Treatment of GDM

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Rationale

As pointed out above, there is considerable controversy about 'the level of hyperglycemia, short of overt diabetes that conveys increased perinatal risk' [6]. However, there is a general consensus that lowering maternal capillary blood glucose concentrations to <95 mg/dl (5.3 mmol/l) in the fasting state, < 140 mg/dl (7.8mmol/l) at 1h or <120 mg/dl (6.7mmol/l) 2h after meals may reduce the risk of excessive fetal growth to approximate the risk in the general population [1], and a major objective of treating GDM is to reduce adverse perinatal events, primarily those associated with excess weight or adiposity of the newborn (cesarean delivery, birth trauma, neonatal morbidities).

Goals

The primary goal that is most often articulated for the treatment GDM is the restoration of fasting and post-meal glucose values to within normal ranges. Some investigators have provided evidence that it is more 'cost-effective' to assess fetal abdominal circumference (AC) by ultrasound in all women with GDM to identify those at low risk of having a large baby (AC <75th per-centile) and concentrate therapeutic efforts on those at a much higher risk of delivering a large baby (AC >75th percentile) [26].

Metabolic Management

Lifestyle Modification

Nutritional Therapy. Medical nutrition therapy (MNT) is referred to as the 'cornerstone' of medical management of GDM; however, relatively little information is available to allow evidence-based recommendations for specific dietary approaches to management of GDM [1]. Furthermore, MNT of GDM is not presently a major focus of research. The clinical guidelines for micro- and macronutrient intake and desired maternal weight gain closely parallel those that are recommended for 'normal, healthy pregnancies' [9, 10]. The significant differences are in recommendations concerning sources of dietary carbohydrate, with emphasis placed on increasing complex carbohydrates and reducing or eliminating monosaccharide, sucrose and other oligosaccharides. Calorie restriction aimed at achieving weight loss (the standard initial dietary recommendation when not pregnant) continues to be viewed as experimental for GDM.

Exercise Therapy. A number of investigators have demonstrated that exercise can effectively improve glycemia in GDM. The optimal frequency and intensity of exercise have not been determined and the overall impact on perinatal and long-term outcomes has not been fully assessed. With 3 or more sessions of exercise (>15min duration), the maximum impact on maternal glucose levels may not be seen for 2-4 weeks [1].

Intensified Metabolic Management

Failure to achieve or to maintain maternal glycemia within the targets mentioned above after initiating MNT, or signs of excessive fetal growth indicate the need for more intensive metabolic therapy. Historically, treatment with insulin has been used in such instances [1]. There is no formally accepted standard protocol for therapy of GDM with insulin. Beneficial effects of therapy with insulin have been reported with a variety of regimens, including once daily administration of a fixed dose of 'NPH' insulin. It is likely that twice daily use of combinations of biosynthetic 'Regular' and 'NHP' human insulin (in premixed fixed or flexible proportions) represents the most widely used algorithm.

In the last decade, additional treatment options have been advocated, including use of 'rapid-acting' insulin analogs (lispro and aspart, glulisine insulins), a long-acting insulin analog (insulin glargine), or oral anti-diabetic medication (sulfonylurea [glyburide], metformin). The advent of new and/or alternate therapeutic options raises issues of cost/benefit, appropriate endpoints, safety, and efficacy. As implied in the Introduction, the time may be at hand to develop indicators or measures of optimal metabolic control that go beyond indices of hyperglycemia alone. For example, do subjects with similar levels of FPG or postprandial glucose values that are achieved by different interventions also have similar levels of FFA, other lipids, individual amino acids, etc., and are the outcomes comparable? Few studies have been designed or analyzed to address questions such as these. However, Langer et al. [27] have recently reported better perinatal outcomes (i.e, lower rate of large for gestational age babies, less macrosomia (birth weight >4,000 g), lower rate of cesarean delivery, and less frequent neonatal morbidities assessed by a 'composite outcome' score), in pregnancies of obese GDM subjects (pre-pregnancy body mass index >30) treated with insulin and 'well-controlled' than in 'well-controlled' diet-treated obese subjects, even though the initial and final glycemic measurements did not differ the 2 groups of subjects.

