Gestational Diabetes Mellitus (GDM) is abnormal glucose tolerance during pregnancy. In pregnancy, insulin resistance occurs due to placental secretion of growth hormone, cortisol, human placental lactogen, and progesterone. In Canada, the prevalence of GDM is 8-18% in the aboriginal population and 3.7% in the non-aboriginal population.¹

Diagnosis

The Canadian Diabetes Association (CDA) guidelines recommend universal screening of all women between 24-28 weeks of gestational age. The screening test for GDM is a 50g 1-hour glucose challenge test (GCT). The patient is given a 50g oral glucose load at any of time of day and plasma glucose (PG) is measured 1 hour later. The confirmatory test is the 75 g 2-hour oral glucose tolerance test (OGTT). The CDA diagnostic criteria for GDM are outlined in Figure 1, and the International Association of Diabetes in Pregnancy Study Groups (IADPSG) has recently published modified criteria.² Women at high risk of developing GDM (Table 1) should be screened in the first trimester and if negative, repeated at 24-28 weeks.¹ Pregnant women who have high HbA_1c values or chronic microvascular and macrovascular complications of diabetes at the time of screening may actually have underlying type 2 diabetes (T2DM).

The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study has shown that even mild hyperglycemia in pregnancy is associated with outcomes such as birth weight greater than the 90^th percentile, increased rate of caesarean section and high cord plasma C-peptide levels which reflect fetal hyperinsulinemia.3 Adverse maternal and fetal outcomes associated with GDM are outlined in Table 2.

Management

Women with GDM should perform self-monitoring of blood glucose, but the glycemic targets to aim for in pregnancy differ from those sought in the non-pregnant female (Table 4).¹ Lifestyle modification and dietary changes with the assistance of a registered dietician are the first steps of treatment. Hypocaloric diets aren’t recommended as they can cause ketosis and lack adequate nutrients. Gentle exercise such as walking is beneficial, although obstetrical concerns may limit physical activity.

Insulin therapy in GDM

Pharmacologic therapies are initiated if a two-week trial of lifestyle modification fails to hit glycemic targets, or if there’s significant fasting hyperglycemia or a very high HbA1c. Insulin lacks significant transplacental passage and is the standard of care for treatment of GDM. It’s started at low doses. Fast-acting prandial insulin analogues such as Lispro and Aspart, regular insulin, and longer-acting insulins such as Neutral Protamine Hagedorn (NPH) are safe in pregnancy. Often, longer-acting insulin is started at bedtime and if the meal sugars are still high, then rapid/short acting prandial insulins are added. The safety of the very long-acting analogues Glargine and Detemir has not been established in pregnancy.¹

Studies suggest that treatment of GDM reduces adverse fetal and maternal outcomes. In a randomized trial, women between 24 and 34 weeks’ gestation who had GDM were assigned to receive dietary advice, blood glucose monitoring, and insulin therapy (intervention group) or routine care, which resembled clinical care without the knowledge of GDM diagnosis. In the intervention group, the composite end point of serious perinatal complications (death, shoulder dystocia, bone fracture or nerve injury) was significantly lower. Maternal outcomes showed higher rates of induction of labour in the intervention group but no difference in rates of caesarean section.⁴

In another randomized trial, women between 24 and 31 weeks gestational age who had mild GDM were assigned to an intervention group that included glucose monitoring, dietary advice and insulin therapy and compared to a control group with routine care. Mild GDM was defined as fasting PG < 5.3 mmol/L and 2 or 3 abnormal values on a 3-hour 100 g OGTT. There was no difference in the primary outcome, which was a composite of stillbirth or perinatal death and neonatal complications such as hyperbilirubinemia, hypoglycemia, hyperinsulinemia and birth trauma. The intervention group, however, had lower rates of shoulder dystocia and delivery by caesarean section, as well as reduced rates of pre-eclampsia and gestational hypertension.⁵

Oral agents in GDM

Oral hypoglycemic agents such as glyburide and metformin are considered second-line agents of treatment for women with GDM who are non-adherent to insulin therapy or refuse insulin. Physicians should discuss with their patients that the use of oral agents in pregnancy is off-label and long-term safety data are limited. Metformin crosses the placenta but transplacental passage of glyburide is controversial.⁶

In a landmark trial, 404 women with GDM at 11 to 33 weeks gestation were randomized to treatment with glyburide or insulin. Both groups had similar rates of macrosomia, neonatal hypoglycemia, fetal anomalies and admissions to neonatal intensive care unit.⁷ Another retrospective study has shown than women with GDM who were treated with glyburide had higher rates of pre-eclampsia and their newborns had greater need for phototherapy treatment than those in the insulin group.⁸

In an open-label trial, women with GDM at 20 to 33 weeks gestation were assigned to treatment with metformin or insulin. Metformin alone or with supplemental insulin wasn’t associated with adverse outcomes such as respiratory distress, need for phototherapy or birth trauma. The group receiving metformin had less neonatal hypoglycemia but more spontaneous pre-term delivery. Women found metformin therapy more acceptable and had less weight gain.⁹ As compared to glyburide, women treated with metformin are more likely to require supplemental insulin for GDM.¹⁰

There are no specific guidelines on the frequency of ante-natal visits, but women with GDM are generally seen at least every 1 to 2 weeks.

Post-partum follow-up

Women with GDM have a 17-63% risk of developing Type 2 DM within 5 to 16 years after the pregnancy.¹¹ Post-partum follow-up with a 75 g OGTT between 6 weeks and 6 months is recommended. Some studies have shown that offspring of mothers with GDM are at an increased risk of obesity and abnormal glucose tolerance but the importance of tight glycemic control to prevent these long-term outcomes isn’t established.¹ Women with previous GDM should plan future pregnancies in consultation with their family physician or an endocrinologist to attain good glycemic control at conception and throughout pregnancy.

References

1. Clinical Practice Guidelines. Canadian Diabetes Association 2008;http://www.diabetes.ca/for-professionals/resources/2008-cpg/.
2. Ryan EA. Diagnosing gestational diabetes. Diabetologia 2011;54(3):480-6.
3. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, et al. NEJM 2008; 358(19):1991-2002.
4. Crowther CA, Hiller JE, et al. Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. NEJM 2005;352(24):2477-86.
5. Landon MB, Spong CY, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. NEJM 2009;361(14):1339-48.
6. Pridjian G, Benjamin TD. Diabetes.
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7. Langer O, Conway DL, et al. NEJM 2000;343(16):1134-8.
8. Jacobson GF, Ramos GA, et al. Am J Obstet Gynecol 2005;193(1):118-24.
9. Rowan JA, Hague WM, et al. MiG Trial Investigators. NEJM 2008;358(19):2003-15.
10. Moore LE, Clokey D, et al. Obstet Gynecol 2010;115(1):55-9.
11. Feig DS, Zinman B, et al. CMAJ 2008;179(3):229-34.