Posts filed under 'Diabetes Mellitus and Pregnancy'
Diabetes Mellitus and Pregnancy
Synonyms and related keywords: gestational diabetes mellitus, gestational diabetes, GDM, infants of diabetic mothers, IDMs, infant of diabetic mother, IDM, maternal hyperglycemia, fetal hyperglycemia, diabetes in pregnancy, diabetes-associated birth defects, diabetic birth defects, gestational DM, macrosomia, macrosomic infant, macrosomic fetus, diabetic pregnancy, fetal macrosomia
INTRODUCTION Depending on the specific population, abnormal maternal glucose regulation occurs in 3-10% of pregnancies. Recent studies suggest that the prevalence of diabetes among women of childbearing age is increasing in the United States. This increase is believed to be attributable to (1) more sedentary lifestyles, (2) changes in diet, (3) continued immigration from high-risk populations, and (4) the virtual epidemic of childhood and adolescent obesity presently evolving in United States. Although 80% or more of this glucose intolerance during pregnancy occurs in women with gestational diabetes mellitus (GDM), the associated fetal and newborn morbidity rates are disproportionate. 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. Recent studies indicate that the risk of these morbidities in individual cases is proportional to the degree of maternalhyperglycemia. For this reason, the excessive fetal and neonatal morbidity attributable to diabetes in pregnancy should be considered preventable. Maternal-fetal metabolism in normal pregnancy With each feeding, the pregnant woman undergoes a complex series of maternal hormonal actions, including a rise in blood glucose and 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:
Background
Pathophysiology
During a healthy pregnancy, mean fasting blood sugar levels decline progressively to a remarkably low value of 74 ± 2.7 (standard deviation) 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 rate of macrosomia. Specifically, when 2-hour postprandial glucose levels are maintained at 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, 17 million people (6.2% of the population) have some form of diagnosed diabetes. Another 6 million people may be undiagnosed. Approximately 4-6% of pregnancies in the United States are complicated by diabetes, of which 90% is gestational diabetes and 3% is type 2 diabetes (ie, preexisting, insulin-resistant, or adult-onset diabetes). The prevalence of type 2 diabetes is increasing markedly in the United States, probably related to rising population obesity and shifts in ethnicity.
Race
The prevalence of gestational diabetes is strongly related to the patient’s race and culture.
- Typically, only 1.5-2% of white persons from the midwestern United States develop GDM, while American Indians from the southwestern United States may have rates as high as 15%.
- In Hispanic, African American, and Asian populations, the rate is 5-8%.
CLINICAL
History
- Current data suggest a strong association between the degree of glycemic control prior to pregnancy and the miscarriage rate. Relaxed glycemic control has been shown to double the miscarriage rate. In addition, more advanced diabetes and miscarriage rates are correlated.
- Patients with long-standing diabetes (glycohemoglobin exceeding 11%) have been shown to have miscarriage rates of up to 44%. Conversely, recent reports demonstrate a normalization of the miscarriage rate with excellent glycemic control.
- 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.
- Most lesions involve the central nervous and cardiovascular systems.
- The fact that no increase in birth defects occurs among the offspring of fathers who are diabetic, women who are prediabetic, and women who develop gestational diabetes after the first trimester is notable. This suggests that periconceptional glycemic control is the main factor in the genesis of diabetes-associated birth defects.
- 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 (HbA1C) values 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 an infant who is malformed was comparable to a normal population when the HbA1C value was less than 7%.
- Because birth defects occur during the critical time 3-6 weeks after conception, preconceptionally institute nutritional and metabolic intervention. Clinical trials of metabolic care have demonstrated that normal malformation rates can be achieved with meticulous periconceptional glycemic control (Fuhrmann, 1983). Subsequent trials comparing a preconceptional intensive metabolic program to standard treatment over 15 years’ duration have demonstrated lower perinatal mortality (0% vs 7%) and congenital anomaly rates (14% to 2%). In addition, when the preconceptional counseling program was discontinued, the congenital anomaly rate increased by more than 50%.
- Although most fetuses of diabetic mothers exhibit growth acceleration, growth restriction occurs with significant frequency in pregnancies complicated by 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.
