Aisling Murphy, MD
Carla Janzen, MD
Stacy L. Strehlow, MD
Jeffrey S. Greenspoon, MD
Sue M. Palmer, MD
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.
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.
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 2010;33:676–682. PMID: 20190296.
Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia and adverse pregnancy outcomes (HAPO study). N Engl J Med 2008;358:1991–2002. PMID: 18463375.
CLASSIFICATION OF DIABETES
The American Diabetes Association (ADA) classifies diabetes mellitus into 4 clinical types:
1. Type 1 diabetes, formerly referred to as insulin-dependent or juvenile-onset diabetes
2. Type 2 diabetes, formerly referred to as non–insulin-dependent or adult-onset diabetes
3. Other specific types of diabetes related to a variety of genetic-, drug-, or chemical-induced diabetes
4. Gestational diabetes
The first 3 categories typically refer to pregestational diabetes or diabetes that has been diagnosed prior to the onset of pregnancy. The severity of pregestational diabetes can be classified according to the White classification system (Table 31–3). This system categorizes diabetes by duration of disease and the presence of end-organ damage, which has prognostic implications for outcomes of women with diabetes mellitus during pregnancy.
Table 31–3. Modified White classification of diabetes complicating pregnancy.
PREGESTATIONAL DIABETES
ESSENTIALS OF DIAGNOSIS
Abnormal maternal glucose tolerance precedes pregnancy.
Associated with increased risk of adverse maternal and fetal outcomes including fetal structural malformations.
Risk of complications correlates with degree of glycemic control.
Pathogenesis
A. Type 1 Diabetes
Type 1 diabetes mellitus, formerly called insulin-dependent diabetes, results from autoimmune destruction of beta cells in the islets of the pancreas, usually leading to an absolute insulin deficiency. Type 1 diabetes accounts for approximately 5–10% of patients with preexisting disease. Although onset generally occurs in the young, type 1 disease can appear in older persons and may occasionally present for the first time during pregnancy.
Type 1 diabetes has multiple identified genetic predispositions. Susceptibility is increased by a gene or genes located near or within the human leukocyte antigen (HLA) locus on the short arm of chromosome 6 (6p). The risk to offspring of developing type 1 with an affected sibling is 5% if 1 haplotype is shared, 13% for 2 haplotypes, and 2% if no haplotypes are shared. If both parents are affected, the risk of the condition is 33%. It is believed that an environmental agent triggers the disease in genetically susceptible individuals. The exact nature of the trigger is, as yet, unknown.
In rare cases, type 1 diabetes is not associated with evidence of autoimmunity and is termed “idiopathic diabetes.” Patients with this form of the disorder suffer from episodic attacks of ketoacidosis. They may have an absolute insulin deficiency only during these attacks.
B. Type 2 Diabetes
Type 2 diabetes mellitus, formerly non–insulin-dependent diabetes, is characterized both by insulin resistance and by beta cell dysfunction. This form of the disorder accounts for 90–95% of all patients with diabetes.
Type 2 diabetes is a multifactorial illness that is influenced by heredity, environment, and lifestyle choices. It is typically gradual in onset and may go undiagnosed for many years. Ketoacidosis is rare in this setting. The majority of affected patients are obese.
Although several genes have been associated with the disorder, progression to frank disease can be modified by factors such as diet and exercise. With type 2 diabetes, the risk of diabetes in a first-degree relative is almost 15%, and approximately 30% more will have impaired glucose tolerance. If both parents are affected, the incidence of diabetes in the offspring is 60–75%, although lifestyle modification can decrease the risk.
Clinical Findings
Profound thirst, increased urination, and weight loss or even overt ketoacidosis are the usual symptoms prompting medical evaluation. According to the ADA, there are 4 ways of diagnosing diabetes in nonpregnant patients:
1. Symptoms of diabetes plus random plasma glucose concentration ≥200 mg/dL. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.
2. Fasting plasma glucose ≥126 mg/dL. Fasting is defined as no caloric intake for at least 8 hours.
3. Two-hour plasma glucose level ≥200 mg/dL during an oral glucose tolerance test (OGTT). The test uses a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved in water.
4. HbA1c ≥6.5% using a standardized assay.
In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day.
