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Current Concepts




ESTATIONAL diabetes mellitus is defined as glucose intolerance that is first detected during pregnancy.1 This simple definition belies the complexity of a condition that spans a spectrum of glycemia, pathophysiology, and clinical effects and for which there is a wide diversity of opinion regarding detection and clinical management. There is convincing evidence that mild maternal hyperglycemia is a risk factor for fetal morbidity,2 but that morbidity occurs only in a minority of cases. Failure to recognize and treat the condition will result in unnecessary morbidity in some pregnancies, whereas overly aggressive approaches to detection and treatment will result in unneeded interventions in many others. We will review current recommendations for the detection and treatment of gestational diabetes, with an emphasis on risk stratification to minimize both undertreatment and overtreatment of individual women.

The risks to the fetus increase in a continuous fashion with increasing maternal glycemia.2-4 Thus, there is no threshold of glycemia that discriminates clearly between low-risk and high-risk pregnancies. The diagnostic criteria for gestational diabetes could be set high to identify only very-high-risk pregnancies (and miss some at-risk pregnancies) or low to identify all at-risk pregnancies (and many no-risk pregnancies). The latter approach was adopted by the Fourth International Workshop-Conference on Gestational Diabetes Mellitus1 and is described below.

Screening procedures identify pregnant women who are at sufficient risk to warrant a diagnostic test, the oral glucose-tolerance test. Screening of all pregnant women by measurement of serum or plasma glucose between 24 and 28 weeks of gestation has been recommended widely.5,6 However, some wom-

en have clinical characteristics that indicate such a low risk of gestational diabetes that screening may not be warranted.1,7,8 Other women have high-risk characteristics that warrant screening early in pregnancy. Accordingly, screening for gestational diabetes should include an assessment of the clinical characteristics of all pregnant women to determine the risk of gestational diabetes (Table 1) and serum glucose screening in women who do not have a low-risk clinical profile (Table 2).1 The initial clinical assessment should be made at the first antepartum visit. Women with high-risk clinical characteristics should then undergo glucose screening as soon as possible. A 50-g oral glucosechallenge test9-11 is usually recommended for this purpose, followed by an oral glucose-tolerance test if the serum glucose concentration at screening is sufficiently high (Table 2).1 However, if the suspicion of overt hyperglycemia is very high (e.g., if polyuria and polydipsia are present), measurement of serum glucose during fasting may be sufficient to confirm the diagnosis of diabetes (Table 3). Women who are found to be at average or low clinical risk (Table 1) at the initial clinical evaluation should be reassessed between 24 and 28 weeks of gestation, along with women at high risk who have not already received a diagnosis of gestational diabetes by that time. At 24 to 28 weeks, women with low-risk clinical characteristics (Table 1) do not need further testing.1 The risk in these women is low,7,8,10 although the effect of not performing glucose screening has not been evaluated thoroughly. Women with any clinical characteristic placing them at risk (average or high risk in Table 1) should undergo glucose testing. In most populations, a two-step testing procedure will limit the number of full glucose-tolerance tests that are performed; step 1 is the 50-g, one-hour glucosechallenge test (Table 2), and step 2 an oral glucosetolerance test performed in women whose one-hour glucose-challenge test indicates an increased risk of gestational diabetes. The frequency of positive screening tests and their specificity for the detection of gestational diabetes vary according to the cutoff point selected for the serum glucose concentration at one hour (Table 2). In some groups (e.g., some Native American peoples), the rates of diabetes and gestational diabetes are so high that proceeding directly to the full oral glucose-tolerance test may be appropriate.1

From the Department of Obstetrics and Gynecology (S.L.K., T.A.B.) and the Department of Medicine (T.A.B.), University of Southern California School of Medicine, Los Angeles. Address reprint requests to Dr. Kjos at 1240 N. Mission Rd., Rm. L1017, Los Angeles, CA 90033, or at ©1999, Massachusetts Medical Society.

The diagnosis of gestational diabetes is based on the results of an oral glucose-tolerance test, except in women with severe hyperglycemia (Table 3), who should be considered to have type 1 or type 2 diabetes and treated accordingly. There is no agreement about the conduct or interpretation of the oral glucose-tolerance test in pregnant women. The apVol ume 341 Numb e r 23 ·


The New England Journal of Medicine Downloaded from on March 17, 2011. For personal use only. No other uses without permission. Copyright © 1999 Massachusetts Medical Society. All rights reserved.