- Excessive body fat stores, stimulated by excessive glucose delivery during diabetic pregnancy, often extend into childhood and adult life.
- The adverse downstream effects of deranged maternal metabolism have been documented well into puberty. Glucose intolerance and higher serum insulin levels are more frequent in offspring of diabetic mothers compared with normal controls. By age 10-16 years, offspring of diabetic mothers have a 19.3% rate of impaired glucose intolerance.
- Macrosomia is typically defined as a birthweight above the 90th percentile for gestational age or greater than 4000 g. 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 type 1 diabetes mellitus 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.
- Birth injury, including shoulder dystocia and brachial plexus trauma, is more common among IDMs, and macrosomic fetuses are at the highest risk.
- The macrosomic fetus 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 with nondiabetic control infants of similar weights.
- When serial ultrasound examination findings from diabetic fetuses are plotted, the growth velocity of the abdominal circumference is well above the growth velocity seen in nondiabetic fetuses and is higher than the growth pattern for the fetal head and femur of diabetic fetuses. The abdominal circumference growth begins to rise significantly above normal after 24 weeks.
- Excess nutrient delivery to the fetus causes macrosomia, but whether fasting or peak glucose values are more correlated with fetal overgrowth is less clear.
- Data from the Diabetes in Early Pregnancy (DIEP) study indicate that fetal birthweight correlates best with second- and third-trimester postprandial blood sugar levels and not with fasting or mean glucose levels.
- 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, excessive fetal insulin levels appear to play some role in mediating excessive fetal growth, as shown in the 1995 study by Simmons, who compared umbilical cord sera in newborn IDMs and normal newborns. Simmons found that the heavier, fatter babies from diabetic pregnancies were also hyperinsulinemic.
- 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 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 with women of normal weight, the former had more than double the risk of macrosomia compared with the women who were of normal weight. This may explain the failure of glycemic control to completely prevent fetal macrosomia in several series.
- 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 diabetic women 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.
Table 1. Perinatal Morbidity Rates in Diabetic Pregnancy
Morbidity Gestational Diabetes Type 1 Diabetes Type 2 Diabetes Hyperbilirubinemia 29% 55% 44% Hypoglycemia 9% 29% 24% Respiratory distress 3% 8% 4% Transienttachypnea 2% 3% 4% Hypocalcemia 1% 4% 1% Cardiomyopathy 1% 2% 1% Polycythemia 1% 3% 3% Adapted from California Department of Health Services, 1991
- Birth injury
- Injuries of birth, including shoulder dystocia and brachial plexus trauma, are more common among IDMs, and macrosomic fetuses are at the highest risk.
- Most of the birth injuries occurring to IDMs 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 rate 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, the ability to predict shoulder dystocia clinically is poor. Warning signs during labor (eg, labor protraction, suspected fetal macrosomia, need for forceps delivery) successfully predict only 30% of these events.
- Common birth injuries associated with diabetes are brachial plexus trauma, 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 IDMs 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
- Hyperinsulinemic IDMs are at increased risk for hypoglycemia after birth, especially those born from mothers with poor glycemic control. The strongest predictor for neonatal hypoglycemia is the mean maternal glucose level during labor. This complication is usually much milder and less common in infants who have mothers who are diabetic; insulin-dependent; and well controlled throughout the entire pregnancy, labor, and delivery.
- Unrecognized postnatal hypoglycemia may lead to neonatal seizures, coma, and brain damage.
- Neonatal hypocalcemia
- Up to 50% of IDMs have low levels of serum calcium (less than 7 mg/100 mL). With improved management of diabetes in pregnancy, this rate has been reduced to 5% or less.
- These changes in calcium appear to be attributable to a functional hypoparathyroidism, although the exact pathophysiology is not well understood.
- Postnatal hyperbilirubinemia
- Hyperbilirubinemia occurs in approximately 25% of IDMs, a rate approximately double that in a normal population. The causes of hyperbilirubinemia in IDMs 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.
- The treatment of this complication is usually phototherapy, but exchange transfusions may be necessary if bilirubin levels are markedly elevated.
- Respiratory problems
- Until recently, neonatal RDS was the most common and serious morbidity in IDMs. 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% (Taeusch, 1979). Nevertheless, RDS continues to be a relatively preventable complication.
