AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Abnormal maternal glucose regulation occurs in 3-10% of pregnancies. Studies suggest that the prevalence of diabetes mellitus (DM) among women of childbearing age is increasing in the United States. This increase is believed to be attributable to more sedentary lifestyles, changes in diet, continued immigration from high-risk populations, and the virtual epidemic of childhood and adolescent obesity that is presently evolving in United States. Gestational diabetes mellitus (GDM) is defined as glucose intolerance of variable degree with onset or first recognition during pregnancy. Gestational diabetes mellitus accounts for 90% of cases of diabetes mellitus in pregnancy. Type II diabetes mellitus accounts for 8% of cases of diabetes mellitus in pregnancy, and given its increasing incidence, preexisting diabetes mellitus now affects 1% of pregnancies.

Infants of mothers with preexisting diabetes experience double the risk of serious injury at birth, triple the likelihood of cesarean delivery, and quadruple the incidence of newborn intensive care unit admission. Studies indicate that the risk of these morbidities is directly proportional to the degree of maternal hyperglycemia. For this reason, the excessive fetal and neonatal morbidity attributable to diabetes in pregnancy should be considered preventable with early diagnosis and effective treatment therapies.

Pathophysiology

Maternal-fetal metabolism in normal pregnancy

With each feeding, the pregnant woman undergoes a complex series of maternal hormonal actions (ie, a rise in blood glucose; the secondary secretion of pancreatic insulin, glucagon, somatomedins, and adrenal catecholamines). These adjustments ensure that an ample, but not excessive, supply of glucose is available to the mother and fetus. The key features of this complex interaction include the following:

• Compared to nonpregnant subjects, pregnant women tend to develop hypoglycemia (plasma glucose mean = 65-75 mg/dL) between meals and during sleep. This occurs because the fetus continues to draw glucose across the placenta from the maternal bloodstream, even during periods of fasting. Interprandial hypoglycemia becomes increasingly marked as pregnancy progresses and the glucose demand of the fetus increases.
• Levels of placental steroid and peptide hormones (eg, estrogens, progesterone, and chorionic somatomammotropin) rise linearly throughout the second and third trimesters. Because these hormones confer increasing tissue insulin resistance as their levels rise, the demand for increased insulin secretion with feeding escalates progressively during pregnancy. Twenty-four–hour mean insulin levels are 50% higher in the third trimester compared to the nonpregnant state.
• If the maternal pancreatic insulin response is inadequate, maternal and, then, fetal hyperglycemia results. This typically manifests as recurrent postprandial hyperglycemic episodes. These postprandial episodes are most significantly accountable for the accelerated growth exhibited by the fetus.
• Surging maternal and fetal glucose levels are accompanied by episodic fetal hyperinsulinemia. Fetal hyperinsulinemia promotes excess nutrient storage, resulting in macrosomia. The energy expenditure associated with the conversion of excess glucose into fat causes depletion in fetal oxygen levels. 
• These episodes of fetal hypoxia are accompanied by surges in adrenal catecholamines, which, in turn, cause hypertension, cardiac remodeling and hypertrophy, stimulation of erythropoietin, red cell hyperplasia, and increased hematocrit. Polycythemia (hematocrit >65%) occurs in 5-10% of newborns of diabetic mothers. This finding appears to be related to the level of glycemic control and is mediated by decreased fetal oxygen tension. High hematocrit values in the neonate lead to vascular sludging, poor circulation, and postnatal hyperbilirubinemia. 

During a healthy pregnancy, mean fasting blood sugar levels decline progressively to a remarkably low value of 74 ± 2.7 (SD) mg/dL. On the other hand, peak postprandial blood sugar values rarely exceed 120 mg/dL. Meticulous replication of the normal glycemic profile during pregnancy has been demonstrated to reduce the macrosomia rate. Specifically, when 2 hour postprandial glucose levels are maintained less than 120 mg/dL, approximately 20% of fetuses demonstrate macrosomia. Conversely, if postprandial levels range up to 160 mg/dL, macrosomia rates rise to 35%. 

Frequency

United States

In the United States today, 21 million people (7% of the population) have some form of diagnosed diabetes. Another 6 million people may be undiagnosed. Approximately 3-10% of pregnancies in the United States are complicated by diabetes, of which 90% is gestational diabetes and 8% is preexisting, insulin-resistant (ie, adult-onset) diabetes. The incidence of insulin-resistant diabetes is increasing markedly in the United States, probably related to rising population obesity and shifts in ethnicity.

In addition to these factors contributing to a rise in the prevalence of diabetes among reproductive aged women, medical interventions during pregnancy may increase the likelihood of developing gestational diabetes. A study reported in 2007 has demonstrated and increased incidence of gestational diabetes mellitus in women receiving prophylactic 17 alpha-hydroxyprogesterone caproate for the prevention of recurrent preterm delivery (from 4.9% in control to 12.9% in treated patients).¹

Race

The prevalence of gestational diabetes is strongly related to the patient's race and culture.

