Glyburide in Pregnancy and Breastfeeding
Fetal Risk Summary
Glyburide is a second generation, oral sulfonylurea agent, structurally similar to acetohexamide and glipizide, that is used for the treatment of adult-onset diabetes mellitus. It is not the treatment of choice for the pregnant diabetic patient.
No fetotoxicity or teratogenicity was observed in pregnant mice, rats, and rabbits fed large doses of the agent (1). In pregnant rats, glyburide crossed the placenta to the fetus (fetal:maternal ratio 0.541) in amounts similar to diazepam (fetal:maternal ratio 0.641) (2).
In studies using in vitro techniques with human placentas, only relatively small amounts of glyburide were observed to transfer from the maternal to the fetal circulation (3,4,5,6,7 and 8), and the use of placentas from diabetic patients (4) or with high glucose concentrations (5) did not change the amounts transferred. Concentrations used on the maternal side of the perfused placenta model were approximately 800 ng/mL, much higher than the average peak serum level of 140350 ng/mL obtained after a single 5-mg oral dose (6). Transport of the drug to the fetal side of the placenta was 0.62% at 2 hours. Since an estimated 3050 ng/mL is required for hypoglycemic action (9), these data indicate that fetal levels of glyburide, in an in vitro model, are below the therapeutic threshold, but do not take into account the effects of potential drug accumulation in the fetus.
In an abstract (7), and later in a full report (8), 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 the dissociation constant (pKa) and lipid solubility providing a 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%. In another abstract, this same group of investigators, using similar in vitro techniques with human placentas, demonstrated that glyburide did not increase glucose transfer to the fetus or affect the placental uptake of glucose (10). In vivo studies of glyburide human placental transport have not been located.
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 (11). 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 6 (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 (11). Two of the infants with defects (anencephaly; ventricular septal defect) were exposed in utero to glyburide during the first 10 and 23 weeks of gestation, respectively, but these and the other malformations observed, with the possible exception of the ear defects, were thought to be related to poor blood glucose control during organogenesis. The authors remarked that the cluster of ear defects, however, suggested a drug effect or synergism between the drug and lack of metabolic control in the mother (11). Sixteen livebirths occurred in the exposed group compared to 36 in controls. The groups did not differ in the incidence of hypoglycemia at birth (53% vs. 53%), but 3 of the exposed newborns (not exposed to glyburide) had severe hypoglycemia lasting 2, 4, and 7 days, even though the mothers had not used oral hypoglycemics close to delivery. The authors attributed this to irreversible b-cell hyperplasia that may have been increased by exposure to oral hypoglycemics (11). 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) (1 exposed infant was not included in these data because of delivery after completion of study).
The use of glyburide in all phases of human gestation has been reported in other studies (12,13,14 and 15). In these studies, glyburide (glibenclamide) was either used alone or combined with the oral antihyperglycemic agent, metformin (see Metformin for details of these studies). Neonatal hypoglycemia (blood glucose <25 mg/dL) was present in 4 of 15 (27%) newborns who were exposed to glyburide during gestation (13,14). This adverse effect was 3.5 times that observed in a group of newborns whose mothers were treated with insulin. Moreover, in 1 newborn, the hypoglycemia persisted for more than 48 hours (13).
A study published in 1995 assessed the risk of congenital malformations in infants of mothers with non-insulin-dependent diabetes (NIDDM) over a 6-year period (16). 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%) 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 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 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 (16). 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 (16).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 37 newborns had been exposed to glyburide during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (2.7%) major birth defect was observed (two expected), which was a cardiovascular defect (0.4 expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.