- 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’ gestation for other than the most urgent fetal and maternal indications, perform an amniocentesis to document pulmonary maturity.
- 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, such as the 1995 study by Hopp et al, have suggested that rapid induction of glycemic control in early pregnancy stimulates retinal vascular proliferation. However, when the total effect of pregnancy on ophthalmologic status was considered, pregnant women 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 referral to an ophthalmologist for baseline studies for pregnant patients with diabetes, with follow-up according to the 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 the glomerular filtration rate increase 30-50% during pregnancy, the degree of proteinuria also increases.
- The most recent studies indicate that pregnancy does not measurably alter the time course of diabetic renal disease and it does not increase the likelihood of progression to end-stage renal disease. The progression to renal disease in diabetic patients appears to be related to the 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 nephropathy progression with 2 years of strict metabolic control showed that none of the patients using the insulin pump progressed to clinical nephropathy, while 5 patients using 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 patients with overt vascular disease or those who have had diabetes for more than 10 years.
- Preeclampsia
- Patient symptomology includes abrupt elevation in blood pressure, significant proteinuria, plasma uric acid levels greater than 6 mg/dL, or evidence of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome.
- Preeclampsia is more frequent among women with diabetes, occurring in approximately 12%, compared with 8% in 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 onset typically is insidious and not confidently recognized until it is severe.
Physical
- Diagnosing diabetes
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- 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 diabetes mellitus is very difficult during pregnancy because severe forms of GDM have similar clinical characteristics. On the other hand, it is not unusual for women tentatively diagnosed with GDM 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-g, 2-hour glucose tolerance test.
- The American Diabetes Association 2002 diagnostic criteria for diabetes mellitus, of which only one of the following must be met, are as follows:
- Symptoms of diabetes and a casual plasma glucose level of greater than 200 mg/dL (11.1 mmol/L): Casual is defined as any time of the day without regard to time since the patient’s last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.
- Fasting plasma glucose level of greater than 126 mg/dL (7 mmol/L): Fasting is defined as no energy (caloric) intake for at least 8 hours.
- Two-hour plasma glucose level 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 IFG and IGT.
- IFG 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.
- IGT is a condition in which the blood sugar level is elevated (140-199 mg/dL) after a 2-h OGTT 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 GDM during pregnancy. As such, they should receive early (first trimester) diabetic screening. Prediabetes, IFG, and IGT are not meaningful terms in treating patients during pregnancy unless they exceed the plasma glucose limits for the diagnosis of GDM.
- Screening for gestational diabetes
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- GDM 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 GDM continues to be controversial. The 2-step system is currently recommended in the United States. A 50-g, 1-hour screening test is administered to all pregnant women at 26-28 weeks’, followed by a 100-g, 3-hour OGTT for those with an abnormal screening result. Alternatively, a 1-step, 75-g, 2-hour test can be administered. Other measurements (eg, maternal HbA1C, random postprandial or fasting blood sugar level, fructosamine level) are not recommended because of low sensitivity.
- OGTT prerequisites for gestational diabetes are as follows:
- One-hour, 50-g glucose challenge result greater than 135 mg/dL
- Overnight fast of 8-14 hours
- Carbohydrate loading for 3 days (>150 g carbohydrates)
- Seated and not smoking during the test
- Two or more values met or exceeded
- Either a 2-hour (75 g of glucose) or 3-hour (100 g of glucose) test
- Plasma glucose criteria for gestational diabetes are as follows:
- Fasting test
- With glucose load of 100 g, result of 95 mg/dL (5.3 mmol/L)
- With glucose load of 75 g, result of 95 mg/dL (5.3 mmol/L)
- One-hour test
- With glucose load of 100 g, result of 180 mg/dL (10 mmol/L)
- With glucose load of 75 g, result of 180 mg/dL (10 mmol/L)
- Two-hour test
- With glucose load of 100 g, result of 155 mg/dL (8.6 mmol/L)
- With glucose load of 75 g, result of 155 mg/dL (8.6 mmol/L)
- Three-hour test – With glucose load of 100 g, result of 140 mg/dL (7.8 mmol/L)
- Fasting test
- Screening for GDM during pregnancy is recommended because less 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 used 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 the risk factors noted above during the first trimester in order to identify those with occult type 2 diabetes. In 1995 when Moses et al assessed the prevalence of GDM in patients with various risk factors, GDM 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 GDM in 61% cases. GDM was present in 4.8% of the women without risk factors. Screen patients with any of the following risk factors for GDM at the first prenatal visit.