• Prevalence rates are higher in African, Hispanic, Native American and Asian women than in white women.
• Typically, only 1.5-2% of Caucasian women develop gestational diabetes mellitus, while Native Americans from the southwestern United States may have rates as high as 15%.
• In Hispanic, African American, and Asian populations, the incidence is 5-8%.
• In these high-risk populations, the recurrence risk with future pregnancies has been reported to be as high as 68%.² In addition, approximately one-third will develop overt diabetes mellitus within 5 years of delivery, with higher risk ethnicities having risks nearing 50%.³
• Race also influences many complications of diabetes mellitus in pregnancy. For instance, African Americans have been shown to have lower rates of macrosomia, despite similar levels of glycemic control. Conversely, Hispanic women have higher rates of macrosomia and birth injury than women of other ethnicities, even with aggressive management.^{4, 5}

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Fetal morbidity with diabetes during pregnancy
• • Miscarriages  
  • • In all women with preexisting diabetes mellitus, there is a 9-14% rate of miscarriage.
    • Current data suggest a strong association between degree of glycemic control prior to pregnancy and miscarriage rate.  Suboptimal glycemic control has been shown to double the miscarriage rate in women with diabetes. A correlation also exists between more advanced diabetes and miscarriage rates. Patients with long-standing (>10 y) and poorly controlled (glycohemoglobin exceeding 11%) diabetes have been shown to have a miscarriage rate of up to 44%. Conversely, reports demonstrate a normalization of miscarriage rate with excellent glycemic control. 
  • Birth defects
  • • Among the general population, major birth defects occur in 1-2% of the population. In women with overt diabetes and suboptimal glycemic control prior to conception, the likelihood of a structural anomaly is increased 4- to 8-fold.
    • Although initial reports demonstrated anomaly rates as high as 18% in women with preexisting diabetes mellitus,⁶ more recent reports with more aggressive preconception and first trimester management report anomaly rates between 5.1 and 9.8%.^{7, 8}
    • Two-thirds of anomalies involve the cardiovascular and central nervous systems. Neural tube defects occur 13-20 times more frequently in diabetic pregnancy. Genitourinary, gastrointestinal, and skeletal anomalies are also more common.
    • The fact that no increase in birth defects occurs among the offspring of fathers who are diabetic and women who develop gestational diabetes after the first trimester is notable. This suggests that periconceptional glycemic control is the main determinant of abnormal fetal development in diabetic women.
    • When the frequency of congenital anomalies in patients with normal or high first-trimester maternal glycohemoglobin values was compared to the frequency in healthy patients, the rate of anomalies was only 3.4% with glycosylated hemoglobin values (HbA1C) of less than 8.5%, whereas patients with poorer glycemic control in the periconceptional period (HbA1C >8.5%) had a 22.4% rate of malformations. An overall malformation rate of 13.3% was reported in 105 patients with diabetes, but the risk of delivering a malformed infant was comparable to a normal population when the glycosylated hemoglobin (HbA1c ) was less than 7%.⁹ More recently, in a review of 7 cohort studies, researchers found that patients with a normal glycohemoglobin (0 SD above normal), the absolute risk of an anomaly was 2%. At 2 SD above normal, this risk was 3%, with an odds ratio of 1.2 (1.1- 1.4). As the glycohemoglobin increased so did the risk for malformation in a direct relationship.¹⁰
    • Because birth defects occur during the critical 3-6 weeks after conception, nutritional and metabolic intervention must be initiated well before pregnancy begins. Clinical trials of intensive metabolic care have demonstrated that malformation rates similar to those in the nondiabetic population can be achieved with meticulous  preconceptional glycemic control.¹¹ Subsequent trials comparing a preconceptional intensive metabolic program to standard treatment over 15 years duration have demonstrated lowered perinatal mortality (0% vs 7%) and reduced congenital anomaly rate (14% to 2%). In addition, when the preconceptional counseling program was discontinued, the congenital anomaly rate increased by over 50%.¹² 
  • Growth restriction
  • • Although most fetuses of diabetic mothers  exhibit growth acceleration, growth restriction occurs with significant frequency in pregnancies in women with preexisting type 1 diabetes. 
    • The most import predictor of fetal growth restriction is underlying maternal vascular disease.  Specifically, pregnant patients with diabetes-associated retinal or renal vasculopathies and/or chronic hypertension are most at risk for growth restriction.  
  • Growth acceleration
  • • Excessive body fat stores, stimulated by excessive glucose delivery during diabetic pregnancy, often extends into childhood and adult life.
    • Approximately 30% of fetuses of women with diabetes mellitus in pregnancy are large for gestational age (LGA). In preexisting diabetes mellitus this incidence appears slightly higher, 38%.⁴