Complications
In the case of preexisting disease, poor periconceptional glucose control is associated with an increased risk of spontaneous abortion and fetal malformations. Later in gestation, poor glycemic control may result in intrauterine fetal demise.
Maternal hyperglycemia causes an overproduction of fetal insulin and insulin-like growth factors, which may lead to macrosomia and its attendant risks including operative delivery, shoulder dystocia, and birth injury. Conversely, in diabetic mothers with vascular disease, intrauterine growth restriction may occur.
Neonatal complications in infants of diabetic mothers may include respiratory distress syndrome (RDS), hypoglycemia, hypocalcemia, and hyperbilirubinemia. Additionally, these children may be more likely to develop diabetes and obesity in the long term. The fetus responds to maternal hyperglycemia with pancreatic hyperplasia and increased basal insulin secretion, which are associated with a lifetime increased risk of diabetes. Mothers with diabetes during pregnancy have offspring with higher rates of diabetes at age 20–24 years than do women who develop diabetes after the pregnancy (45% vs. 8.6%). This observation suggests that the hyperglycemia during pregnancy had an effect beyond the mother’s genetic tendency.
Pregnant women with diabetes are also at increased risk of complications including preeclampsia, preterm delivery, and, in the case of type 1 disease, diabetic ketoacidosis.
Treatment
Prevention of hyperglycemia through rigorous control of blood glucose level is the mainstay of treatment in the pregnant woman with pregestational diabetes. This is best accomplished by careful preconceptional counseling and achievement of normal HbA1c levels before pregnancy in pregestational diabetics, frequent (usually 4–5 times per day) home glucose level monitoring, adjustment of diet, and regular exercise.
Non–weight-bearing or low-impact exercise can be initiated or continued. Even short episodes of exercise will sensitize the patient’s response to insulin for approximately 24 hours. All care providers should stress the importance of diet. Soluble fiber provides satiety and improves both the number of insulin receptors and their sensitivity. Carbohydrate restriction improves glycemic control and may enable a patient to achieve her glycemic goals using diet and activity. Calories are prescribed at 25–35 kcal/kg of actual body weight, generally 1800–2400 kcal/d. Diet should be approximately 40% carbohydrate, 40% fat, and 20% protein usually divided into 3 meals and 2 or 3 snacks per day. A bedtime snack is particularly important to prevent nocturnal hypoglycemia. When postprandial values exceed the targets, it is important to review all recent food intake and to adjust food choice, preparation, and portion size.
Self-monitoring of fasting, 1- or 2-hour postprandial, and nighttime blood glucose levels using a glucose meter provides instant feedback to assess the patient’s diet and behavior. When the glycemic goals are met, the feedback is a powerful motivator. Diet and/or activity errors are identified and corrected as needed. Optimal glucose levels during pregnancy are fasting levels of 70–95 mg/dL and 1-hour postprandial values <130–140 mg/dL or 2-hour postprandial values <120 mg/dL.
A minimum of 2 visits to a dietitian improves education and active participation regarding diet. Food records are useful. The dietitian reviews content and calories and suggests how to include favorite ethnic foods to improve compliance. Other family members should be encouraged to participate in the dietary education because their understanding and support increase the chance for a successful diet. Often, the other family members will benefit from the healthful diet changes. Additional follow-up visits between patient and dietitian are important when glycemic goals are not reached, weight change is too great or too small, or the patient is having difficulty maintaining the diet.
When normoglycemia cannot be achieved with diet and exercise alone, medication is added. Although not endorsed by either the American College of Obstetricians and Gynecologists or the ADA, oral hypoglycemic agents such as glyburide and metformin are commonly employed.
Glyburide, a sulfonylurea, is variously categorized as either pregnancy class B or C. It is believed to cross the placenta in only minimal amounts, and studies to date have demonstrated generally favorable results when compared to insulin. Glyburide is commenced at doses of 2.5–5 mg/d and titrated upward to a maximum of 20 mg/d to achieve optimal blood glucose control.
Metformin, a biguanide that suppresses hepatic glucose production and increases insulin sensitivity, has been used for many years as a first-line agent in nonpregnant patients with type 2 diabetes. It is pregnancy category B but is known to cross the placenta and is therefore usually avoided in the first trimester. Studies to date have shown metformin to be a safe and effective treatment for diabetes in pregnancy, although in a randomized controlled trial comparing treatment with metformin to treatment with glyburide, significantly more patients in the metformin group required the addition of insulin in order to achieve euglycemia.
