According to the Centers for Disease Control and Prevention, diabetes mellitus was estimated to affect 24 million people in the United States in 2008, an increase of 3 million over the preceding 2 years. Prevalence of diabetes, primarily type 2 disease, is expected to rise even further by 2030, as a consequence of population aging, lifestyle changes, and increasing obesity rates. Approximately 25% of adults with the condition are currently undiagnosed.
Data suggest that this upward trend in prevalence is also affecting pregnant women. Preexisting diabetes affects 1% of all pregnancies, whereas approximately 7% of pregnant women are diagnosed with gestational diabetes mellitus (GDM), a condition traditionally defined as glucose intolerance with onset or first recognition during pregnancy. Even higher rates may be seen in certain minority groups, in particular African American and Hispanic gravidas.
Before the introduction of insulin in 1922, women with preexisting diabetes did not often conceive. When pregnancy did occur, it commonly resulted in the death of the mother. This fact prompted Joseph de Lee to recommend in his seminal 1913 textbook that all such pregnancies be terminated. He observed that “the attempt to carry the pregnancy up to term or even to viability of the child is too perilous.”
The introduction of insulin, as well as improvements in general obstetric care, rapidly decreased maternal mortality. However, the risk of stillbirth and neonatal death remained much higher in diabetics than in the general population until the 1960s. Since that time, there has been a dramatic decrease in perinatal mortality due to improved neonatal intensive care, fetal surveillance, and greatly improved diabetic control, the result of self-blood glucose monitoring and intensified insulin regimens. Today, if good glycemic control is achieved, the risk of perinatal mortality approaches that of the general obstetric population. Nevertheless, both preexisting diabetes and GDM continue to pose significant risks during pregnancy.
Currently, the priorities for diabetes care providers are first to identify and control diabetes prior to conception and second to appropriately screen and treat GDM during pregnancy in an effort to prevent maternal and fetal/neonatal complications. Evidence exists that treatment of even mild GDM results in improved outcomes in both mother and baby.
Metabolism in Normal & Diabetic Pregnancy
To accommodate the growth of a healthy fetus, profound metabolic changes occur in all pregnant women during gestation. In particular, it is well established that insulin sensitivity decreases in normal women as gestation advances. However, despite much research, the mechanism behind this phenomenon is unknown. Alterations in maternal cortisol levels, as well as in the placental hormones including estrogen, progesterone, placental growth factor, and human placental lactogen (hPL) (also known as human chorionic somatomammotropin), have all been implicated.
Although some degree of insulin resistance occurs in all women, only a relatively small number develop GDM. Affected women share the same risk factors as patients with type 2 diabetes, and like type 2 disease, GDM is characterized both by insulin resistance and by inadequate insulin secretion. It therefore appears that GDM may be considered as type 2 diabetes that is unmasked by the diabetogenic milieu of pregnancy.
Insulin is an anabolic hormone with essential roles in carbohydrate, fat, and protein metabolism. It promotes the uptake of glucose, storage of glucose as glycogen, lipogenesis, and uptake and utilization of amino acids. A lack of insulin or decreased peripheral responsiveness to insulin results in hyperglycemia and lipolysis. Elevation of free fatty acids leads to an increase in the formation of ketone bodies, acetoacetate, and β-hydroxybutyrate. When blood glucose levels exceed the renal threshold for absorption of filtered glucose, glycosuria occurs and causes an osmotic diuresis with dehydration and electrolyte losses.
In the first trimester of normal pregnancies, insulin sensitivity is unchanged or increased. This appears to be because both estrogen and progesterone levels rise at this time but their effects on insulin activity are antagonistic. Progesterone causes insulin resistance, whereas estrogen has the opposite effect. Because insulin secretion rises while insulin sensitivity is unchanged, the result is a decrease in fasting glucose levels, which reach a nadir by the 12th week. The decrease averages 15 mg/dL; thus, fasting values of 70–80 mg/dL are common by the 10th week of pregnancy.
