery to lessen the possibility of prolonged hypoglycemia in the newborn. The timing when therapy should be changed to insulin is not certain, but at least 4 days before delivery appears reasonable based on one case.

Breast Feeding Summary

Tolbutamide is excreted into breast milk. Following long-term dosing with 500 mg orally twice daily, milk levels 4 hours after a dose in two patients averaged 3 and 18 g/mL (27). Milk:plasma ratios were 0.09 and 0.40, respectively. The effect on an infant from these levels is unknown, but hypoglycemia is a potential toxicity. The American Academy of Pediatrics, although noting the possibility of jaundice in the nursing infant, considers tolbutamide to be compatible with breast feeding (28).


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