- Maternal age older than 35 years
- Previous infant weighing less than 4000 g
- Previous unexplained fetal demise
- Previous pregnancy with GDM
- Strong immediate family history of type 2 diabetes mellitus or GDM
- 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)
- For third-trimester screening, patients with risk factors who have negative test results in the first trimester should be retested at 26-28 weeks’ gestation. 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 be instituted. 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 be followed appropriately with a second screening.
- 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, according to Coustan et al in 1986, results from tests performed in fasting subjects are more likely to be falsely elevated than results from tests conducted between meals.
DIFFERENTIALS
Acute Abdomen and Pregnancy
Acute Renal Failure
Acute Respiratory Distress Syndrome
Acute Tubular Necrosis
Appendicitis
Autoimmune Thyroid Disease and Pregnancy
Cholecystitis
Cholelithiasis
Chronic Renal Failure
Diabetes Mellitus, Type 1
Diabetes Mellitus, Type 2
Diabetic Foot Infections
Diabetic Ketoacidosis
Diabetic Nephropathy
Diabetic Ulcers
Early Pregnancy Loss
Fetal Growth Restriction
Hypertension
Hypoglycemia
Pulmonary Edema, Cardiogenic
WORKUP
Lab Studies
- Repeat 24-hour urine studies in women with elevated creatinine value in first trimester or 24-hour protein or creatinine clearance less than 100 mL/min
- Repeat HbA1C
- Blood sugar levels from capillary device 4-7 times daily in all women with diabetes
- Repeat 24-hour urine studies
- 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 – Ultrasonogram (crown-rump length) for dating and viability
- Second trimester
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- Detailed anatomy ultrasonogram at 18-20 weeks’ gestation
- Fetal echocardiogram if HbA1C value was elevated in first trimester
- Third trimester
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- Growth ultrasonogram to assess fetal size every 4-6 weeks from 26-36 weeks’ gestation in women with overt preexisting diabetes
- Growth ultrasonogram for fetal size at least once at 36-37 weeks’ gestation for women with GDM (Consider performing this study more frequently if macrosomia is suggested.)
Other Tests
- First trimester – Ophthalmologic evaluation
Procedures
- Third trimester – Amniocentesis for fetal lung profile if delivery is contemplated prior to 39 weeks’ gestation
TREATMENT
Medical Care
- 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.
- Whether the target glucose levels to be maintained before and during a diabetic pregnancy should be designed to limit macrosomia or to closely mimic nondiabetic pregnancy profiles remains controversial. As reported by Jovanovic-Peterson et al in 1991, the American Diabetes Association currently recommends the following, based on evidence from the DIEP study, to limit fetal macrosomia:
- Fasting whole blood glucose level less than 95 mg/dL (5.3 mmol/L)
- Fasting plasma glucose level less than 105 mg/dL (5.8 mmol/L)
- One-hour postprandial whole blood glucose level of less than 140 mg/dL (7.8 mmol/L)
- One-hour postprandial plasma glucose less than 155 mg/dL (8.6 mmol/L)
- Alternatively, the American Diabetes Association (also based on the DIEP study) recommends the following:
- Fasting whole blood glucose level less than 95 mg/dL (5.3 mmol/L)
- Fasting plasma glucose level less than 105 mg/dL (5.8 mmol/L)
- Two-hour postprandial whole blood glucose level less than 120 mg/dL (6.7 mmol/L)
- Two-hour postprandial plasma glucose level less than 130 mg/dL (7.2 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 mg/d folic acid 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 bed rest in the third trimester if necessary.
- 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 patients to continue avoidance of pregnancy until their HbA1C value is in within the reference range (less than 6.5%).
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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.