    • Maternal obesity, common in type 2 diabetes, appears to significantly accelerate the risk of infants being LGA.   
  • Fetal obesity
  • • Macrosomia is typically defined as a birthweight above the 90th percentile for gestational age or greater than 4000 grams. In pregnant diabetic women, macrosomia occurs in 15-45% of cases, a 3-fold increase from normoglycemic controls.
    • Newborns with macrosomia experience excessive rates of neonatal morbidity, as illustrated by a study by Hunter et al in 1993, which compared the neonatal morbidity among infants of 230 women with insulin-dependent diabetes and infants of 460 women without diabetes. The infants of diabetic mothers (IDMs) had 5-fold higher rates of severe hypoglycemia, a 4-fold increase in macrosomia, and a doubled increase in neonatal jaundice.¹³
    • Birth injury, including shoulder dystocia and brachial plexus trauma, are  more common among infants of diabetic mothers, and macrosomic fetuses are at the highest risk.
    • The macrosomic fetus in diabetic pregnancy develops a unique pattern of overgrowth, involving central deposition of subcutaneous fat in the abdominal and interscapular areas. Skeletal growth is largely unaffected.  Neonates of diabetic mothers have a larger shoulder and extremity circumference, a decreased head-to-shoulder ratio, significantly higher body fat and thicker upper extremity skin folds compared to nondiabetic control infants of similar weights. Since fetal head size is not increased during poorly controlled diabetic pregnancy but shoulder and abdominal girth can be markedly augmented, the risk of injury to the fetus after delivery of the head (eg Erb palsy) is significantly increased.   
    • When serial ultrasound examination findings from diabetic fetuses are plotted, the growth velocity of the abdominal circumference is often well above the growth centiles seen in nondiabetic fetuses and is higher than the fetal head and femur centiles. The accelerated growth of the abdominal circumference begins to rise significantly above normal after 24 weeks. 
  • Metabolic syndrome
  • • The adverse downstream effects of abnormal maternal metabolism on the offspring have been documented well into puberty. Glucose intolerance and higher serum insulin levels are more frequent in children of diabetic mothers as compared to normal controls. By age 10-16 years, offspring of diabetic pregnancy have a 19.3% rate of impaired glucose intolerance.¹⁴ 
    • The childhood metabolic syndrome includes childhood obesity, hypertension, dyslipidemia, and glucose intolerance. A growing body of literature supports a relationship between intrauterine exposure to maternal diabetes and risk of a metabolic syndrome later in life.^{15, 16}
    • Fetuses of diabetic women that are born large for gestational age appear to be at the greatest risk.¹⁶ 
  • Role of glucose levels
  • • Excess nutrient delivery to the fetus causes macrosomia and truncal fat deposition, but whether fasting or peak glucose values are more correlated with fetal overgrowth is less clear.
    • Data from the Diabetes in Early Pregnancy project indicate that fetal birthweight correlates best with second- and third-trimester postprandial blood sugar levels and not with fasting or mean glucose levels.¹⁷
    • More recent data from the ACHOIS trial demonstrated a positive relationship between severity of maternal fasting hyperglycemia and risk of shoulder dystocia, with a 1 mmol increase in fasting glucose leading to a relative risk for shoulder dystocia of 2.09 (1.03- 4.25).¹⁸
    • When postprandial glucose values average 120 mg/dL or less, approximately 20% of infants can be expected to be macrosomic. When postprandial levels range as high as 160 mg/dL, macrosomia rates can reach 35%.
    • In addition, there appears to be a role for excessive fetal insulin levels in mediating accelerated fetal growth. In the study by Simmons et al which compared umbilical cord sera in infants of diabetic mothers newborns and controls, the heavier, fatter babies from diabetic pregnancies were also hyperinsulinemic.¹⁹ 
  • Role of maternal obesity
  • • Maternal obesity has a strong and independent effect on fetal macrosomia. Birthweight is largely determined by maternal factors other than hyperglycemia, with the most significant influences being gestational age at delivery, prepregnancy maternal body mass index (BMI), maternal height, pregnancy weight gain, the presence of hypertension, and cigarette smoking.
    • When women who are very obese (weight >300 lb) were compared to women of normal weight, the obese women had more than double the risk of macrosomia compared to the women who were of normal weight. This may explain the failure of glycemic control to completely prevent fetal macrosomia in several series.  
• Perinatal morbidity and birth injury  
• • Perinatal mortality
  • • In diabetic pregnancy, perinatal mortality has decreased 30-fold since the discovery of insulin in 1922 and intensive obstetrical and infant care in the 1970s. Nevertheless, the current perinatal mortality rates among women who are diabetic remain approximately twice those observed in the nondiabetic population.
    • Congenital malformations, respiratory distress syndrome (RDS), and extreme prematurity account for most perinatal deaths in contemporary diabetic pregnancies.  