Due to its extensive safety record, insulin remains the first-line treatment of diabetes in pregnancy for many obstetricians. Daily doses of 0.7 U/kg in the first trimester increasing progressively to 1 U/kg later in gestation are commonly employed, although obese women may require significantly higher amounts. Doses are usually divided into basal coverage with intermediate-acting agents such as NPH (neutral protamine Hagedorn) and prandial coverage with rapid-acting or regular insulin. Subcutaneous insulin pumps may also be considered in selected patients.
Preconception Care
Patients with preexisting diabetes should be encouraged to see a physician for care prior to conception. Preconceptional care has been shown to result in improved pregnancy outcomes. Evaluation at the preconceptional visit includes the following:
1. A complete history and physical examination. To provide a risk assessment, a comprehensive review of the patient’s history should be performed. Any teratogenic medications such as angiotensin-converting enzyme inhibitors should be discontinued, and prenatal vitamins containing a minimum of 0.4 mg of folic acid should be prescribed.
2. An assessment of glycemic control. Adjustments in medications, diet, and exercise can be made to optimize glycemic control. The goal is to achieve an HbA1c of <7% to minimize the risks of spontaneous abortion and congenital anomalies.
3. An eye examination for retinopathy. Patients with retinopathy should be followed carefully for evidence of progression. If needed, laser therapy can be performed during gestation.
4. An assessment of renal function. Renal function is assessed with a serum creatinine level and a 24-hour urine collection or urinary albumin/creatinine ratio to measure protein excretion. Patients with overt nephropathy should be advised of the risks of pregnancy complications, which include worsening renal function, preeclampsia, fetal growth restriction, and preterm delivery.
5. An assessment of thyroid function. Thyroid function should be assessed, particularly in type 1 diabetics, because of the association between autoimmune thyroid disease and diabetes. In addition patients with longstanding diabetes or hypertension may be screened for ischemic heart disease with an electrocardiogram.
Antenatal Care
After confirmation of pregnancy, patients should have regular antenatal care to assess glycemic control. Evaluation is by self-monitoring of blood glucose, and treatment is adjusted accordingly.
In the first trimester, an ultrasound may be obtained to document viability, particularly if glycemic control is suboptimal. Routine antenatal laboratory evaluations should be undertaken. A urine culture is particularly important because diabetic patients are at increased risk of asymptomatic bacteriuria.
In the second trimester, a fetal ultrasound for anatomy is recommended given the risk of fetal anomalies. Fetal echocardiography is indicated in patients with preexisting diabetes to screen for congenital heart disease.
In the third trimester, further ultrasounds are indicated to assess fetal growth. This also applies to patients who have received a diagnosis of gestational diabetes. In addition, in light of the increased risks of fetal demise, surveillance of fetal well-being is commenced, usually at 32–34 weeks of gestation. This consists of twice weekly nonstress testing or a modified biophysical profile twice weekly. Maternal fetal movement monitoring (“kick counts”) using a count to 10 or similar method is recommended for all pregnant women, including those with diabetes, to reduce the stillbirth rate.
Timing of delivery involves balancing the risks of delivery, in particular prematurity and RDS, with the risks of expectant management, namely stillbirth. When fetal assessment is not reassuring, the mature fetus should be delivered. In such cases near term, amniocentesis to obtain amniotic fluid for pulmonary maturity may be helpful. If the fetus is mature, delivery may proceed. If the fetus is immature, then a decision must be made in which the risk of fetal jeopardy is balanced against the risks of preterm birth. Participation of the patient, her partner, and the neonatology and perinatology departments may facilitate a plan.
In the absence of a clear indication for delivery, such as the development of preeclampsia, assessment of fetal lung maturity is recommended for elective delivery prior to 39 weeks. In patients with GDM or preexisting diabetes who require insulin or oral medications to maintain euglycemia, expectant management beyond the due date is generally not recommended.