- According to the American Diabetes Association report from 2002, carbohydrates should account for no more than 50% of the diet, with protein and fats equally accounting for the remainder. However, Major et al reported in 1998 that moderate restriction of carbohydrates to 35-40% has been shown to decrease maternal glucose levels and improve maternal and fetal outcomes.
- Nutritional therapy should be supervised by a trained professional, ideally a registered dietitian, with formal dietary assessment and counseling provided at several points. For women who are obese (BMI >30 kg/m2), a 30-33% energy restriction (to £105 kJ/kg/d [25 kcal/kg/d] actual weight) has been shown to reduce hyperglycemia and plasma triglyceride levels with no increase in ketonuria.
- Glucose monitoring
- The availability of capillary, glucose, and chemical 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. Meticulous 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 requires meticulous daily attention by both the patient and physician.
- 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 insulin 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 continually 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.
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Unique pathophysiological features
- Women with GDM present particular challenges to the clinician because they have their metabolic disorder for a limited time and may not appreciate the potential risks to their fetus (ie, macrosomia, hypoglycemia, poor neonatal transition). For this reason, early and thorough education about the effects of their disordered metabolism on fetal growth and oxygenation is necessary.
- Once the patient understands the benefits of maintaining excellent glucose control for approximately 10 weeks, compliance markedly improves.
- Dietary therapy
- Metabolic management of a patient with GDM is focused on dietary control, regular home glucose monitoring, and judicious use of insulin therapy.
- Most patients with GDM diagnosed in the third trimester can maintain 1-hour postprandial blood glucose levels less than 130 mg/dL via diet manipulation alone (ie, multiple, small, nonglycemic meals and increased exercise).
- Glucose monitoring
- A home glucose monitor is essential to assist the patient in choosing the types and timing of food ingestion. For the first 1-2 weeks, the patient should perform capillary glucose checks upon awakening (fasting) and 1 hour after each major meal. Midmorning, midafternoon, and bedtime snacks are essential to blunt the glucose surge occurring after meals.
- Once the patient has demonstrated success in controlling postprandial glucose with diet, the occurrence of abnormal fasting levels is exceedingly rare and the morning checks can be discontinued. Fasting checks are reinstituted if any postprandial glucose levels are abnormal.
- Insulin therapy
- Clinicians and GDM patients may be reluctant to start insulin therapy, but this intervention may be key in achieving a good outcome.
- Recent research from a study in which randomized subjects with GDM whose fetuses had abdominal circumferences above the 75th percentile either dieted or took twice-daily insulin therapy suggests that the earlier insulin therapy is started, the better the outcome. Although the gestational age at delivery was similar in insulin- and diet-treated groups, birth weights (3647 ± 67 g vs 3878 ± 84 g; P less than .02), the prevalence of infants who were large for gestational age (13% vs 45%, P less than .02), and neonatal skin-fold measurements at 3 sites (P less than .005) were reduced in the insulin-treated group.
- In a historical control study of early aggressive insulin treatment of patients with GDM, fasting or postprandial glucose values exceeded 120 mg/dL when the patient exceeded 90 mg/dL. In 1992, the prevalence of macrosomia decreased from 18% to 7% and the cesarean delivery rate dropped from 30% to 20%. A policy of insulin treatment was estimated to save more than $800,000 yearly in one county.
- Determine the insulin regimen based on the patient’s individual glucose profile. Typically, one to several postprandial glucose levels become consistently above target because the patient’s ability to compensate for rising insulin resistance with diet becomes inadequate. When more than 20% of postprandial blood sugar values exceed 130 mg/dL, administering rapid-acting lispro or aspart insulin injections (4-8 U to start) before meals is usually successful in controlling glucose overshoots. If more than 10 U of short-acting insulin is needed prior to the noon meal, adding an 6-12 U dose of neutral protamine Hagedorn (NPH) insulin prior to breakfast helps achieve smoother control. When more than 10% of fasting glucose levels rise above 95 mg/dL, a starting dose of 6-8 U of NPH insulin at bedtime can be used.
- The doses are scaled up as necessary once or twice weekly to keep glucose levels on target.
- 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 that change smoothly even while the patient sleeps or is otherwise preoccupied.