• • Birth injury
  • • Injuries of birth, including shoulder dystocia and brachial plexus trauma, are more common among infants of diabetic mothers, and macrosomic fetuses are at the highest risk.
    • Most of the birth injuries occurring to infants of diabetic mothers are associated with difficult vaginal delivery and shoulder dystocia. While shoulder dystocia occurs in 0.3-0.5% of vaginal deliveries among healthy pregnant women, the incidence is 2- to 4-fold higher in women with diabetes. With strict glycemic control, the birth injury rate has been shown to be only slightly higher than controls (3.2 vs 2.5%).
    • Currently, clinical ability to predict shoulder dystocia is poor. Warning signs during labor (labor protraction, suspected fetal macrosomia, need for operative vaginal delivery) successfully predict only 30% of these events.
    • Common birth injuries associated with diabetes are brachial plexus, facial nerve injury, and cephalohematoma.  
  • Polycythemia
  • • A central venous hemoglobin concentration greater than 20 g/dL or a hematocrit value greater than 65% (polycythemia) is not uncommon in infants of diabetic mothers and is related to glycemic control.
    • Hyperglycemia is a powerful stimulus to fetal erythropoietin production mediated by decreased fetal oxygen tension.
    • Untreated neonatal polycythemia may promote vascular sludging, ischemia, and infarction of vital tissues, including the kidneys and central nervous system.  
  • Hypoglycemia
  • • Approximately 15-25% of neonates delivered from women with diabetes during gestation develop hypoglycemia during the immediate newborn period.²⁰ Neonatal hypoglycemia is less frequent when tight glycemic control is maintained during pregnancy²¹ and in labor. 
    • Unrecognized postnatal hypoglycemia may lead to neonatal seizures, coma, and brain damage.
  • Neonatal hypocalcemia
  • • Up to 50% of infants of diabetic mothers have low levels of serum calcium (<7 mg/100 mL). With improved management of diabetes in pregnancy, this occurrence has been reduced to 5% or less. 
    • These changes in calcium appear to be attributable to a functional hypoparathyroidism, though the exact pathophysiology is not well understood.
  • Postnatal hyperbilirubinemia
  • • Hyperbilirubinemia occurs in approximately 25% of infants of diabetic mothers, a rate approximately double that in a healthy population. The causes of hyperbilirubinemia in infants of diabetic mothers are multiple, but prematurity and polycythemia are the primary contributing factors. Increased destruction of red blood cells contributes to the risk of jaundice and kernicterus.
    • Treatment of this complication is usually by phototherapy, but exchange transfusions may be necessary if bilirubin levels are markedly elevated.  
  • Respiratory problems
  • • Until recently, neonatal respiratory distress syndrome (RDS) was the most common and serious morbidity in infants of diabetic mothers. In the 1970s, improved prenatal maternal management for diabetes and new techniques in obstetrics for timing and mode of delivery resulted in a dramatic decline in its incidence from 31% to 3%.²² Nevertheless, respiratory distress syndrome continues to be a relatively preventable complication.
    • The majority of the literature indicates a significant biochemical and physiological delay in infants of diabetic mothers. Tyden²³ and Landon²⁴ and colleagues reported that fetal lung maturity occurred later in pregnancies with poor glycemic control regardless of class of diabetes when infants were stratified by maternal plasma glucose levels.
    • The nondiabetic fetus achieves pulmonary maturity at a mean gestational age of 34-35 weeks. By 37 weeks’ gestation, more than 99% of healthy newborn infants have mature lung profiles as assessed by phospholipid assays. However, in a diabetic pregnancy, presuming that the risk of respiratory distress has passed is unwise until after 38.5 gestational weeks have been completed.
    • Prior to contemplating any delivery before 38.5 weeks for other than the most urgent fetal and maternal indications, perform an amniocentesis to document pulmonary maturity.  
• Maternal morbidity
• • Diabetic retinopathy
  • • This is the leading cause of blindness in women aged 24-64 years. Some form of retinopathy is present in virtually 100% of women who have had type 1 diabetes for 25 years or more; of these women, approximately 1 in 5 is legally blind.
    • A prospective study showed that while half the patients with preexisting retinopathy experienced deterioration during pregnancy, all the patients had partial regression following delivery and returned to their prepregnant state by 6 months postpartum.
    • Other studies have suggested that rapid induction of glycemic control in early pregnancy stimulates retinal vascular proliferation.²⁵ However, when the total effect of pregnancy on ophthalmologic status was considered, women with pregnancies had a slower progression of retinopathy than nonpregnant women, probably because the modest deterioration in retinal status during rapid improvement in control is offset by the excellent control during the remainder of the pregnancy.
    • Current management recommendations include baseline ophthalmology referral for pregnant patients with diabetes, with follow-up according to degree of retinopathy.  
  • Renal function
  • • In general, patients with underlying nephropathy can expect varying degrees of deterioration of renal function during a pregnancy.  As renal blood flow and glomerular filtration rate increase 30-50% during pregnancy, the degree of proteinuria will also increase. 
    • The most recent studies indicate that pregnancy does not measurably alter the time course of diabetic renal disease, nor does it increase the likelihood of progression to end stage renal disease. The progression to renal disease in diabetic patients appears to be related to duration of diabetes and degree of glycemic control.
    • Patients using the subcutaneous insulin pump have lower mean glucose levels than those using intermittent injections. The effect on progression of nephropathy of 2 years of strict metabolic control showed that none of the patients managed on the insulin pump progressed to clinical nephropathy, while 5 patients with conventional treatment did.
    • Perinatal complications are greatly increased in patients with diabetic nephropathy. Preterm birth, intrauterine growth restriction, and preeclampsia are all significantly more common in women with diabetic nephropathy during pregnancy.  
  • Chronic hypertension
  • • This complicates approximately 1 in 10 diabetic pregnancies overall. Patients with underlying renal or retinal vascular disease are at a substantially higher risk, with 40% having chronic hypertension.
    • Patients with chronic hypertension and diabetes are at increased risk of intrauterine growth restriction, superimposed preeclampsia, abruptio placentae, and maternal stroke. 
    • Baseline renal function determination is recommended in all patients with preexisting diabetes. Renal function assessments in each trimester should be performed in those with overt vascular disease or who have had diabetes for more than 10 years.  
  • Preeclampsia
  • • Consists of abrupt elevation in blood pressure, significant proteinuria, plasma uric acid levels greater than 6 mg/dL or evidence of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. 
    • Preeclampsia is more frequent among women with diabetes, occurring in approximately 12% as compared to 8% of the nondiabetic population. The risk of preeclampsia is also related to maternal age and the duration of preexisting diabetes. In patients who have chronic hypertension coexisting with diabetes, preeclampsia may be difficult to distinguish from near-term blood pressure elevations.
    • The rate of preeclampsia has been found to be related to the level of glycemic control, with fasting plasma glucose (FPG) less than 105, the rate of preeclampsia was 7.8%, if FPG was greater than 105, the rate of preeclampsia was 13.8%.²⁶
    • In this same study, pregravid body mass index was also significantly related to the development of preeclampsia.