Preterm labor is more frequent among patients with diabetes. The main goal of tocolysis is to delay delivery so that glucocorticoid therapy to accelerate fetal lung maturation can be administered over 48 hours. Magnesium sulfate tocolysis is widely used. Nifedipine is a reasonable alternative. Beta-adrenergic mimetics such as terbutaline should be avoided if possible because these drugs may cause severe hyperglycemia and, rarely, ketoacidosis. Because glucocorticoids also cause hyperglycemia, a continuous intravenous infusion of insulin may be necessary to maintain normal glucose levels.
Maternal diabetes is not an indication for caesarean section in and of itself; however, if macrosomia coexists, the risk of shoulder dystocia is greatly increased. Therefore, the American College of Obstetricians and Gynecologists recommends that elective caesarean be considered in this setting, in particular if the estimated fetal weight is >4500 g.
American College of Obstetricians and Gynecologists. Pregestational Diabetes Mellitus. ACOG Practice Bulletin No. 60. Washington, DC: American College of Obstetricians and Gynecologists; 2005.
American Diabetes Association. Standards of medical care. Diabetes Care 2010;33:S11–S61. PMID: 20042772.
Boulot P, Chabbert-Buffet N, d’Ercole C, et al; Diabetes and Pregnancy Group, France. French multicentric survey of outcome of pregnancy in women with pregestational diabetes. Diabetes Care2003;26:2990–2993. PMID: 14578228.
SEVERE HYPERGLYCEMIA & KETOACIDOSIS
The metabolic changes that result in decreased insulin sensitivity during pregnancy also make severe hyperglycemia and ketoacidosis more common. Presenting symptoms of ketoacidosis are similar to the nonpregnant patient and include nausea, vomiting, dehydration, abdominal pain, and confusion. Abnormal laboratory findings include an anion gap metabolic acidosis (arterial pH <7.3), low serum bicarbonate (<15 mEq/L), hyperglycemia, and elevated serum ketones. Management is essentially the same in pregnant and nonpregnant patients and consists of insulin therapy, careful monitoring of potassium level, and fluid replacement. Attention should also be paid to fetal well-being, but diabetic ketoacidosis is not an indication for delivery, because although fetal heart rate monitoring often demonstrates nonreassuring patterns initially, these usually improve as maternal ketoacidosis is corrected.
Intrapartum Management
The goal of intrapartum management is to avoid maternal hyperglycemia and thus minimize the risk of neonatal hypoglycemia after delivery.
Glucose infusion is provided to all patients in labor as 5% dextrose in lactated Ringer’s solution or a similar crystalloid. The rate usually is 125 mL/h (providing 6.25 g of glucose per hour) unless the patient requires more. Intravenous fluid bolus prior to conduction anesthesia should not contain glucose.
A bedside glucose monitor can be used to monitor glucose levels every 2–4 hours in early labor and every 1–2 hours in active labor. Patients requiring insulin may receive a continuous infusion of regular insulin, often prepared as 25 U in 250 mL of saline (0.1 U/mL) according to the institution’s protocol for intravenous insulin. Most patients require approximately 0.5–2.0 U/h, although rates are adjusted based on the capillary glucose level.
Cervical ripening for induction of labor, if indicated, is conducted in the same manner as for nondiabetic parturients. Continuous electronic fetal monitoring is used. In diabetic pregnancies, the fetus’s ability to tolerate the stress of labor may be limited. Fetal heart rate abnormalities should be evaluated with acoustic or scalp stimulation or fetal oxygen saturation monitoring. If fetal well-being cannot be demonstrated, expeditious delivery, often by caesarean section, is indicated. If fetal macrosomia is suspected, operative vaginal delivery should be considered with great caution, if at all. The infant of the diabetic is at increased risk for shoulder dystocia, and this should be anticipated with adequate personnel, obstetric anesthesia, and neonatal resuscitation available at delivery.
If a repeat caesarean delivery or other elective surgery is planned, it should be scheduled for early morning, if possible. The patient should take her evening insulin or oral hypoglycemic dose on the preceding night, but the morning dose should be held. The morning of surgery, the glucose level is monitored and basal insulin needs usually are treated with continuous intravenous insulin to maintain blood glucose between 70 and 120 mg/dL.