Rapid-Acting Insulin Analogs

The rapid-acting insulin analogs (lispro, aspart and glulisine insulin) play an established role outside pregnancy in the management of type-1 DM and they are commonly used in patients with type-2 DM who require multiple daily injections. When used prior to pregnancy, rapid-acting analogs are commonly continued during gestation although their safety and efficacy during pregnancy have not been established by controlled clinical trials. The use of these analogs during pregnancy varies in different regions and among individual physicians.

The potential use of these analogs in the management of GDM has been explored to a limited extent. Jovanovic et al. [28] found no difference in immunological response to the administration of regular human insulin or lispro insulin (Humalog™) in women with GDM, and lispro insulin was not detectable in cord blood. The area under the glucose curve following a meal test was less and episodes of hypoglycemia fewer with lispro insulin. Human NPH insulin was used to provide 'basal' needs. No fetal or neonatal abnormalities were noted in either treatment group [28]. Data are not currently available from pregnancies in which intermediate (insulin detemir) and/or long-acting analogs (insulin glargine) have been used in the treatment of GDM. The cost of treatment with an insulin analog is considerably greater than the cost of using regular and NPH human insulin. Therefore, the safety, efficacy and clinical benefit should be demonstrated before the wide use of insulin analog therapy of GDM is endorsed.

Medical Therapy with Glyburide

In the past, the American Diabetes Association [29] and the American College of Obstetricians and Gynecologists [30] have recommended that oral medications not be administered for the treatment of GDM because of concerns about increased risks of congenital malformations and neonatal hypoglycemia that might be associated with their use. After finding very limited transplacental passage of glyburide in perfusion studies with term human placentas [31], Langer et al. [32] performed a randomized clinical trial comparing the results of treating GDM (meeting their criteria for use of 'intensified medical therapy') with insulin and glyburide. The primary endpoint, glycemic control, was comparable in the 2 groups, perinatal outcomes did not differ and glyburide was not detectable in cord blood taken at delivery. Only 8/201 (4%) subjects in the gly-buride treatment group failed to have an adequate glycemic response requiring transfer to therapy with insulin. The conclusion was reached that 'in women with gestational diabetes, glyburide is a clinically effective alternative to insulin therapy' [32]. These results have generated cautious optimism about the potential use of this oral agent in the treatment of GDM. Although additional studies of glyburide treatment by others have followed, to date none has involved a sample approaching the size used in the initial clinical trial.

Medical Therapy with Metformin

For nearly 50 years, metformin has been used in the treatment of type-2 DM. Reports of its limited use during pregnancy have intermittently been published. Although substantial amounts of metformin cross the placenta, in recent years interest in its use in childbearing women has increased substantially. A major factor in this trend is the evidence that administration of metformin to women with the polycystic ovary syndrome enhances ovulation and improves fertility. Some reports also suggest that administration of metformin during pregnancy as well as during induction of ovulation can reduce fetal loss and lessen the risk of developing GDM. A prospective, double-blind, randomized, placebo-controlled, clinical trial has not been completed to address the issues regarding the benefit and safety of exposure of the mother and fetus to metformin for the duration of pregnancy [33]. The potential effects in the offspring must be evaluated through childhood and puberty into adulthood.

There is also renewed interest in the use of metformin for the treatment of some patients with type-2 DM or GDM. In Australia and New Zealand, a randomized clinical trial of metformin versus insulin treatment of GDM has been initiated and guidelines have been published in Australia regarding the potential use of metformin in GDM subjects poorly controlled with diet but refusing therapy with insulin, and as an adjunct to insulin in the presence of severe obesity and very severe insulin resistance [34]. As mentioned above, the potential effects in the offspring must be evaluated through childhood and puberty into adulthood.

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