Epidemiology and Disease Pathology of Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is defined as glucose intolerance that is first detected during pregnancy, and it includes previously undiagnosed diabetes and impaired glucose tolerance (IGT).[1,2] It is a condition in which the glucose level is elevated and other diabetic symptoms (polyuria, polydipsia, and unexplained weight loss) appear[3,5]. GDM usually becomes apparent during the 24th to 28th weeks of pregnancy. It is associated with both impaired insulin secretion and the blocking effects of other hormones on the insulin that is produced, a condition referred to as insulin resistance. Diabetic symptoms usually disappear following delivery.[1]

Epidemiology

In the US, approximately 2% to 5% of all pregnancies are complicated by GDM.[1] The prevalence of GDM varies worldwide and depends on the population being studied and the diagnostic tests employed.[1,4]

Approximately 40% of women with GDM who are obese before pregnancy develop type 2 diabetes within 4 years. The chance of developing diabetes during this same period is lower if the women are not obese.[5] Some of the risk factors for GDM are listed in Table 1.

Table 1. Summary of reported risk factors for GDM[1]

Certain subgroups of women are at much higher risk. At high risk are the Pima Indians of Arizona, whose risk of GDM (approximately 40%) is about 10-fold higher than that of the general population.[2,6] In a study that examined the effects of race on prevalence of GDM, African American women had a 1.5-fold higher rate of GDM than white women and a 2-fold higher risk than Filipino women.[2,7] Another study explored whether racial differences in a United States population influence disease prevalence and perinatal outcome in GDM. The adjusted relative risk of GDM was significantly higher in black (1.81, P <0.05) and Hispanic (2.45, P <0.001) women than in white women.[1,8]

Etiology and pathogenesis

Classification

Diabetes mellitus can occur during pregnancy in 2 forms: pregestational and gestational diabetes. Both the American Diabetes Association (ADA) and the World Health Organization (WHO) have classified diabetic pregnancies according to etiology (Table 2). The WHO classification differs from the ADA classification only by recognizing IGT before pregnancy.

Table 2. Classification of diabetes in pregnancy[9]

Natural history and pathophysiology

Pregnancy is a diabetogenic state. The exact cause of gestational diabetes is not known, but there are some theories as to why the condition occurs.

The endocrine regulation of carbohydrate metabolism changes during pregnancy. Levels of insulin antagonists and steroid hormones increase along with the level of some enzymes with insulinase activity like oxytocinase, histaminase, and alkaline phosphatase. Up to the 37th to 38th gestational weeks, insulin demand may intensify 3- to 4-fold compared with that prior to pregnancy. The elevated insulin need is compensated by the hypertrophy and hyperplasia of the β-cell mass.[10] The changes in maternal metabolism during normal pregnancy include[10]

• decreased fasting plasma glucose level
• increased postprandial plasma glucose level
• increased preprandial and postprandial insulin levels
• β-cell hypertrophy and hyperplasia
• decreased insulin sensitivity
• improved lipolysis

Glycemic control in normal pregnancy is characterized by 'accelerated starvation'. Accelerated starvation leads to lower fasting glucose levels. The normal decrease in maternal insulin sensitivity during pregnancy is beneficial for the growth of the fetus, since post-prandial hyperglycemia enhances glucose transer to the fetus. Enhanced glucose transfer to the fetus is referred to as 'facilitated anabolism' and is a result of enhanced maternal lipolysis, which occurs because of the inability of insulin to suppress lipolysis in adipose tissue. However, these alterations in the metabolism of carbohydrates and lipids may lead to hyperglycemia and ketosis. However, patients with insulin-dependent diabetes mellitus (IDDM, type 1) are more prone to develope diabetic ketoacidosis during pregnancy than are patients with noninsulin-dependant diabetes mellitus (NIDDM, type 2) or gestational diabetes.[9-12]

Some hormones produced by the placenta (estrogen, cortisol, and human placental lactogen) can have a blocking effect on insulin, which usually begins about 20 to 24 weeks into the pregnancy. As the placenta grows, more of these hormones are produced, and insulin resistance becomes greater. Normally, the pancreas is able to make additional insulin to overcome insulin resistance, but when the production of insulin is not enough to overcome the effect of the placental hormones, GDM results.[13]

The hormones that lead to fetal growth and development do so by mobilizing the mother’s nutritional resources, primarily glucose, making them available to the fetus. The plasma levels of the critical anabolic hormones (human chorionic gonadotropin, human placental lactogen, progesterone, estrogen) present during pregnancy increase in the last 20 weeks of gestation. Human placental lactogen plays a vital role in triggering the changes that lead to glucose intolerance. It has strong anti-insulin and lipolytic effects. Peripheral insulin sensitivity during the third trimester decreases to 50% and basal hepatic glucose output is 30% higher than that seen in the first trimester, despite higher insulin levels.[2,14]

This combination of increased mobilization of glucose and decreased sensitivity to insulin places women at risk of developing diabetes during pregnancy. There is evidence that women who develop GDM secrete less insulin in response to a glucose load than women who do not acquire the disease.[3,15,16]

Complications of GDM during pregnancy

GDM, if not treated properly, is associated with adverse maternal and fetal outcomes.

Maternal risks

Maternal morbidity may be immediate or long-term. Studies have shown an increase in pre-eclampsia, polyhydramnios, preterm delivery, and operative delivery.[18-21] Long-term, women with GDM have a significant risk of developing diabetes later in life, as well as hypertension, hyperlipidemia, urinary tract infections, and electrocardiogram abnormalities, and thus may have high mortality (Figure 1).[18]

Figure 1. Epidemiology of GDM and its association with type 2 diabetes[1]

Fetal risks

Infants of mothers with GDM are vulnerable to several chemical imbalances, such as low serum calcium and low serum magnesium levels, but, in general, there are two major risks: macrosomia and hypoglycemia.[22] Macrosomia refers to a baby that is considerably larger than normal. All of the nutrients the fetus receives come directly from the mother's blood. If the maternal blood has too much glucose, the pancreas of the fetus senses the high glucose levels and produces more insulin in an attempt to use this glucose. The fetus converts the extra glucose to fat. Even when the mother has GDM, the fetus is able to produce all the insulin it needs. The combination of high blood glucose levels from the mother and high insulin levels in the fetus results in large deposits of fat, which causes the fetus to grow excessively large. Hypoglycemia refers to low blood sugar in the baby immediately after delivery.[10] This problem occurs if the mother's blood sugar levels have been consistently high, causing the fetus to have a high level of insulin in its circulation. After delivery, the baby continues to have a high insulin level, but it no longer has the high level of sugar from its mother, resulting in the newborn's blood sugar level becoming very low.

Increased maternal glucose levels are associated with a high rate of perinatal complications, including birth trauma and jaundice. Rarely, late intrauterine fetal death occurs. Other problems associated with overt diabetic pregnancies have been reported with varying frequency in the infants of women with GDM. They include hypocalcemia, hypomagnesemia, polycythemia, and respiratory distress syndromes.[22]

References

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