Physical

• Diagnosing diabetes
• • Patients with type 1 diabetes are typically diagnosed during an episode of hyperglycemia, ketosis, and dehydration; this occurs most commonly in childhood or adolescence, before pregnancy. Type 1 diabetes is diagnosed only rarely during pregnancy and is most often accompanied by unexpected coma because early pregnancy may provoke diet and glycemic control instability in patients with occult diabetes. A pregnancy test should be ordered in all reproductive-aged women admitted to the hospital for blood sugar management. 
  • Diagnosing type 2 insulin-resistant diabetes is difficult during pregnancy because severe forms of gestational diabetes mellitus have similar clinical characteristics. On the other hand, it is not unusual for women tentatively diagnosed with gestational diabetes mellitus in early pregnancy to be found to have overt diabetes after delivery. Although a first-trimester HbA1C value of 8% is highly suggestive of preexisting type 2 diabetes, definitive diagnosis of type 2 diabetes must be made after pregnancy using the 75-gram, 2-hour glucose tolerance test. 
  • According to the American Diabetes Association "Standards of Medical Care in Diabetes--2007,"²⁷ diagnostic criteria for diabetes mellitus are as follows, and one of the following must be met:
  • • Symptoms of diabetes and a casual plasma glucose greater than 200 mg/dL (11.1 mmol/L). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.
    • Fasting plasma glucose greater than 126 mg/dL (7.0 mmol/L).  Fasting is defined as no caloric intake for at least 8 h.
    • Two-hour plasma glucose greater than 200 mg/dL (11.1 mmol/L) during a 75 g, 2-hour oral glucose tolerance test (OGTT).
  • In the absence of unequivocal hyperglycemia with acute metabolic decompensation, the diagnosis should be confirmed by repeat testing on a different day.
  • Prediabetes is a term used to distinguish people who are at increased risk of developing diabetes. People with prediabetes have impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Some people may have both impaired fasting glucose and impaired glucose tolerance. 
  • • Impaired fasting glucose is a condition in which the fasting blood sugar level is elevated (100-125 mg/dL) after an overnight fast but is not high enough to be classified as diabetes.
    • Impaired glucose tolerance is a condition in which the blood sugar level is elevated (140-199 mg/dL after a 2-h oral glucose tolerance test) but is not high enough to be classified as diabetes.
    • Patients with prediabetes identified prior to pregnancy should be considered at extremely high risk of developing gestational diabetes mellitus during pregnancy. As such, they should receive early (first trimester) diabetic screening. Prediabetes, impaired fasting glucose, and impaired glucose tolerance are not meaningful terms in managing patients during pregnancy unless they exceed the plasma glucose limits for diagnosing gestational diabetes mellitus.  
• Screening for gestational diabetes mellitus (GDM) 
• • Gestational diabetes mellitus only occurs during pregnancy. The diagnosis is established by glucose tolerance testing.
  • Risk factors for gestational diabetes include advanced maternal age, ethnicity, obesity, obstetrical history of diabetes or macrosomia, and strong family history of diabetes. 
  • The best method for diagnosing gestational diabetes mellitus continues to be controversial. The 2-step system is currently recommended in the United States. A 50-gram 1-hour glucose challenge test (GCT) is administered to all pregnant women at 26-28 weeks, followed by a 100-gram, 3-hour oral glucose tolerance test (OGTT) for those with an abnormal screening result. Alternatively, for high risk women, a one-step approach can be used by proceeding directly to the 100-g, 3-hour OGTT. 
  • The sensitivity of gestational diabetes mellitus testing depends on the threshold value used for the 50-g glucose challenge. Current recommendations from the American Diabetes Association "Standards of Medical Care in Diabetes--2007"²⁷ and the American College of Obstetricians and Gynecologists²⁸ note that a threshold value of 140 mg/dL results in approximately 80% detection of gestational diabetes, while using a threshold of 130 mg/dL results in 90% detection. A potential disadvantage of using the lower value of 130 mg/dL is an approximate doubling in the number of OGTTs performed. 
  • Other tests (eg, maternal HbA1C, random postprandial or fasting blood sugar level, or fructosamine level) are not recommended because of low sensitivity.
  •  Oral Glucose Tolerance Test For Gestational Diabetes can be summarized as follows:
  • • One-hour 50-g glucose challenge result greater than 130 mg/dL
    • Overnight fast of 8–14 hours
    • Carbohydrate loading 3 days including more than 150 g carbohydrate
    • Seated, not smoking during the test
    • Two or more values must be met or exceeded for the diagnosis of gestational diabetes.

Table 2. Plasma Glucose Criteria for Gestational Diabetes

Time	100 g Glucose Load, mg/dL (mmol/L)
Fasting	95 (5.3)
1-h	180 (10.0)
2-h	155 (8.6)
3-h	140 (7.8)

• Screening for gestational diabetes mellitus during pregnancy is recommended because fewer than 20% of women with significant glucose intolerance during pregnancy exhibit glucosuria or other symptoms during pregnancy. However, whether universal screening of all pregnant women or targeted screening of patients with risk factors is most efficacious continues to be controversial. At present, both methods (universal and selective screening) are employed in reputable centers. In areas in which the prevalence of insulin resistance is 5% or higher (eg, the southwestern and southeastern United States), universal screening is recommended. 
• • First-trimester screening should be performed on patients with risk factors during the first trimester in order to identify those with occult type 2 diabetes. In 1995, when Moses et al assessed the prevalence of gestational diabetes mellitus in patients with various risk factors, gestational diabetes mellitus was diagnosed in 6.7% of the women overall, in 8.5% of the women aged 30 years, in 12.3% of the women with a preconception BMI of 30, and in 11.6% of women with a family history of diabetes in a first-degree relative. A combination of one or all of these risk factors predicted gestational diabetes mellitus in 61% cases. Gestational diabetes mellitus was present in 4.8% of the women without risk factors.²⁹ Screen patients with any of the following risk factors for gestational diabetes mellitus at the first prenatal visit:
  • • Maternal age older than 35 years
    • Previous infant weighing less than 4000 grams
    • Previous unexplained fetal demise
    • Previous pregnancy with gestational diabetes mellitus
    • Strong immediate family history of NIDDM or gestational diabetes mellitus
    • Obesity (>90 kg)
    • Fasting glucose value greater than 140 mg/dL (7.8 mmol/L) or random glucose value greater than 200 mg/dL (11.1 mmol/L) 
  • Patients with risk factors who have negative test results in the first trimester should be retested at 26-28 weeks. Because the insulin resistance that causes hyperglycemia becomes increasingly prevalent as the third trimester progresses, the condition may be missed during early testing on patients who will become glucose intolerant later. However, performing the test too late in the third trimester abbreviates the time in which metabolic intervention can take place. For this reason, glucose tolerance testing in all patients is typically performed at 26-28 weeks' gestation. 
  • Patients with a single abnormal value on a 3 hour glucose tolerance test are likely to exhibit some degree of glucose intolerance. When left untreated, these patients are at higher risk for macrosomia and neonatal morbidity. Consequently, patients with a single abnormal value should receive dietary and physical activity counseling. If the abnormal value on the OGTT was obtained prior to 26 weeks, repeat OGTT should be performed approximately 4 weeks later.
  • Whether administered at 12 or 26 weeks' gestation, the glucose challenge test can be performed without regard to recent food intake (ie, nonfasting state). Indeed, results from tests performed in fasting subjects are more likely to be falsely elevated than results from tests conducted between meals.³⁰