- Although an early study cited improved control, it also noted at least one major complication (eg, diabetic ketoacidosis, infection, hypoglycemic coma) in 42% of patients. Subsequent studies have been more optimistic, reporting more uniformly successful outcomes.
- Oral hypoglycemic agents
- Interest in the second-generation oral sulfonylurea, glyburide, has been rekindled following recent reports of its effectiveness and safety.
- Glyburide minimally transports across the human placenta. This is probably largely due to the high plasma protein binding coupled with a short half-life.
- The results of a randomized trial comparing glyburide with insulin were published in 2000, studying 404 pregnancies. At the conclusion of this trial, no difference was noted in the mean maternal blood glucose level, the percentage of infants who were large for gestational age, the birthweight, or neonatal complications between the groups. Only 4% of the glyburide study arm required the addition of insulin to achieve glucose control.
- Glyburide should not be used in the first trimester because its effects on the embryo, if any, are unknown.
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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 for trending of 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 2. 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 less than 60 min Performed in all patients Nonstress test Twice weekly 2 heart rate accelerations in 20 min Begin at 28-34 wk with type 1 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 nonstress test Ultrasound biophysical profile Weekly Score of 8 in 30 min 3 movements = 2 1 flexion = 2
30 seconds of breathing = 2
2 cm of 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 or significant hypertension, begin formal biophysical testing as early as 28 weeks’ gestation. In patients who are at lower risk, most centers begin formal fetal testing by 34 weeks’ gestation. Fetal movement counting is performed in all pregnancies from 28 weeks onward.
- Assessing fetal growth
- Monitoring fetal growth continues to be a challenging and imprecise process. Although the tools available now (eg, serial plotting of fetal growth parameters) are superior to those used previously for clinical estimations, accuracy is still only plus or minus 15%.
- In 1994, Tongsong et al reported on several polynomial formulas using combinations of head, abdominal, and limb measurements that were developed to predict the weight of a macrosomic fetus from ultrasound parameters. Unfortunately, in these formulas, small errors in individual measurements of the head, abdomen, and femur are typically compounded.
- In obese fetuses, the inaccuracies are further magnified. In 1992, Bernstein and Catalano reported significant correlation 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 less than .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.
- 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’ gestation might reduce the risk of shoulder dystocia, a coinciding increase in the incidence of failed labor inductions and poor neonatal pulmonary status would also occur. Because fetal growth from 37 weeks’ gestation 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’ gestation 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 for women with diabetes on or before 39 weeks’ gestation does not increase the risk of cesarean delivery and may reduce the risk of macrosomia
- If the fetus is not macrosomic and results from biophysical testing are reassuring, the obstetrician can await spontaneous labor. In patients with GDM and superb glycemic control, continued fetal testing and expectant management can be considered until 41 weeks’ gestation. In a fetus with an abdominal circumference measurably larger than the head circumference or with an estimated fetal weight of greater than 4000 g, consider induction. After 40 or more weeks’ gestation, 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
- Thus, an optimal time for delivery of most diabetic pregnancies is typically on or after the 39th week. Only deliver a patient with diabetes before 39 weeks’ gestation without documented fetal lung maturity for compelling maternal or fetal indications. For elective induction, 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 delivery 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 g or more.
MEDICATION
Clinicians and GDM 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).