A study published in 2000 compared the pregnancy outcomes in gestational diabetic women with singleton pregnancies who were randomly assigned to treatment with glyburide or insulin (17). A majority of the women (83%) were Hispanic, mostly Mexican American. The study was not blinded. The goals of treatment were the achievement of a mean glucose concentration of 90105 mg% and fasting, preprandial, and postprandial glucose levels of 6090 mg%, 8095 mg%, and <120 mg%, respectively. A total of 404 women were enrolled, 201 in the glyburide group and 203 in the insulin group. The mean glucose concentrations, fasting, preprandial, and postprandial concentrations, and the glycosylated hemoglobins in the glyburide and insulin groups were 114 mg% vs. 116 mg%, 104 mg% vs. 108 mg%, 104 mg% vs. 107 mg%, 130 mg% vs. 129 mg%, and 5.7% vs. 5.6%, respectively. These results are indicative of mild hyperglycemia. There were no significant differences between the groups in terms of any characteristic, including the gestational age at start of therapy and at delivery. The mean doses of glyburide and insulin were 9 6 mg/day and 85 48 units/day, respectively. Eight (4%) of the women randomized to glyburide failed to achieve good glycemic control and were changed to insulin. The mean blood glucose concentrations and the mean fasting, preprandial, and postprandial values did not differ significantly between the glyburide and insulin groups. Nor was there a difference in the mean glycosylated hemoglobin values, 5.5% vs 5.4%, respectively, measured late in the 3rd trimester. In 12 randomly selected women a mean 8 4 hours after the last dose, the glyburide maternal serum concentrations ranged from 50 to 150 ng/mL, whereas glyburide was undetectable in cord serum. No significant differences were measured between the groups in terms of neonatal features, metabolic outcomes, or perinatal mortality (17).
In summary, although the use of glyburide may be beneficial for decreasing the incidence of fetal and newborn morbidity and mortality in developing countries and in some populations where the proper use of insulin is problematic, insulin is still the treatment of choice for this disease. Oral hypoglycemic agents are not indicated for the pregnant diabetic since they do not usually provide good control in patients who cannot be controlled by diet alone (18). The study cited above, however, did have good outcomes in gestational diabetes, but additional studies are needed before this therapy can be recommended. Moreover, it cannot be recommended for other types of diabetes, such as types I and II. Even though the above study did not detect glyburide in cord blood in a randomly selected, small sample, the drug has been shown to cross the placenta. In contrast, insulin does not cross the placenta and, thus, eliminates the additional concern that the drug therapy itself may adversely affect the fetus. For most diabetics, 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 (19,20). If oral hypoglycemics are used during pregnancy, consideration should be given to changing the therapy to insulin to lessen the possibility of prolonged hypoglycemia in the newborn. Based on the report above, however, this precaution may not apply to glyburide.
Breast Feeding Summary
No reports have been located that describe the use of glyburide during lactation or measure the amount of drug in milk. Other antidiabetic sulfonylurea agents are excreted into milk (e.g., see Chlorpropamide and Tolbutamide), and a similar excretion pattern for glyburide should be expected. The effect on the nursing infant from exposure to these agents via the milk is unknown, but hypoglycemia is a potential toxicity.
- Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:202.
- Sivan E, Feldman B, Dolitzki M, Nevo N, Dekel N, Karasik A. Glyburide crosses the placenta in vivo in pregnant rats. Diabetologia 1995;38:7536.
- Elliott BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol 1991;165:80712.
- Elliott BD, Bynum D, Langer O. Glyburide does not cross the diabetic placenta in significant amounts. Society of Perinatal Obstetricians Abstracts. Am J Obstet Gynecol 1993;168:360.
- Elliott BD, Bynum D, Langer O. Maternal hyperglycemia does not alter in-vitro placental transfer of the oral hypoglycemic agent glyburide. Society of Perinatal Obstetricians Abstracts. Am J Obstet Gynecol 1993;168:360.
- Elliott B, Langer O, Schenker S, Johnson R. Glyburide is insignificantly transported to the fetal circulation by the human placenta in vitro (abstract). Am J Obstet Gynecol 1991;164:247.
- Elliott B, Schenker S, Langer O, Johnson R, Prihoda T. Oral hypoglycemic agents: profound variation exists in their rate of human placental transfer. Society of Perinatal Obstetricians Abstracts. 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.
- American Hospital Formulary Service. Glyburide. Drug Information 1997. Bethesda, MD:American Society of Health-System Pharmacists, 1997:24338.
- Elliott BD, Crosby-Schmidt C, Langer O. Human placental glucose uptake and transport are not altered by pharmacologic levels of the oral hypoglycemic agent, glyburide. Society of Perinatal Obstetricians Abstracts. Am J Obstet Gynecol 1994;170:321.
- Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to oral hypoglycaemic drugs. Lancet 1991;338:8669.
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- 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.
- Langer O, Conway DL, Berkus MD, Xenakis EMJ, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343:11348.
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