Antidiabetic Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Two cases of rosiglitazone use in pregnancy have been located and neither was associated with developmental toxicity. Insulin is the treatment of choice for pregnant diabetic patients because, in general, other hypoglycemic agents do not provide adequate glycemic control. Moreover, insulin, unlike most oral agents, does not cross the placenta to the fetus, thus eliminating the additional concern that the drug therapy itself will adversely affect the fetus. Carefully prescribed insulin therapy provides better control of the mother’s 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, the American College of Obstetricians and Gynecologists recommends that insulin be used for types I and II diabetes occurring during pregnancy and, if diet therapy alone is not successful, for gestational diabetes (1,2).
FETAL RISK SUMMARY
Rosiglitazone, a thiazolidinedione antidiabetic agent, is used as an adjunct to diet and exercise to improve glycemic control in patients with type II diabetes (noninsulin-dependent diabetes mellitus). It is used either alone or in combination with metformin. Rosiglitazone is not an insulin secretagogue, but acts to decrease insulin resistance in the periphery and in the liver (i.e., decreases insulin requirements). Rosiglitazone undergoes extensive metabolism to inactive metabolites. The plasma half-life of rosiglitazone-related materials (parent drug and inactive metabolites) ranges from 103 to 158 hours and the binding to plasma proteins, primarily albumin, is high (99.8%) (3).
Reproduction studies with rosiglitazone have been conducted in rats and rabbits at doses up to 20 and 75 times, respectively, the AUC at the maximum recommended human daily dose (MRHDD). No teratogenicity or adverse effect on implantation or the embryos were observed in either species, but placental pathology was noted in rats. Moreover, dosing during midgestation to late gestation was associated with fetal death and growth restriction in both rats and rabbits. Treatment extending through the lactation period in rats was associated with reduced litter size and decreased neonatal viability and postnatal growth. Growth restriction was reversible after puberty. For effects on the placenta, embryo, fetus, and offspring, the no-effect dose levels were approximately 4 times the MRHDD for both species (3).
Consistent with the molecular weight of the free base (about 357) and prolonged elimination half-life of the parent drug and/or inactive metabolites, rosiglitazone crosses the human placenta. In 31 women undergoing an elective abortion at 8–12 weeks’ gestation and given two 4 mg doses before the procedure, rosiglitazone was detected in 19 fetuses (4). The mean fetal tissue concentration was about 53 ng/g. The drug was more likely to be detected at 10 or more weeks’ gestation (4). Using the technique of dual perfusion of placental lobule, rosiglitazone, in the presence of human serum albumin, readily crossed the placenta (5). In contrast, a study using 10 near-term placentas in an ex vivo human perfusion model found minimal transfer and fetal accumulation of rosiglitazone (6).
A 2002 report described the use of rosiglitazone in early pregnancy (7). A 35-year-old woman with several diseases (hypertension, diabetes mellitus, hypercholesterolemia, anxiety disorder, epilepsia, and morbid obesity) who conceived while being treated with multiple drugs: rosiglitazone (4 mg/day), gliclazide (a sulfonylurea), atorvastatin, acarbose, spironolactone, hydrochlorothiazide, carbamazepine, thioridazine, amitriptyline, chlordiazepoxide, and pipenzolate bromide (an antispasmodic). Pregnancy was diagnosed in the 8th week of gestation and all medications were stopped. She was treated with methyldopa and insulin for the remainder of her pregnancy. At 36 weeks’ gestation, a repeat cesarean section delivered a healthy, 3.5-kg female infant with Apgar scores of 7 and 8 at 1 and 5 minutes, respectively. The infant was developing normally after 4 months (7).
A 2005 case report described the use rosiglitazone between the 13th and 17th week of gestation in a woman with type 2 diabetes (8). Before the 13th week, the woman’s diabetes had been managed with diet and exercise. Insulin was started after rosiglitazone was stopped and the woman delivered a healthy, 4.5-kg male infant at 37 weeks’ gestation. No major or minor malformations were observed (8).
Rosiglitazone is sometimes used for the treatment of insulin resistance in women with polycystic ovarian syndrome. Spontaneous ovulation and enhancement of clomiphene-induced ovulation resulting in conception has been reported after the use of rosiglitazone (9–11). Because this treatment may result in pregnancy, appropriate contraception is advised (12).
BREASTFEEDING SUMMARY
No reports describing the use of rosiglitazone during human lactation have been located. The molecular weight of the free base (about 357) and long elimination half-life (103–158 hours) suggest that excretion into breast milk should be expected. The effect of this exposure on a nursing infant is unknown. However, weak bases are known to accumulate in milk with concentrations higher than those in maternal plasma.
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. Avandia. SmithKline Beecham Pharmaceuticals, 2000.
4.Chan LYS, Yeung JHK, Lau TK. Placental transfer of rosiglitazone in the first trimester of human pregnancy. Fertil Steril 2005;83:955–8.
5.Patrikeeva S, Hemauer S, Nanovskaya T, Hankins G, Ahmed M. Transplacental transfer and distribution of rosiglitazone (abstract). Am J Obstet Gynecol 2006;195:S128.
6.Holmes HJ, Casey BM, Bawdon RE. Placental transfer of rosiglitazone in the ex vivo human perfusion model. Am J Obstet Gynecol 2006;195:1715–9.
7.Yaris F, Yaris E, Kadioglu M, Ulku C, Kesim M, Kalyoncu NI. Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman. Reprod Toxicol 2004;18:619–21.
8.Kalyoncu NI, Yaris F, Ulku C, Kadioglu M, Kesim M, Unsal M, Dikici M, Yaris E. A case of rosiglitazone exposure in the second trimester of pregnancy. Reprod Toxicol 2005;19:563–4.
9.Cataldo NA, Abbasi F, McLaughlin TL, Lamendola C, Reaven GM. Improvement in insulin sensitivity followed by ovulation and pregnancy in a woman with polycystic ovary syndrome who was treated with rosiglitazone. Fertil Steril 2001;76:1057–9.
10.Belli SH, Graffigna MN, Oneto A, Otero P, Schurman L, Levalle OA. Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome. Fertil Steril 2004;81:624–9.
11.Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D, Ke RK. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 2003;79:562–6.
12.O’Moore-Sullivan TM, Prins JB. Thiazolidinediones and type 2 diabetes: new drugs for an old disease. Med J Aust 2002;176:381–6.