Postpartum Care
Postpartum, the patient should start back on an ADA diet as soon as clinically indicated. Insulin sensitivity increases markedly postpartum. In patients with GDM, blood glucose should normalize after delivery. In pregestational patients, as a rule of thumb, insulin doses can be reduced to approximately half the pregnancy dose. Close monitoring of blood glucose should be continued, particularly in the setting of type 1 disease. If the patient underwent surgery, a sliding scale may be implemented until oral intake can be established. The glucose levels should be kept below 140–150 mg/dL to assist the patient in healing. Breastfeeding is strongly encouraged and may be protective against development of childhood diabetes in the infant. Postfeed hypoglycemia can be avoided by increasing caloric intake in the form of snacks.
Contraception
Contraceptive options for diabetic women without vascular complications are the same as for nondiabetic women. In women with an increased risk for embolism, hormonal contraception containing estrogen is not recommended, but progesterone-only methods, including the levonorgestrel intrauterine system, can be offered. Permanent sterilization should be made available to women with diabetes who have completed childbearing.
Prognosis
The prognosis for women with pregestational diabetes is generally not altered by pregnancy. A small percentage of women with end-organ damage related to diabetes prior to pregnancy may experience worsening of their disease. Women with moderate to severe diabetic nephropathy prior to pregnancy (defined as serum creatinine of ≥1.9 mg/dL) are at increased risk of permanent decline in renal function with pregnancy. Approximately 10% of women meeting these criteria progressed to end-stage renal disease. Similarly, diabetic retinopathy worsens in some women during pregnancy. The strict glycemic control achieved during pregnancy is associated with worsening proliferative retinopathy. Laser therapy, however, is an effective treatment of retinopathy and is safe during pregnancy.
GESTATIONAL DIABETES MELLITUS
ESSENTIALS OF DIAGNOSIS
GDM has been traditionally defined as any degree of glucose intolerance with onset or first recognition during pregnancy.
The hallmark of GDM is insulin resistance.
GDM is associated with an increased risk of maternal and fetal/neonatal complications.
Pathogenesis
Approximately 7% of pregnancies are affected by GDM, ranging from 1–14%, depending on the population studied and the diagnostic criteria employed. However, prevalence of the disease is expected to continue to rise as a result of the increasing prevalence of risk factors such as obesity in the gravid population.
The hallmark of GDM is insulin resistance, and as such, it is etiologically similar to type 2 diabetes. Indeed, many patients with a diagnosis of GDM that is made early in gestation may in fact have glucose intolerance that antecedes the pregnancy. Likewise, it is known that as many as 50% of patients with GDM will ultimately go on to develop type 2 diabetes later in life. In recognition of this, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recently recommended that high-risk women found to have diabetes by standard criteria early in pregnancy be classified as having “overt” rather than “gestational” diabetes.
GDM and type II diabetes are pathogenetically related. In fact, GDM can be considered to be type 2 disease that is unmasked by the metabolic changes of pregnancy. Therefore, it is not surprising that the risk factors for both conditions are similar and include obesity, family history, minority ethnicity, and older age.
The progressive insulin resistance that occurs in normal pregnancies is associated with an increase in insulin release by the beta cells of the pancreas in order to maintain glucose homeostasis. Women with GDM exhibit more insulin resistance than normal patients, which is a function of their prepregnancy metabolic state. GDM becomes manifest when the beta cells are unable to overcome the decreased insulin sensitivity and hyperglycemia results.
Women with GDM continue to demonstrate postpartum defects in insulin action. These defects include the regulations of glucose clearance, glucose production, and plasma-free fatty acid concentrations, together with defects in pancreatic beta cell function, which precede the development of type 2 diabetes.
Clinical Findings
Despite decades of research, the optimal approach to screening and diagnosis of GDM has remained the subject of much controversy. Risk assessment for GDM is performed at the first prenatal visit in all women who do not already have diagnosed diabetes. Women at high risk should undergo screening with plasma glucose as soon as feasible. High-risk characteristics include the following:
1. Age >35–40 years
2. Obesity (nonpregnant body mass index [BMI] >30)
3. Prior history of GDM
4. Heavy glycosuria (>2+ on dipstick)
5. History of unexplained stillbirth
6. Polycystic ovarian syndrome
7. Strong family history of diabetes
If results of testing do not demonstrate diabetes, these women should be retested between 24 and 28 weeks’ gestation.