However, in the second trimester, higher postprandial glucose levels occur, facilitating transfer of glucose across the placenta from mother to fetus. Glucose transfer occurs via a facilitated diffusion that becomes saturated at 250 mg/dL. Fetal glucose levels are 80% of maternal levels. In contrast, maternal amino acid levels are lowered due to active placental transport to the fetus. Lipid metabolism in the second trimester shows continued maternal storage until midgestation, then enhanced mobilization (lipolysis) as fetal fuel demands increase.
hPL, which increases up to 30-fold during pregnancy, is thought to be the hormone mainly responsible for insulin resistance and lipolysis. hPL also decreases the hunger sensation and diverts maternal carbohydrate metabolism to fat metabolism in the third trimester. hPL is similar in structure to growth hormone and acts by reducing the insulin affinity to insulin receptors. The net effect is to favor placental transfer of glucose to the fetus and to reduce the maternal use of glucose. The hPL levels rise steadily during the first and second trimesters, with a plateau in the late third trimester.
Maternal cortisol levels, which likewise rise during pregnancy, may also contribute to insulin resistance by stimulating endogenous glucose production and glycogen storage and decreasing glucose utilization.
Recently, researchers have challenged the view that the insulin resistance of pregnancy is mediated entirely by hormonal changes. Attention has turned to the role adipokines such as tumor necrosis factor-α (TNF-α), adiponectin, and leptin may play. In particular, the change in TNF-α level has been found to be a significant predictor of insulin resistance during pregnancy. TNF-α is produced by the placenta as well as by adipose tissue and may act in a paracrine fashion to impair insulin signaling mechanisms, resulting in decreased insulin sensitivity.
Fetal Effects of Hyperglycemia
Elevated glucose levels are toxic to the developing fetus, producing an increase in miscarriages and major malformations in direct proportion to the glucose level. The mechanism by which teratogenesis occurs has not been definitively established, but oxidative stress as a consequence of fetal hyperglycemia may play a role. These birth defects (Table 31–1), which may be fatal or seriously deleterious to quality of life, are largely preventable by improvement in preconception glucose control.
Table 31–1. Some Congenital Anomalies of Infants of Diabetic Mothers. ||Download (.pdf)
Table 31–1. Some Congenital Anomalies of Infants of Diabetic Mothers.
|Cardiac||Atrial septal defects|
|Ventricular septal defects|
|Transposition of the great vessels|
|Coarctation of the aorta|
|Tetralogy of Fallot|
|Central nervous system||Neural tube defects|
|Spinal||Caudal regression syndrome, sacral agenesis|
Because most malformations occur within the first 8 weeks of gestation, when most women are just beginning prenatal care, preconception care is essential for women with diabetes. Hemoglobin A1c (HbA1c), which reflects the blood glucose concentration over the previous 2 months, can predict the risk for malformations when measured in the first trimester (Table 31–2).
Table 31–2. Relationship between Initial Pregnancy Value of Glycosylated Hemoglobin and Rate of Major Fetal Congenital Malformations. ||Download (.pdf)
Table 31–2. Relationship between Initial Pregnancy Value of Glycosylated Hemoglobin and Rate of Major Fetal Congenital Malformations.
|Initial Maternal Hemoglobin A1c Level||Major Congenital Malformations (%)|
The fetus continues to experience the effects of hyperglycemia beyond the period of organogenesis. Whereas glucose crosses the placenta, insulin does not. This leads to increased fetal production of insulin to compensate for its hyperglycemic environment.
Insulin and insulin-like growth factors promote excessive fetal growth, which may result in macrosomia. Macrosomia, variously defined as a birth weight of more than 4000 g or more than 4500 g, is a risk factor for both maternal and fetal morbidity. Maternal risks include caesarean delivery, vaginal laceration, and postpartum hemorrhage. Shoulder dystocia with resultant birth injury, in particular Erb's palsy, is the most feared fetal complication.
There is a disproportionate increase in subcutaneous fat and visceromegaly in macrosomic infants of diabetic mothers, which results in a relatively large abdominal circumference with normal head and skeletal growth. This abnormal growth dynamic appears to predispose these infants to shoulder dystocia. In the presence of maternal diabetes, birth weights of greater than 4500 g have been associated with rates of shoulder dystocia of up to 50% in some studies.
In addition, fetal hyperinsulinemia leads to enlargement of internal organs such as the heart. Ventricular septal hypertrophy may, in rare cases, lead to cardiac failure as a result of left ventricular outflow obstruction.
International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care
Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia and adverse pregnancy outcomes (HAPO study). N Engl J Med