Causes

See Frequency.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• First trimester (in addition to normal prenatal laboratory tests)
• • Hemoglobin A1C
  • Blood urea nitrogen
  • Creatinine
  • Thyroid-stimulating hormone
  • Free thyroxine
  • Spot urine protein-to-creatinine ratio
  • Capillary blood sugar levels 4-7 times daily
• Second trimester
• • Repeat spot urine protein-to-creatinine study in women with elevated value in first trimester
  • Repeat HbA1C
  • Capillary blood sugar levels 4-7 times daily
• If preeclampsia is suggested
• • 24-hour urine collection
  • Blood urea nitrogen and creatinine
  • Liver function tests
  • Uric acid
  • CBC count with platelets
  • Assessment of fetal well-being with nonstress test, amniotic fluid index, fetal growth and Doppler examination of the umbilical cord and middle cerebral artery

Imaging Studies

• First trimester
• • Sonogram (crown-rump length) for dating and viability
  • Consider nuchal translucency if high risk for cardiac defects (high glycohemoglobin)
• Second trimester
• • Detailed anatomy sonogram at 18-20 weeks
  • Fetal echocardiogram if HbA1C value was elevated in first trimester
• Third trimester
• • Growth sonogram to assess fetal size every 4-6 weeks from 26-36 weeks in women with overt preexisting diabetes
  • Growth sonogram for fetal size at least once at 36-37 weeks for women with gestational diabetes mellitus (Consider performing this study more frequently if macrosomia is suggested.)

Other Tests

• Consider an ophthalmologic evaluation in the first trimester.
• If diabetes is longstanding or associated with known microvascular disease, obtain a baseline maternal ECG and echocardiogram.