In the past, universal plasma screening was recommended for all women. However, it is acceptable to forgo this in women deemed to be of low risk. A low-risk individual meets all of the following criteria:
1. Age <25 years
2. Not a member of an ethnic group at increased risk (ie, not Hispanic American, African American, Native American, Asian American, or Pacific Islander)
3. BMI ≤325
4. No previous history of abnormal glucose tolerance
5. No previous history of adverse obstetric outcome
6. No known diabetes in a first-degree relative
However, when these criteria are applied, only 10% of the population will be exempt from screening; therefore, many obstetricians believe it is more practical to administer a plasma glucose screen in all pregnant women.
Currently, both the American College of Obstetricians and Gynecologists and the ADA advocate a 2-step approach to screening. Step 1 consists of a 1-hour 50-g oral glucose challenge test (GCT), which is administered between 24 and 28 weeks of gestation. The GCT can be performed at any time of day and without regard to time of prior meal. If this screening test is positive, it is followed by the diagnostic test, a 3-hour 100-g OGTT.
The correct threshold for an abnormal result for the GCT has not been definitively defined. The original blood glucose value for an abnormal screen (>140 mg/dL) was chosen arbitrarily and later validated by its ability to predict future development of diabetes in the mother and not by any correlation with adverse pregnancy outcome. In fact, the blood glucose threshold above which adverse outcomes begin to increase has never been established. The recent Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study addressed this issue and found that no discrete threshold exists. Instead, there is a continuous relationship between blood glucose levels and adverse outcome. This study confirmed that even in women who did not meet the criteria for a diagnosis of GDM, the risk of complications increased in proportion to an increase in blood glucose.
At the blood glucose threshold of 140 mg/dL, 80% of patients with GDM will be detected, but approximately 15% of all patients screened will require further definitive testing. Lowering the threshold from 140 to 130 mg/dL, as many experts advocate, would result in a detection rate of 90%, but would result in false-positive screens in many more women. In patients whose screening result is >200 mg/dL, a diagnosis of GDM can be made without further testing.
Diagnostic testing is usually accomplished by administration of a 3-hour 100-g OGTT after an overnight fast. Two different classification schemes of results are employed, which were adapted from the original O’Sullivan and Mahar whole blood values. There is no clear advantage to one scheme over the other. A diagnosis of GDM is made when 2 or more thresholds are met or exceeded. However, morbidity is increased with even a single abnormal value, and therefore, many physicians advocate initiation of dietary therapy in this scenario.
Outside of the United States, a 1-step approach to testing using a 2-hour 75-g oral glucose load is widely used. In 2010, following publication of the findings of the HAPO study, the IADPSG proposed that this 1 -step approach replace the current screening and diagnostic tests. Based on the recommendations of the IADPSG, the diagnosis of GDM can be made if there is 1 or more abnormal value on the 75-g OGTT. Thresholds for both the 100-g and 75-g OGTT are listed in Table 31–4.
Table 31–4. Diagnostic criteria for gestational diabetes mellitus.
Complications
Similar to pregestational diabetes, GDM is associated with an increased risk of maternal and fetal complications including preeclampsia, stillbirth, and macrosomia. Infants born to mothers with gestational diabetes are at increased risk of hypoglycemia, hyperbilirubinemia, hypocalcemia, and RDS.
GDM may also be associated with long-term health consequences for the fetus. Offspring of mothers with GDM appear to be at increased risk of obesity and impaired glucose tolerance later in life.
Unlike offspring of women with pregestational diabetes, fetuses of women with true GDM are not at increased risk of fetal structural malformation.
Treatment
Treatment of women with GDM focuses on achieving rigorous control of blood glucose level and thus minimizing the risk of maternal and fetal complications. At time of diagnosis, dietary counseling is provided, and patients are prescribed a 1800–2400 kcal/d diabetic diet. Diet should be approximately 40% carbohydrate, 40% fat, and 20% protein usually divided into 3 meals and 2 or 3 snacks per day.
Patients are advised to initiate home glucose monitoring of fasting, 1- or 2-hour postprandial, and nighttime blood glucose levels using a glucose meter. Optimal glucose levels during pregnancy are fasting levels of 70–95 mg/dL and 1-hour postprandial values <130–140 mg/dL or 2-hour postprandial values <120 mg/dL. When postprandial values exceed the targets, it is important to review all recent food intake and to adjust food choice, preparation, and portion size. When normoglycemia cannot be achieved with diet and exercise alone, medication is added.
