Troglitazone in Pregnancy and Breastfeeding
Fetal Risk Summary
Troglitazone, a thiazolidinedione antidiabetic agent, is used as an adjunct to diet and exercise, either alone or in combination with a sulfonylurea, a sulfonylurea and metformin, or insulin, to improve glycemic control in type II diabetes (non-insulin-dependent diabetes mellitus) (1,2). Troglitazone decreases hepatic glucose output by inhibiting liver gluconeogenesis and improves target cell response to insulin. It is not an insulin secretagogue. [Troglitazone, approved in 1997, was withdrawn in 2000 because of its link with fatal liver failure. It is included here because human pregnancy exposures have probably occurred.] Reproduction studies with troglitazone have been conducted in rats and rabbits (1). Doses 39 times the human exposure from 400 mg/day based on the area under the plasma concentration curve (HE) produced no adverse effects on fertility or reproduction in male and female rats. No evidence of teratogenicity was found in rats and rabbits given doses up to 9 and 3 times the HE, respectively. However, in rats, the highest dose was associated with decreased fetal and newborn pup weights. Much smaller doses given to rats late in gestation and during lactation caused delayed postnatal development that was attributed to decreased body weight. The no-effect dose was 1% of the maximum dose used above (1).
It is not known if troglitazone crosses the human placenta. The molecular weight (about 442) is low enough that transfer to the fetus should be expected.
Troglitazone (during days 128 of the menstrual cycle) was given either alone or in combination with clomiphene (during days 37 of the cycle) to induce ovulation in women with clomiphene-resistant polycystic ovary syndrome (all of the women had previously failed to ovulate with clomiphene 200 mg/day) (3). Ovulation was successfully induced in 15 of 18 patients and 7 of these women achieved pregnancy. Assuming that conception occurred in mid-cycle, then the last dose of troglitazone was taken on day 14 of gestation. The outcomes of the seven pregnancies were two 1st-trimester spontaneous abortions and five full-term healthy infants (3). In another case involving a woman with the hyperandrogenic, insulin-resistant acanthosis nigricans syndrome, troglitazone was discontinued when pregnancy was diagnosed (4). The outcome of the pregnancy was not mentioned.
Except for the reports of early pregnancy exposure noted above, no other cases describing the use of troglitazone during human pregnancy have been located. 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 effect 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, 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 (5,6). An additional concern is the severe idiosyncratic hepatocellular injury that has been reported in adults who were taking troglitazone (1,7).
Breast Feeding Summary
No reports describing the use of troglitazone in human lactation have been located. The drug has been detected in the milk of lactating rats (1). This is consistent with its relatively low molecular weight (about 442), and excretion into human breast milk should be expected. The effects of this exposure on a nursing infant are unknown. However, because of the severe idiosyncratic hepatocellular injury that has been reported in adults who were taking troglitazone, the drug should probably not be used during nursing.
- Product information. Rezulin. Parke-Davis, 2000.
- Sparano N, Seaton TL. Troglitazone in type II diabetes mellitus. Pharmacotherapy 1998;18:53948.
- Mitwally MFM, Kuscu NK, Yalcinkaya TM. High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome. Hum Reprod 1999;14:27003.
- Elkind-Hirsch KE, McWilliams RB. Pregnancy after treatment with the insulin-sensitizing agent troglitazone in an obese woman with hyperandrogenic, insulin-resistant acanthosis nigricans syndrome. Fert Steril 1999;71:9437.
- 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.
Rezulin labeling updated to recommend more frequent patient monitoring. JAMA 1998;279:9.