| Drug Name | Insulin (Novolin, Humulin, Humalog, Novolog, Lente, Iletin, NPH) |
|---|---|
| Description | DOC for all types of diabetes mellitus during pregnancy. Stimulates proper use of glucose by cells and reduces blood glucose levels. |
| Adult Dose | 0.5-1 U/kg/d SC in divided doses; base dose on IBW; titrate dose to maintain a premeal and bedtime glucose level of 80-110 mg/dL; combine short- and longer-acting insulin to maintain blood glucose within target |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity; hypoglycemia |
| Interactions | Medications that may decrease hypoglycemic effects include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin Medications that may increase hypoglycemic effects include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone |
| Pregnancy | B – Usually safe but benefits must outweigh the risks. |
| Precautions | Hyperthyroidism may increase renal clearance, and more may be needed to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments may be necessary in patients diagnosed with renal and hepatic dysfunction |
| Drug Name | Glyburide (Micronase, DiaBeta, Glynase, PresTab) |
|---|---|
| Description | Appears to acutely lower blood glucose by stimulating release of insulin from pancreas, an effect dependent on functioning beta cells in pancreatic islets. Mechanism by which DiaBeta lowers blood glucose during long-term administration not clearly established. |
| Adult Dose | No fixed dosage; fasting blood glucose must be measured periodically to determine minimum effective dose 2.5-5 mg/d PO, with breakfast or first may meal, is usual starting dose; not to exceed 20 mg/d PO; patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg/d PO |
| Pediatric Dose | Not established. |
| Contraindications | Documented hypersensitivity; diabetic ketoacidosis, with or without coma; type 1 diabetes mellitus |
| Interactions | Clofibrate, fenfluramine, histamine H2 antagonists, androgens, azole antifungals, anticoagulants, chloramphenicol, fluconazole, gemfibrozil, magnesium salts, methyldopa, MAOIs, probenecid, salicylates, sulfinpyrazone, urinary acidifiers, NSAIDs, and sulfonamides may enhance hypoglycemic effects; closely observe patient for hypoglycemia; when such drugs are withdrawn, closely observe patient for loss of control Possible interaction between glyburide and fluoroquinolone antibiotics has been reported, resulting in potentiation of hypoglycemic action of glyburide; mechanism not known Possible interactions between glyburide and coumarin derivatives have been reported that may either potentiate or weaken effects of coumarin derivatives; mechanism not known Nicotinic acid, oral contraceptives, isoniazid, hydantoins, estrogens, diazoxide, corticosteroids, cholestyramine, beta-blockers, calcium channel blockers, phenothiazines, rifampin, thiazide diuretics, urinary alkalinizers, and sympathomimetics may decrease hypoglycemic effects; closely monitor patient for loss of control; when withdrawn, closely observe patient for hypoglycemia Potential interaction between PO miconazole and PO hypoglycemic agents leading to severe hypoglycemia has been reported; whether interaction also occurs with IV, topical, or vaginal preparations of miconazole is not known May increase effects of digitalis glycosides |
| Pregnancy | C – Safety for use during pregnancy has not been established. |
| Precautions | Caution in hepatic and renal impairment; cardiovascular disorders may occur; risk factors include elderly age, malnutrition, irregular eating, impaired renal function, and possibly hepatic dysfunction (if prolonged or recurrent, hospital admission should be strongly considered); may cause rash; nausea, vomiting, leukopenia, agranulocytosis, aplastic anemia (very rare), intrahepatic cholestasis (very rare), disulfiram reaction, flushing, headache, nausea, and SIADH causing hyponatremia |
FOLLOW-UP
Further Inpatient Care
- Maintenance of intrapartum metabolic homeostasis optimizes postnatal infant transition by reducing neonatal hyperinsulinemia and subsequent hypoglycemia.
- The use of a combined insulin and glucose infusion during labor to maintain maternal blood sugars in a narrow range (80-110 mg/dL) during labor is a common and clinically efficient practice. Typical infusion rates are 5% dextrose in Ringer lactate solution at 100 mL/h and regular insulin at 0.5-1.0 U/h. Capillary blood sugar levels are monitored hourly in these patients.
- For patients with diet-controlled GDM or mild type 2 diabetes, avoiding dextrose in all intravenous fluids normally maintains excellent blood glucose control. After 1-2 hours of monitoring, typically no further assessments of capillary blood sugar are necessary.
- The most critical metabolic problem affecting IDMs is hypoglycemia. Unmonitored and uncorrected hypoglycemia can lead to neonatal seizures, brain damage, and death. The strongest predictor of neonatal hypoglycemia is the maternal mean blood glucose level during labor.
- IDMs also appear to have disorders of both catecholamine and glucagon metabolism and have a diminished capability to mount normal compensatory responses to hypoglycemia.
- Thus, current recommendations specify frequent blood glucose checks and early oral feeding when possible (ideally from the breast), with infusion of intravenous glucose if oral measures prove insufficient. Most neonatologists maintain strict monitoring of the glucose levels of newborn IDMs for at least 4-6 hours (frequently 24 h), often necessitating admission to a newborn special care unit.