Procedures

Consider an amniocentesis for fetal lung profile if delivery is contemplated prior to 39 weeks’ gestation.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Prepregnancy management of women with preexisting diabetes
• • If a reduction in diabetes-associated neonatal morbidity is to be achieved, counsel the patient before conception and perform a medical risk assessment in all women with overt diabetes and those with a history of gestational diabetes mellitus during a previous pregnancy.  
  • Key features of an effective diabetes management program
  • • Perform a thorough assessment of cardiovascular, renal, and ophthalmologic status.
    • Institute a regimen of frequent and regular monitoring of both preprandial and postprandial capillary glucose levels.
    • Controversy exists as to whether the target glucose levels to be maintained during diabetic pregnancy should be designed to limit macrosomia or to closely mimic nondiabetic pregnancy profiles. The Fifth International Workshop Conference on Gestational Diabetes³¹ currently recommends the following:
    • • Fasting plasma glucose –90-99 mg/dL (5.0–5.5  mmol/L) and
      • One-hour postprandial plasma glucose less than 140  mg/dL (7.8 mmol/L) or
      • Two-hour postprandial plasma glucose less than 120-127 mg/dL (6.7–7.1 mmol/L) 
  • • The insulin regimen should result in a smooth glucose profile throughout the day, with no hypoglycemic reactions between meals or at night. Initiate the regimen early enough before pregnancy so that the glycohemoglobin level is lowered into the reference range for at least 3 months before conception.
    • Patients should take a prenatal vitamin containing at least 1.0 mg of folic acid daily for at least 3 months prior to conception to minimize the risk of neural tube defects in the fetus.
    • The development of family, financial, and personal resources necessary to achieve successful pregnancy is important. Pay particular attention to support systems that permit extended bedrest in the third trimester if necessary. 
  • Preemptive outreach
  • • In many perinatal centers, diabetes-in-pregnancy programs focus on outreach to nonpregnant reproductive-aged women with diabetes in order to minimize the morbidity attendant to poor periconceptional control.
    • Urge nonpregnant women to continue to avoid pregnancy until their HbA1C value is in within the reference range (<6.5%).  
• Pregnancy management of women with diabetes mellitus 
• • Dietary therapy  
  • • The goal of dietary therapy is to avoid single large meals and foods with a large percentage of simple carbohydrates. A total of 6 feedings per day is preferred, with 3 major meals and 3 snacks to limit the amount of energy intake presented to the bloodstream at any interval. Examples include foods with complex carbohydrates and cellulose, such as whole grain breads and legumes.
    • Carbohydrates should account for no more than 50% of the diet, with protein and fats equally accounting for the remainder.²⁷ However, moderate restriction of carbohydrates to 35–40% has been shown to decrease maternal glucose levels and improve maternal and fetal outcomes.³²
    • Nutritional therapy should be supervised by a trained professional, ideally a registered dietitian, with formal dietary assessment and counseling provided at several points. For obese women (BMI >30 kg/m²), a 30–33% calorie restriction (to 25 kcal/kg actual weight per day or less) has been shown to reduce hyperglycemia and plasma triglycerides with no increase in ketonuria. 
  • Glucose monitoring  
  • • The availability of capillary glucose test strips has revolutionized the management of diabetes, and these should now be considered the standard of care for pregnancy monitoring. The discipline of measuring and recording blood glucose levels prior to and after meals clearly has a positive effect on improving glycemic control.
    • Individualize the frequency and timing of home glucose monitoring. A typical schedule involves capillary glucose checks upon awakening in the morning, 1 hour after breakfast, before and after lunch, before dinner, and at bedtime. Place emphasis on gaining and sustaining compliance with the target glucose levels mentioned above. Superb glycemic control requires attention to both preprandial and postprandial glucose levels.  
  • Insulin therapy  
  • • The goal of insulin therapy during pregnancy is to achieve glucose profiles similar to those of nondiabetic pregnant women. Given that healthy pregnant women maintain their postprandial blood sugar excursions within a relatively narrow range (70-120 mg/dL), the task of reproducing this profile is requires meticulous daily attention by both the patient and physician.
    • Insulins lispro, aspart, regular and NPH are well-studied in pregnancy and regarded as safe and efficacious.  Insulin glargine is less well-studied, and given its long pharmacologic effect, may exacerbate periods of maternal hypoglycemia.
    • As pregnancy progresses, the increasing fetal demand for glucose fasting and the progressive lowering of fasting and between-meal blood sugar levels increases the risk of symptomatic hypoglycemia. Upward adjustment of short-acting insulins to control postprandial glucose surges within the target band only exacerbates the tendency to interprandial hypoglycemia. Thus, any insulin regimen for pregnant women requires combinations and timing of insulin injections quite different from those that are effective in the nonpregnant state. Further, the regimens must be continuously modified as the patient progresses from the first to the third trimester and insulin resistance rises. Strive to stay ahead of the rising need for insulin, and increase insulin dosages preemptively.  
  • Insulin pump  
  • • In a select group of patients, use of an insulin pump may improve glycemic control while enhancing patient convenience. These devices can be programmed to infuse varying basal and bolus levels of insulin, which change smoothly even while the patient sleeps or is otherwise preoccupied.
    • The effectiveness of continuous subcutaneous insulin infusion in pregnancy is well established.^{33, 34} Hieronimus et al compared outcomes of 33 pregnant women managed with insulin pump to 23 receiving multiple injections, reporting similar HbA1c levels, macrosomia rates, and cesarean rates.³⁵ Lapolla et al reported a small cohort of 25 women treated with insulin pump in pregnancy compared to conventional insulin treatment (n=68) and found no³⁶ differences in glycemic control or perinatal outcome.³⁷ 
  • Oral hypoglycemic agents - Glyburide  
  • • Interest in the second-generation oral sulfonyurea, glyburide, has been rekindled following reports of its effectiveness and safety.³⁶  
    • Glyburide is minimally transported across the human placenta.  This is probably largely due to the high plasma protein binding coupled with a short half-life.^{38, 36} In addition, a human placenta perfusion study demonstrated active glyburide transport from the fetus to the mother.³⁹
    • Glyburide should not be used in the first trimester because its effects, if any, on the embryo are unknown.  Research in this area, though needed, has been difficult given the known teratogenic effects of the first generation agents, which readily crossed the placenta.
    • A randomized trial comparing glyburide to insulin was published in 2000, studying 404 pregnancies. At the conclusion of this trial, there was no difference between the groups in the mean maternal blood glucose, the percentage of infants who were large for gestational age, the birthweight, or neonatal complications. Only 4% of the glyburide study arm required addition of insulin to achieve glucose control.³⁶
    • Since this study, several prospective and retrospective studies involving more than 775 pregnancies have concluded glyburide is equally as safe and efficacious as insulin.
    • All studies comparing glyburide to traditional insulin have demonstrated similar levels of glycemic control. Most studies show no differences in maternal or neonatal outcomes with glyburide.
    • Success rates for achieving glycemic control with glyburide vary from 79-86%. Studies evaluating predictors of failure with glyburide cite the following risk factors: advanced maternal age, earlier gestational age at diagnosis, higher gravidity and parity, and higher mean fasting glucose.^{40, 41, 42, 43}
    • Glyburide has been shown to be safe in breastfeeding, with no transfer into human milk. 
  • Oral hypoglycemic agents — Metformin  
  • • Metformin is a biguanide, which functions mainly by decreasing hepatic glucose output.
    • Metformin crosses the placenta and cord levels have demonstrated even higher levels than maternal levels.⁴⁴
    • An initial retrospective study of 50 patients on metformin was concerning for increased rates of preeclampsia and perinatal mortality when metformin was used in the third trimester.⁴⁵ It should be noted that in this study the patients on metformin had a higher BMI and were also older than the patient on glyburide or insulin.
    • Since this initial study, several other prospective and retrospective studies involving over 300 patients have demonstrated similar efficacy, safety, and maternal and fetal outcomes. Subsequent studies have not confirmed the increased rates of preeclampsia or perinatal mortality.
    • There is currently an ongoing randomized controlled trial that may help answer the many questions regarding metformin use in pregnancy. 
• Peripartal management of patients and fetuses with diabetes  
• • Prenatal obstetric management 
  • • The goals of management of third-trimester pregnancies in women with diabetes are to prevent stillbirth and asphyxia, while minimizing maternal and fetal morbidity associated with delivery.
    • Monitoring fetal growth is essential to select the proper timing and route of delivery. This is accomplished by frequent testing for fetal well-being and serial ultrasound examinations to follow fetal size.
  • Periodic fetal biophysical testing  
  • • Various fetal biophysical tests are available to the clinician to ensure that the fetus is well oxygenated, including fetal heart rate testing, fetal movement assessment, ultrasound biophysical scoring, and fetal umbilical Doppler studies.
    • If applied properly, most of these can be used with confidence to provide assurance of fetal well-being while awaiting fetal maturity.

