Medications

Women may have persistent hyperglycemia despite medical nutritional therapy and exercise. To improve macrosomia and morbidities, they may then initiate insulin or oral antihyperglycemic therapy. There is not a consensus on who should receive insulin therapy as opposed to other agents.

Insulin

The dose of insulin is initiated in accord with fasting and postprandial glucose concentrations, although the dose eventually required varies with underlying insulin resistance. If fasting glucose levels are elevated, an intermediate-acting insulin such as NPH is given before bedtime at an initial dose of 0.2 U/kg body mass. If postprandial glucose concentrations are elevated, a short-acting insulin, such as insulin lispro at 1-1.5 U per 10 g carbohydrate, is also given. Women may undergo four injections per day if both occur. As insulin resistance increases as the pregnancy progresses, the dose will change over time, by as much as a total of 1.0 U/kg total between the first and third trimesters. Doses may need to be adjusted as much as 2.0 U/kg to overcome changes in weight, especially in women who are morbidly obese at baseline. Insulin is typically divided so that half is given as intermediate acting and half is given as three preprandial short-acting injections (50). In the event of acute hypoglycemia, 10-20 g of carbohydrate addresses symptoms immediately, followed by a reduction in the amount of insulin, with each of unit of insulin lowering blood glucose by 25 mg/dl.

Instead of using glucose results to initiate or adjust insulin, as is commonly done, more direct evidence of fetal hyperinsulinemia has been used (51). Targeting insulin administration to women with ultrasound evidence (greater than 75th percentile abdominal circumference early in the third trimester) may more accurately target treatment to macrosomia and avoid treatment of women at lower risk (51). Kjos et al. (51) randomized women to intervention vs. insulin therapy, with the intervention women receiving insulin if fetal abdominal circumference was greater than or equal to 70th percentile of weight or if fasting plasma glucose measurements were greater than or equal to 120 mg/dl. Macrosomia was similar between groups, along with a broad range of neonatal outcomes including hypoglycemia requiring intravenous glucose, jaundice requiring phototherapy, birth trauma and transfusion. Thirty-eight percent of women in the experimental group avoided insulin. See Chap. 18 for more details.

Oral Antihyperglycemic Agents

Glyburide While not endorsed by medical organizations in the USA, oral antihyperglycemic gents are commonly used in other countries for the treatment of hyperglycemia during GDM pregnancies. The two in common usage are glyburide, an insulin secretagogue, and metformin, an insulin sensitizer.

Langer et al. (52) randomized 404 women with GDM who required therapy beyond nutrition and exercise. Women were randomly assigned between 11 and 33 weeks of gestation to receive glyburide or insulin, with adjustments made as necessary to achieve normoglycemia. Secondary end points included maternal and neonatal complications. While 4% of women in the glyburide group eventually required insulin therapy, there were no significant differences between the glyburide and insulin groups in the percentage of infants who were large for gestational age (12 and 13%, respectively); who had macrosomia, defined as a birth weight of 4,000 g or more (7 and 4%); who had lung complications (8 and 6%); who had hypoglycemia (9 and 6%); who were admitted to a neonatal intensive care unit (6 and 7%); or who had fetal anomalies (2 and 2%). The cord-serum insulin concentrations were similar in the two groups, and glyburide was not detected in the cord serum of any infant in the glyburide group. However, the study was not necessarily powered to find significant differences between groups with these rates of complications.

Theoretical concerns about glyburide include the possible acceleration of postpartum incidence of maternal diabetes and the unknown effects on the long-term development of the offspring (53). In a review of the trial and other retrospective studies of glyburide use, Moore (53) noted that the rate of glyburide failure may be higher, in the order of 20%, particularly if the initial fasting glucose level exceeded 115 mg/dl, rates of neonatal hyperbilirubinemia might be higher among glyburide users, and that glyburide users also achieved significantly lower fasting and postprandial glucose levels. It is likely that the controversy will not be settled until larger trials, stratified by therapy, are performed.

Metformin Metformin has not been compared directly with glyburide, although both metformin and glyburide have been compared with insulin in randomized studies. In the MiG study, Rowan et al. (54) randomized 751 women with GDM at 20-33 weeks of gestation to open treatment with metformin (with supplemental insulin if required) or insulin. The primary outcome was a composite of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-min Apgar score less than 7 or prematurity. The trial was designed to rule out a 33% increase (from 30 to 40%) in this composite outcome in infants of women treated with metformin as compared with those treated with insulin. Secondary outcomes included neonatal anthropometric measurements, maternal glycemic control, maternal hypertensive complications, postpartum glucose tolerance, and acceptability of treatment. About half of the women (46%) randomized to metformin eventually required supplemental insulin during the trial in order to achieve glycemic goals. The rate of the primary composite outcome was similar in both groups (32.0% vs. 32.2%) as was the rate of secondary outcomes, although women in the metformin group greatly preferred their assignment compared with women in the insulin group (76.6% vs. 27.2%). In the Langer et al. (52) trial of glyburide vs. insulin, only 4% of women randomized to glyburide eventually required insulin.

In meta-analyses of metformin observational studies (55), first trimester exposure to metformin did not increase risk of major malformations, and in the MiG study, second and third trimester exposure to metformin also was not associated with malformations (54). Metformin may have the added benefit of reducing the incidence of recurrent GDM among women with polycystic ovary disease, although progression to GDM was not compared to a control group not using metformin (56).

Treatment or observational trials examining the impact of treatment of therapy on other outcomes, particularly long-term outcomes, have not been conducted. While macrosomia is relatively easy to measure, it may not fully capture the fetal metabolic changes associated with GDM. Neonates of women with GDM have body composition different from that of women with normal glucose tolerance (57). While infants have similar birth weight across groups, fat mass, percent body fat, and subcutaneous and abdominal measures of fat are greater in the infants of women with GDM. These differences persist regardless of whether infants were large or average for gestational age (57).

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