As with pregestational diabetes, treatment of GDM that has failed treatment with dietary modification alone typically starts with insulin as first-line therapy. However, a number of studies have demonstrated that oral hypoglycemics such as glyburide and metformin are efficacious at achieving glycemic control with a favorable safety profile for the fetus. Glyburide, a sulfonylurea, is variously categorized as either pregnancy class B or C. It is believed to cross the placenta in only minimal amounts, and studies to date have demonstrated generally favorable results when compared to insulin. Glyburide is commenced at doses of 2.5–5 mg/d and titrated upward to a maximum of 20 mg/d to achieve optimal blood glucose control.
Antenatal Care
Women with GDM that is well controlled by diet alone usually do not require antenatal fetal testing. In the setting of excellent glycemic control achieved by diet alone, fetal surveillance with nonstress testing or biophysical profiles may be initiated at 40 weeks. However, for women who require medication for control of their blood sugars, who are noncompliant, or who have GDM that is not well controlled, earlier initiation of fetal surveillance and ultrasound assessment of fetal growth are advised.
Intrapartum Management
As with women with pregestational diabetes, the goal of intrapartum management of women with GDM is to avoid maternal hyperglycemia and thus minimize the risk of neonatal hypoglycemia after delivery.
Glucose infusion is provided to all patients in labor as 5% dextrose in lactated Ringer’s solution or a similar crystalloid. The rate usually is 125 mL/h (providing 6.25 g of glucose per hour) unless the patient requires more. Intravenous fluid bolus prior to conduction anesthesia should not contain glucose.
A bedside glucose monitor can be used to monitor glucose levels every 2–4 hours in early labor and every 1–2 hours in active labor. Patients requiring insulin may receive a continuous infusion of regular insulin, often prepared as 25 U in 250 mL saline (0.1 U/mL) according to the institution’s protocol for intravenous insulin. Most patients require approximately 0.5–2.0 U/h, although rates are adjusted based on the capillary glucose level.
Cervical ripening for induction of labor, if indicated, is conducted in the same manner as for nondiabetic parturients. Continuous electronic fetal monitoring is used. If fetal well-being cannot be demonstrated, expeditious delivery, often by caesarean section, is indicated. If fetal macrosomia is suspected, operative vaginal delivery should be considered with great caution, if at all. The infant of the diabetic is at increased risk for shoulder dystocia, and this should be anticipated with adequate personnel, obstetric anesthesia, and neonatal resuscitation available at delivery.
If a repeat caesarean delivery or other elective surgery is planned, it should be scheduled for early morning, if possible. The patient should take her evening insulin or oral hypoglycemic dose on the preceding night, but the morning dose should be held. The morning of surgery, glucose level is monitored and basal insulin needs usually are treated with continuous intravenous insulin to maintain blood glucose between 70 and 120 mg/dL.
Postpartum Care
Because GDM resolves with delivery of the fetus and placenta, routine postpartum care in the immediate postpartum period is sufficient. For the patient with true GDM, all medications for blood sugar control are discontinued after delivery, as is blood glucose monitoring.
Prognosis
Women diagnosed with GDM are at increased risk to develop type 2 diabetes in the future. They have about a 50% risk of developing the disease within 10–15 years. Lifestyle modification may delay or entirely prevent the onset of diabetes in adults with impaired glucose tolerance, and therefore, counseling of a patient with GDM should include a discussion of the long-term prevention of progression to nongestational diabetes.
All patients with GDM should have a 2-hour, 75-g OGTT approximately 6 weeks postpartum. Those with normal glucose tolerance should be reassessed every 3 years. Those with impaired glucose tolerance or impaired fasting glucose should be reevaluated annually (Table 31–5).
Table 31–5. Categories of increased risk for diabetes.
All women should be encouraged to eliminate or reduce any other risk factors (in addition to glucose intolerance) for cardiovascular disease. In practice, this means referral to programs, as needed, to cease smoking and to avoid environmental smoke; to engage in regular physical activity; to consume an appropriate diet; to achieve and maintain a normal weight; and to be treated for individual cardiovascular disease risk factors.
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