- Current evidence indicates that with proper encouragement, sustained breastfeeding is possible for a significant proportion of patients with overt diabetes. In fact, recent evidence indicates that breastfed infants have a much lower risk of developing diabetes than those exposed to cow’s milk proteins.
- Recent studies of breastfeeding women with diabetes indicate that lactation, even for a short duration, also has a beneficial effect on overall maternal glucose and lipid metabolism. For postpartum women who had GDM during their pregnancies, breastfeeding may offer a practical low-cost intervention that helps reduce or delay the risk of subsequent diabetes in women with prior GDM.
- In 1995, Webster et al longitudinally compared breastfeeding habits among women with diabetes and without diabetes. At discharge, 63% of IDMs and 78% of mothers without an IDM were breastfeeding. At 8 weeks, the proportions of each were nearly identical (58% and 56%, respectively). At 3 months, 47% of mothers with diabetes and 33% mothers without diabetes continued to breastfeed.
- Intensive management of women with glucose intolerance during pregnancy has resulted in markedly improved outcomes in recent years. Despite these advances, care of the infant of a mother with diabetes continues to require vigilance and meticulous monitoring with a full understanding of the quality of glycemic milieu in which it developed.
Deterrence/Prevention
- Prevention of gestational diabetes is an attractive concept, but no progress has been made, despite attempts in smaller studies. Because body fat and diet contribute to the risk of GDM, patients who lose weight prior to pregnancy and follow an appropriate diet may lower their risk of GDM. However, the pregnancy hormones impose such a high degree of insulin resistance that in very susceptible individuals, even marked weight loss and attention to diet are not likely to be successful.
Patient Education
- Education is the cornerstone of effective metabolic management of the patient with diabetes during pregnancy. The American Diabetes Association offers educational curricula specific to each type of diabetes encountered during pregnancy (type 1 diabetes mellitus, type 2 diabetes mellitus, GDM), specifically organized around each phase of pregnancy. This information can be transmitted to the patient by office staff and labor/delivery nurses. However, specially trained and certified nurses and dietitians (ie, certified diabetes educators) are the most effective in this regard. Most large programs treating women with diabetes during pregnancy assist the patient with a staff that includes a registered nurse, a certified diabetes educator, a dietitian knowledgeable about pregnancy, and a social worker. Successful management of diabetic pregnancy is optimized when this type of team care is available.
- The diabetes-in-pregnancy team is also able to help the patient during the puerperal period with the challenges of lactation, diet, sleep, and glycemic control. This team is also most effective in providing a smooth return to nonpregnant metabolic management.
- For excellent patient education resources, visit eMedicine’s Diabetes Center or Pregnancy and Reproduction Center.
MISCELLANEOUS
Medical/Legal Pitfalls
- Structural defects occur in 3-8% of offspring of diabetic pregnancy, but this rate drops 3- to 4-fold if excellent glycemic control is maintained during the period of embryogenesis.
- Thus, it is incumbent upon the medical provider, when discussing pregnancy plans with a woman with preexisting diabetes, to mention the preventability of these birth defects with good periconceptional glycemic control.
- The patient should be advised to use a reliable method of contraception until she has achieved a preconceptional HbA1C level within the reference range. This counseling should be recorded in the patient’s medical record.
- Permanent palsy of the arm and hand after a difficult delivery of an obese fetus usually leads to litigation and, in some cases, large judgments. Although current scientific data establishing the foreseeability and preventability of these injuries remain inadequate, defending obviously high-risk cases can be difficult.
- The obstetrician managing the patient’s third-trimester prenatal care and labor may be judged at fault should an injury occur during delivery if an ultrasound suggests that fetal weight exceeds 10 lb, labor proceeds slowly, or a difficult forceps or vacuum procedure is necessary to deliver the fetal head. Thus, obtaining an ultrasound-based estimation of fetal weight in the last 2-3 weeks prior to delivery and offering cesarean delivery to a patient with an estimated fetal weight of more than 4500 g or a labor course that is protracted such that she is unable to expel the fetal head spontaneously after 2-3 hours of pushing effort are prudent.
Add comment February 1, 2007