Table 3. Biophysical Tests of Fetal Well-Being for Diabetic Pregnancy  

Test	Frequency	Reassuring Result	Comment
Fetal movement counting	Every night from 28 wk	10 movements in <60 min	Performed in all patients
Nonstress test (NST)	Twice weekly	2 heart rate accelerations in 20 min	Begin at 28-34 wk with insulin-dependent diabetes, and begin at 36 wk in diet-controlled GDM.
Contraction stress test	Weekly	No heart rate decelerations in response to 3 contractions in 10 min	Same as for NST
Ultrasound biophysical profile	Weekly	Score of 8 in 30 min	3 movements = 2 1 flexion = 2 30 s breathing = 2 2 cm amniotic fluid = 2

• Initiate testing early enough to avoid significant stillbirth but not so early that a high rate of false-positive test results is encountered. In patients with poor glycemic control, intrauterine growth restriction or significant hypertension begin formal biophysical testing as early as 28 weeks. In patients who are at lower risk, most centers begin formal fetal testing by 34 weeks. Fetal movement counting is performed in all pregnancies from 28 weeks onward.
• There is no consensus regarding antenatal testing in gestational diabetes with good diet control.
• Assessing fetal growth  
• • Monitoring fetal growth continues to be a challenging and imprecise process. Although the tools available now, serial plotting of fetal growth parameters, are superior to those used previously for clinical estimations, accuracy is still only within ±15%.
  • In the obese fetus, the inaccuracies are further magnified. In 1992, Bernstein and Catalano reported that significant correlation exists between the degree of error in the ultrasound-based estimation of fetal weight and the percent of body fat on the fetus (r = 0.28, P <.05). Perhaps this is why no single formula has proven to be adequate in identifying a macrosomic fetus with certainty.
  • Despite problems with accuracy, ultrasound-based estimations of fetal size have become the standard of care. Estimate fetal size once or twice at least 3 weeks apart in order to establish a trend. Time the last examination to be at 36-37 weeks' gestation or as close to the planned delivery date as possible.  
• Timing and route of delivery  
• • Select the timing of delivery to minimize morbidity for the mother and fetus. Delaying delivery to as near as possible to the expected date of confinement helps maximize cervical maturity and improves the chances of spontaneous labor and vaginal delivery. However, the risks of advancing fetal macrosomia, birth injury, and in utero demise increase as the due date approaches.
  • Although delivery as early as 37 weeks might reduce the risk of shoulder dystocia, a concomitant increase in the incidence of failed labor inductions and poor neonatal pulmonary status would also occur. Because fetal growth from 37 weeks onward may be 100-150 g/wk, the reduction in net fetal weight and the risk of shoulder dystocia by inducing labor 2 weeks early may theoretically improve outcome.
  • In 1993, when Kjos et al compared the outcomes associated with labor induction in patients with gestational diabetes at 38 weeks versus expectant management with fetal testing, they found that expectant management increased the gestational age at delivery by 1 week, but the cesarean delivery rate was not significantly different. However, the prevalence of infants who were macrosomic in the expectantly managed group (23%) was significantly greater than those in the active induction group (10%). This suggests that routine induction of women with diabetes on or before 39 weeks' gestation does not increase the risk of cesarean delivery and may reduce the risk of macrosomia.⁴⁶
  • If the fetus is not macrosomic and results from biophysical testing are reassuring, the obstetrician can await spontaneous labor. In patients with gestational diabetes mellitus and superb glycemic control, continued fetal testing and expectant management can be considered until 41 weeks' gestation. In the fetus with an abdominal circumference significantly larger than the head circumference or an estimated fetal weight above 4000 grams, consider induction. After 40 or more weeks, the benefits of continued conservative management are likely to be less than the danger of fetal compromise. Induction of labor before 41 weeks' gestation in pregnant women with diabetes, regardless of the readiness of the cervix, is prudent.
  • An optimal time for delivery of most diabetic pregnancies is typically on or after the 39th week. Deliver a patient with diabetes before 39 weeks' gestation without documented fetal lung maturity only for compelling maternal or fetal indications. For elective induction prior to 38.5 weeks, fetal lung maturity should be verified via amniocentesis.
  • Because the risk of shoulder dystocia and fetal injury in labor is increased 3-fold in diabetic pregnancy, elective cesarean section should be considered if the fetus is suspected to be significantly obese. The American College of Obstetricians and Gynecologists recommends offering diabetic patients cesarean delivery if the fetal weight is estimated to be 4500 grams or more. 

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Clinicians and gestational diabetes mellitus patients are reluctant to start insulin therapy, but it is key to achieving a good outcome. Research suggests that early intervention with insulin or glyburide is superior to diet therapy alone. Determine the choice of insulin and regimen based on the patient's individual glucose profile. Postprandial glucose levels become consistently above the target with diet therapy. When more than 20% of postprandial blood glucose levels exceed 130 mg/dL, administer lispro insulin (4-8 U SC initially) before meals. If more than 10 U of regular insulin is needed before the noon meal, adding 8-12 U of NPH insulin before breakfast helps achieve control. When more than 10% of fasting glucose levels exceed 95 mg/dL, initiate 6-8 U NPH insulin hs. Titrate doses prn according to blood glucose levels.

Drug Category: Insulins

Essential in regulating carbohydrate, protein, and fat metabolism. Primarily affect carbohydrate homoeostasis by binding to specific cell-surface receptors on insulin-sensitive tissues (eg, liver, muscles, adipose tissue).