Risk Factor: CM
Class: Hormones/ Antidiabetic agents
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 (1). Mild fetotoxicity (type not specified), observed at all doses tested in rats, was thought to be caused by the hypoglycemic action of glipizide. No teratogenic effects were observed in rats or rabbits (1).
In an abstract (2) and later in a full report (3), 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 weights (shown in parenthesis) were tolbutamide (270) 21.5%, chlorpropamide (277) 11.0%, glipizide (446) 6.6%, and glyburide (494) 3.9%.
A 1984 source cited a study that described the use of glipizide in four diabetic patients from the 32nd week of gestation through delivery (4). 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 (NIDDM) during a 6-year period (5). 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 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 1125 infants, 18 (14.4%) major, 6 (4.8%) minor; Group 2147 infants, 14 (9.5%) major, 9 (6.1%) minor; Group 360 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 4 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 (5). 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 (5).
In 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. Oral hypoglycemic agents are not indicated for the pregnant diabetic, because they will not provide good control in patients who cannot be controlled by diet alone (6). Moreover, insulin, unlike glipizide, does not cross the placenta and, thus, 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 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 (7,8). If glipizide is used during pregnancy, therapy should be changed to insulin, and glipizide should be discontinued before delivery (the exact time before delivery is unknown) to lessen the possibility of prolonged hypoglycemia in the newborn.
Breast Feeding Summary
No reports have been located that describe the use of glipizide during lactation or that measure the amount of drug excreted in milk. Other antidiabetic sulfonylurea agents are excreted into milk (e.g., see Chlorpropamide and Tolbutamide), and a similar excretion pattern for glipizide 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.
- Product information. Glucotrol. Pfizer Inc, 1997.
- Elliott B, Schenker S, Langer O, Johnson R, Prihoda T. Oral hypoglycemic agents: profound variation exists in their rate of human placental transfer (abstract). Am J Obstet Gynecol 1992;166:368.
- 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;171:65360.
- Onnis A, Grella P. The Biochemical Effects of Drugs in Pregnancy. Vol 2. West Sussex, England:Ellis Horwood Limited, 1984:1745.
- Towner D, Kjos SL, Leung B, Montoro MM, Xiang A, Mestman JH, Buchanan TA. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care 1995;18:144651.
- Friend JR. Diabetes. Clin Obstet Gynecol 1981;8:35382.
- American College of Obstetricians and Gynecologists. Diabetes and pregnancy. Technical Bulletin No. 200, December 1994.
- Coustan DR. Management of gestational diabetes. Clin Obstet Gynecol 1991;34:55864.