When treatment for gestational diabetes is indicated, the drug of choice, insulin, can be problematic for some women because of the need for daily injections, which can affect compliance. The cost of therapy may also be an issue for women in lower socioeconomic groups.
The use of oral hypoglycemic agents for treating women with gestational diabetes has not been recommended in the past because many of these drugs cross the placenta, increasing the risk of neonatal hypoglycemia. But there are now several studies that provide encouraging data suggesting that the second-generation sulfonylurea glyburide is a safe option for both the woman and baby.
The first study indicating that glyburide might be a safe option for treating gestational diabetes was conducted in 1994, using the human placental perfusion model, which entails taking the term placenta after birth and reconstructing the blood vessels of the mother and newborn to determine whether a drug crosses the placenta. The investigators showed that while most of the oral hypoglycemic drugs tested crossed the placenta, a minimal amount of glyburide passed the placenta (Am. J. Obstet. Gynecol. 1994;171:653–60).
One of the investigators, Dr. Oded Langer, and associates conducted a randomized, controlled trial comparing insulin with glyburide in 404 women with singleton pregnancies and gestational diabetes who started treatment between 11 and 33 weeks' gestation. The study was published in 2000. Both treatments were equally effective in achieving the target level of glycemic control in the women, with 4% of women on glyburide requiring treatment with insulin.
Importantly, there were no significant differences in neonatal complications between the two groups: The percentages of babies who were large for gestational age, had macrosomia, had lung complications, were hypoglycemic, were admitted to neonatal intensive care units, or had fetal anomalies were similar in both groups. Serum insulin levels in the cord were similar in both groups, and no glyburide was detected in the cord serum of babies in the glyburide group, confirming the 1993 study (N. Engl. J. Med. 2000;343:1134–8).
A recent meta-analysis completed by Motherisk of all studies on this topic also found no evidence of an increased risk to the newborn associated with glyburide treatment, corroborating the 2000 study.
Why glyburide does not cross the placenta is an interesting question, one that several research groups are investigating. The placenta is not just a passive barrier, and it has different carrier systems that can selectively efflux different drugs from the baby back to the mother. We also know that the opposite occurs. For example, the placenta carries iron from the mother to the baby; even when the mother is anemic, the placenta ensures that the baby receives iron.
We published a paper earlier this year using the same placental perfusion model used in the 1993 study, but put glyburide on both sides of the placenta and found that it is actively pumped from the baby to the mother (Am. J. Obstet. Gynecol. 2006;195:270–4). The central thinking now is that the most likely placental transporter for glyburide is the breast cancer-resistant protein abundantly available in the placenta.
Glyburide provides an example of a drug that has not been given to women with gestational diabetes because of the false impression that it does cross the placenta, but the available data indicate that despite being a small molecule, it does not.
These novel findings may have major implications for women with gestational diabetes who require treatment because many would be happy not to have to use insulin daily. In many parts of the world, glyburide is already widely used for treating gestational diabetes. And although some women will require insulin, or a combination of glyburide with insulin, there are many women with gestational diabetes who will do well with glyburide. Glyburide is available as a generic, which is a significant cost advantage.
Finally, this may be one of the first examples of a medication that is considered safe to use in pregnancy because it has been found not to cross the placenta. In the future, drug therapy in pregnancy may involve the development of drugs that are pumped by the placenta back to the mother, using placental transporters to control fetal exposure (Placenta 2006;27:861–8).