Antidiabetic Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Although the use of glipizide may be beneficial for decreasing the incidence of fetal and newborn morbidity and mortality in developing countries where the proper use of insulin is problematic, insulin is still the treatment of choice for this disease during pregnancy. Moreover, insulin, unlike glipizide, does not cross the placenta, which eliminates the additional concern that the drug therapy itself 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 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, the American College of Obstetricians and Gynecologists recommends that insulin be used for types 1 and 2 diabetes occurring during pregnancy and, if diet therapy alone is not successful, for gestational diabetes (1,2). If glipizide is used during pregnancy, therapy should be changed to insulin. If glipizide is continued, it should be stopped before delivery (the exact time before delivery is unknown) to lessen the possibility of prolonged hypoglycemia in the newborn.
FETAL RISK SUMMARY
Glipizide is an oral sulfonylurea agent, structurally similar to glyburide that is used for the treatment of adult-onset diabetes mellitus. It is not the treatment of choice for the pregnant diabetic patient.
Reproductive studies in male and female rats showed no effect on fertility. Mild fetotoxicity (type not specified) was observed at all doses tested in rats and was thought to be caused by the hypoglycemic action of glipizide. No teratogenic effects were observed in rats or rabbits (3).
A 1994 report described the in vitro placental transfer, using a single cotyledon human placenta, of four oral hypoglycemic agents (4). 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 percentage placental transfer at 3 hours of the four agents and their approximate molecular weights (shown in parentheses) were tolbutamide (270) 21.5%, chlorpropamide (277) 11.0%, glipizide (446) 6.6%, and glyburide (494) 3.9% (4).
A 1984 source cited a study that described the use of glipizide in four diabetic patients from the 32nd week of gestation through delivery (5). No adverse effects in the fetuses were observed.
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 (6). 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 (5 sets of twins and 16 with two or three separate singleton pregnancies during the study period). A total of 56 (16.9%) 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 CNS, face, heart and great vessels, gastrointestinal, genitourinary, and skeletal (includes caudal regression syndrome) systems. Minor anomalies included all of these, except those of the CNS, 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; and 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 (1) the independent associations between the risk of major anomalies (but not minor defects) and poor glycemic control in early pregnancy and (2) a younger maternal age at the onset of diabetes. Moreover, the study did not find an association between the use of oral hypoglycemics during organogenesis and congenital malformations, in that the observed anomalies appeared to be related to poor maternal glycemic control (6).
BREASTFEEDING SUMMARY
Nondetectable levels of glipizide were reported in three of four milk samples from two women nursing their infants (7). The two women were on a steady-state dose of glipizide (5-mg immediate-release tablet every morning for 6 and 15 days). In one woman, the peak milk concentration (3 hours after dose) was 0.20 mcg/mL and the trough level was nondetectable (detection limit 0.08 mcg/mL). In the second woman, both the peak and trough samples had nondetectable glipizide levels. Blood glucose levels were normal in both of the exclusively breastfed infants (7).
References
1.American College of Obstetricians and Gynecologists. Pregestational diabetes mellitus. ACOG Practice Bulletin. No. 60. March 2005. Obstet Gynecol 2005;105:675–85.
2.American College of Obstetricians and Gynecologists. Gestational diabetes. ACOG Practice Bulletin. No. 30. September 2001. Obstet Gynecol 2001;98:525–38.
3.Product information. Glucotrol. Pfizer Inc., 1997.
4.Elliott BD, Schenker S, Langer O, Johnson R, Prihoda T. Comparative placental transport of oral hypoglycemic agents in humans: a model of human placental drug transfer. Am J Obstet Gynecol 1994;171:653–60.
5.Onnis A, Grella P. The Biochemical Effects of Drugs in Pregnancy. Vol 2. West Sussex, England: Ellis Horwood Limited, 1984:174–5.
6.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.
7.Feig DS, Briggs GG, Kraemer JM, Ambrose PJ, Moskovitz DN, Nageotte MP, Donat DJ, Padilla G, Wan S, Klein J, Koren G. Transfer of glyburide and glipizide into breast milk. Diabetes Care 2005;28:1851–5.