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Oral Antidiabetic Drugs in Pregnancy

Diabetes mellitus is one of the most common medical conditions occurring during pregnancy. Diabetes in pregnancy may be either pre-existing type 1 or type 2 diabetes mellitus, or, more commonly, gestational diabetes mellitus (GDM). GDM is defined as carbohydrate intolerance first diagnosed during pregnancy. Based on this definition, GDM may actually represent a mix of women who have abnormal glucose tolerance in pregnancy or undiagnosed type 2 diabetes. Nevertheless, GDM and type 2 diabetes share the problems of impaired insulin secretion and insulin resistance.

The complications of poor maternal sugar control can range from aberrant growth of the fetus to three to eight fold increased risk for stillbirth. Other complications in infants include metabolic (low sugar and low calcium), hematological (increased red blood cells and bilirubin), respiratory, and increased rate of birth trauma. Congenital anomalies and spontaneous abortions are more serious complications in pregestational or pre-existing diabetes than in GDM.

Good sugar control achieved with intensive therapy prevents complications and improves pregnancy outcome and overall quality of life. Diet is the mainstay of treatment in GDM whether or not pharmacologic therapy is introduced. Dietary control with a reduction in fat intake and the substitution of complex carbohydrates for refined carbohydrates seeks to achieve and maintain the maternal blood glucose profile essential during gestation.

Insulin has long been the only accepted pharmacologic agent of choice for women with GDM and type 2 diabetes in pregnancy. NPH insulin is the only basal insulin that has been adequately studied in pregnancy. Human regular insulin and the insulin analogs lispro and apart are classified as pregnancy risk category B by the U.S. Food and Drug Administration. When compared with regular insulin, the rapid-acting insulin analogs have been shown to be as efficacious in reducing hyperglycemia during pregnancy, With a safety profile that resulted in a low incidence of neonatal complications.

Although oral antidiabetic medications were used in pregnant patients in the 1970s and 1980s, concerns arose from some studies that found increased rates of perinatal death and neonatal hypoglycemia (low sugar). Because of these concerns, the use of oral antidiabetic medications in pregnancy was strongly discouraged. However, more recent data on these drugs suggest an important paradigm shift regarding their use during pregnancy. Oral agents are a pragmatic alternative to insulin therapy in pregnancy because they are easy to administer, non-invasive, often cheaper, and therefore user-friendly.

SULFONYLUREAS. Since the original study on Glyburide in 2000, many experts and authoritative organizations in the United States such as The Fifth International Workshop on Gestational Diabetes and the North American Diabetes in Pregnancy Study Group have endorsed the use of this oral agent as an alternative to insulin in pregnancy.

Glyburide is also known as Glibenclamide in Europe and here in the Philippines. It is the most common oral agent used in GDM. This drug increases insulin secretion and indirectly diminishes insulin resistance. Its onset of action is app’roximately four hours, and duration of action is around 10 hours. Thus, Glyburide may cover the basal requirement as well as the after-meal sugar excursions. Its starting dose is 2.5mg a day, which can be increased by 5mg increments to a maximum of 20mg a day. Glyburide does not cross the placenta, which is good proof that it may not affect the fetus during pregnancy. Several retrospective and randomized studies have evaluated the efficacy of oral agents during pregnancy, with an 80 to 85 percent reported success rate in studies using Glyburide treatment. Moreover, when insulin and Glyburide were compared, similar success rates were reported in terms of sugar control and pregnancy outcome.

Although the drug has not been approved for use in pregnancy by the American Diabetes Association or American Collage of Obstetrics and Gynecology (ACOG), in a survey of ACOG fellows, 13 percent stated that they use Glyburide as first-line therapy for the treatment of gestational diabetes.

BIGUANIDES. Metformin is an insulin sensitizer that’reduces insulin resistance and suppresses liver production of glucose. Although Metformin crosses the placenta, it is categorized as a class B drug (Table 1). Its use in GDM is after the first trimester, controlling against the risk of fetal anomalies. To date, no randomized study addressing the use of oral agents during the’first trimester or during organogenesis has been performed. Two studies demonstrated that the use of Metformin preconception and during the first trimester is not associated with major fetal malformations, and might be even protective against early pregnancy loss in women with polycystic ovary syndrome (PCOS). However, there is no justification to maintain a PCOS patient on Metformin throughout pregnancy if she does not develop GDM. Most of the studies applicable to PCOS restricted Metformin exposure to the first trimester; it was discontinued as soon as pregnancy was diagnosed. Evidence beyond the first trimester is anecdotal or based on small sample sizes. We should await the results of ongoing randomized trials addressing the possible effect of Metformin in pregnancy.

THIAZOLIDENEDIONES (TZD).This class of oral hypoglycemic drugs includes Rosiglitazone and Pioglitazone. The mechanism of action is reduction of cellular insulin resistance through the peroxisome pro liferator-activated receptor.TZDs are classified as pregnancy category C. These drugs are known to cross the placenta. Few data are available regarding TZD use in the second and third trimesters of pregnancy.

ALPHA GLUCOSIDASE INHIBITORS. Drugs in this class act by slowing the absorption of carbohydrates from the intestines, thus minimizing the post-meal rise in blood glucose. Acarbose, miglitol, and voglibose are currently in clinical use. The experience in pregnancy is minimal with fewer than 100 patients to date. Their ability to decrease glucose to targeted levels required in pregnancy is less effective than Glyburide.

USE OF ORAL ANTIDIABETIC AGENTS IN BREASTFEEDING. Women who are on oral anticliabetic medications prior to pregnancy are often anxious to return to their oral agents postpartum, after being put on insulin for the duration of the pregnancy. The first-generation sulfonylureas, tolbutamide and
chlorpropamide, have been found to cross into breast milk. Very small studies support the safety of second-generation sulfonylureas (Glipizide and Glyburide) in lactation. To date, there have been three studies which looked at the use of Metformin in breastfeeding, and they suggest that Metformin is excreted into breast milk at very low levels.

THE ROAD AHEAD. Although not yet universally accepted, the introduction of insulin analogues and oral antidiabetic agents (mainly Glyburide) has profoundly altered the management approach in the treatment of diabetes in pregnancy. The major obstacle to the creation of evidence-based criteria is the fear of the potential adverse drug effects on the fetus. We therefore excitedly await the clinical results of the brave doctors who chose to tread the research path of diabetes – pregnancy.

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