CHLORPROPAMIDE

Fetal Risk Summary

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

In a study using neurulating mouse embryos in whole embryo culture, chlorpropamide produced malformations and growth retardation at concentrations similar to therapeutic levels in humans (1). The defects were not a result of hypoglycemia or of chlorpropamide metabolites.

When administered near term, chlorpropamide crosses the placenta and may persist in the neonatal serum for several days (2,3 and 4) . One mother, who took 500 mg/day throughout pregnancy, delivered an infant whose serum level was 15.4 mg/dL at 77 hours of life (2). Infants of three other mothers, who were consuming 100–250 mg/day at term, had serum levels varying between 1.8 and 2.8 mg/dL 8–35 hours after delivery (3). All four infants had prolonged symptomatic hypoglycemia secondary to hyperinsulinism lasting for 4–6 days. Another newborn, whose mother had been taking chlorpropamide, had severe, prolonged hypoglycemia and seizures (4). In other reports, totaling 69 pregnancies, chlorpropamide in doses of 100–200 mg or more/day either gave no evidence of neonatal hypoglycemia and hyperinsulinism or no constant relationship between daily maternal dosage and neonatal complications (5,6). One reviewer, however, thought that chlorpropamide should be stopped at least 48 hours before delivery to avoid this potential complication (7).

In an abstract (8), and later in a full report (9), the in vitro placental transfer, using a single-cotyledon human placenta, of four oral hypoglycemics 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 effects. The cumulative percent placental transfer at 3 hours of the four agents and their approximate molecular weights (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 that expected in diabetes mellitus, was not found with chlorpropamide in several studies (10,11,12,13,14,15,16,17,18 and 19) . Four malformed infants have been attributed to chlorpropamide but the relationship is unclear (10,13): Hand and finger anomalies (10) Stricture of lower ileum, death (10) Preauricular sinus (10) Microcephaly and spastic quadriplegia (13) In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 18 newborns had been exposed to chlorpropamide during the 1st trimester (F. Rosa, personal communication, FDA, 1993). No major birth defects were observed (one expected).

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 (20). The duration of exposure ranged from 3–28 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 to 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 (20). In total, six of the 11 infants with defects had been exposed in utero to chlorpropamide. The defects noted were (length of exposure during pregnancy in weeks): Severe microtia right ear; multiple tags left ear (22 weeks) Bilateral auricular tags (8 weeks) Single umbilical artery (14 weeks) Ear tag (10 weeks) Facial, auricular, and vertebral defects; deafness, ventricular septal defect (15 weeks) Multiple vertebral anomalies; ventricular septal defect; severe aortic coarctation; bilateral ear tags and posterior rotated ears (14 weeks) Sixteen livebirths occurred in the exposed group compared to 36 in controls (20). 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 (two women had used chlorpropamide) close to delivery. The authors attributed this to irreversible b-cell hyperplasia that may have been increased by exposure to oral hypoglycemics (20). Hyperbilirubinemia was noted in 10 (67%) of 15 exposed newborns compared to 13 (36%) of 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) (one exposed infant not included in these data because presented after completion of study).

A study published in 1995 assessed the risk of congenital malformations in infants of mothers with non-insulin-dependent diabetes during a 6-year period (21). Women were included in the study if, during the first 8 weeks of pregnancy, they had not participated in a preconception care program and then had been treated either with diet alone (group 1), diet and oral hypoglycemic agents (predominantly chlorpropamide, glyburide, or glipizide) (group 2), or diet and exogenous insulin (group 3). The 302 women eligible for analysis gave birth to 332 infants (five sets of twins and 16 with two or three separate singleton pregnancies during the study period). A total of 56 (16.9%) of the infants had one or more congenital malformations, 39 (11.7%) of which were classified as major anomalies (defined as those that were either lethal, caused significant morbidity, or required surgical repair). The major anomalies were divided among those involving the central nervous system, face, heart and great vessels, gastrointestinal, genitourinary, and skeletal (includes caudal regression syndrome) systems. Minor anomalies included all of these, except those of the central nervous system, and a miscellaneous group composed of sacral skin tags, cutis aplasia of the scalp, and hydroceles. The number of infants in each group and the number of major and minor anomalies observed were: group 1–125 infants, 18 (14.4%) major, 6 (4.8%) minor; group 2–147 infants, 14 (9.5%) major, 9 (6.1%) minor; group 3–60 infants, 7 (11.7%) major, 2 (3.3%) minor. There were no statistical differences among the groups. Six (4.1%) of the infants exposed in utero to oral hypoglycemic agents and four other infants in the other two groups had ear anomalies (included among those with face defects). Other than the incidence of major anomalies, two other important findings of this study were the independent associations between the risk of major anomalies (but not minor defects) and poor glycemic control in early pregnancy, and a younger maternal age at the onset of diabetes (21). Moreover, the study did not find an association between the use of oral hypoglycemics during organogenesis and congenital malformations because the observed anomalies appeared to be related to poor maternal glycemic control (21).

In summary, although the use of chlorpropamide 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 since they will not provide good control in patients who cannot be controlled by diet alone (7). Moreover, insulin, unlike chlorpropamide, 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 (22,23). If chlorpropamide is used during pregnancy, therapy should be changed to insulin and chlorpropamide discontinued before delivery (the exact time before delivery is unknown) to lessen the possibility of prolonged hypoglycemia in the newborn.

Breast Feeding Summary

Chlorpropamide is excreted into breast milk. Following a 500-mg oral dose, the milk concentration in a composite of two samples obtained at 5 hours was 5 µmg/mL (G.G. D'Ambrosio, personal communication, Pfizer Laboratories, 1982). The effects on a nursing infant from this amount of drug are unknown, but hypoglycemia is a potential toxicity.

References

1. Smoak IW. Embryopathic effects of the oral hypoglycemic agent chlorpropamide in cultured mouse embryos. Am J Obstet Gynecol 1993;169:409–14.
2. Zucker P, Simon G. Prolonged symptomatic neonatal hypoglycemia associated with maternal chlorpropamide therapy. Pediatrics 1968;42:824–5.
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.
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6. Sutherland HW, Bewsher PD, Cormack JD, et al. Effect of moderate dosage of chlorpropamide in pregnancy on fetal outcome. Arch Dis Child 1974;49:283–91.
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19. Douglas CP, Richards R. Use of chlorpropamide in the treatment of diabetes in pregnancy. Diabetes 1967;16:60–1.
20. Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to oral hypoglycaemic drugs. Lancet 1991;338:866–9.
21. Towner D, Kjos SL, Leung B, Montoro MM, Xiang A, Mestman JH, Buchanan TA. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care 1995;18:1446–51.
22. American College of Obstetricians and Gynecologists. Diabetes and pregnancy. Technical Bulletin. No. 200. December 1994.
23. Coustan DR. Management of gestational diabetes. Clin Obstet Gynecol 1991;34:558–64.