2 mmol/liter) 14–18 20–25 ~80 ~90 *Recommendations are adapted from Metzger et al. ‡Values are measured at any time except during the oral glucose-challenge test or oral glucose-tolerance test. At present there are no data on perinatal or maternal outcomes to support the use of those criteria. three-hour test. multiply by 0. repeat at 24–28 History of glucose intolerance weeks if no diagnosis Previous infant with macrosomia of gestational diabetes Current glycosuria mellitus by that time Average risk Between 24 and 28 weeks of The patient fits neither the low. 2011. black. one-hour and two-hour values from the 100-g. DIAGNOSIS TIME OF MEASUREMENT OF DIABETES DURING PREGNANCY. most of these women and their infants are not at risk for glucose-related morbidity (Fig.1 Use of those criteria increased the percentage of pregnant women classified as having gestational diabetes from 4 percent (according to the criteria of the National Diabetes Data Group5) to 7 percent in a group that consisted predominantly of white women. risk of fetal macrosomia and cesarean delivery in the absence of specific treatment. SERUM OR PLASMA GLUCOSE SCREENING GESTATIONAL DIABETES MELLITUS WITH THE 50-g ORAL GLUCOSE-CHALLENGE TEST. 100-g test with use of criteria developed to quantify the risk of subsequent diabetes in the mother. The serum glucose cutoff points for the 75-g.17 The Fourth International WorkshopConference on Gestational Diabetes Mellitus1 (Table 3). CLINICAL SCREENING FOR GESTATIONAL DIABETES MELLITUS.16 The incidence rates may be different in other races and ethnic groups. the World Health Organization. ‡The percentage may vary according to race or ethnic group and the glucose-tolerance-test criteria used for diagnosis.1 †Assessment is performed at the initial antepartum visit and repeated at 24 to 28 weeks of gestation in patients in whom gestational diabetes has not been diagnosed.16 However. For personal use only. or Indigenous Australian. three-hour oral glucose-tolerance test. diagnostic testing may be performed without prior glucose screening.1 †Venous serum or plasma glucose concentration is measured by methods with high precision and appropriate quality control. The data are most convincing for an association with preeclampsia20.8 mmol/liter) »130 mg/dl (7. No other uses without permission.1 Two or more of the values must be met or exceeded for a diagnosis of gestational diabetes to be made with the use of either test. incorporating lower glucose concentrations. 1).* RECOMMENDATION FOR SERUM OR PLASMA GLUCOSE SCREENING TABLE 3. two-hour glucose-tolerance tests in pregnant women.14 identify additional pregnant women with an increased 1750 · Dec em b er 2 . ANTEPARTUM IMPLICATIONS AND TREATMENT proach recommended in 1979 by the National Diabetes Data Group5 was based on a three-hour. South or East Asian. Pacific Islander. without regard to the time of the last meal. †Values shown are for a 100-g. TABLE 2.05551.13. ‡Low-risk races and ethnic groups are those other than Hispanic.* GLUCOSE CONCENTRATION DIABETES MELLITUS TYPE GESTATIONAL DIABETES MELLITUS† RISK CATEGORY AND CLINICAL CHARACTERISTICS† 1 OR 2 High risk (one or more of the following) At initial antepartum visit or Marked obesity as soon as possible thereDiabetes in first-degree relative after.16 The more inclusive criteria (Table 3) were adopted by the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Native American. §Abnormal values should be present on at least two occasions.1 with venous serum or plasma glucose concentrations measured by methods with high precision and appropriate quality control. two-hour oral glucose-tolerance test are identical to the fasting.21 and more controversial for an association with pregnancy-induced The New England Journal of Medicine Downloaded from nejm. All rights reserved.12 Other criteria.18 and the European Diabetic Pregnancy Study Group19 have proposed different criteria for interpreting the results of 75-g. .15. 19 9 9 Implications Antepartum morbidity in women with gestational diabetes is limited to an increased frequency of hypertensive disorders. In women with very-high-risk clinical characteristics. Copyright © 1999 Massachusetts Medical Society.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 1. which can be performed at any time of day.* PROPORTION OF WOMEN WITH POSITIVE TEST‡ FOR SERUM GLUCOSE CUTOFF POINT† SENSITIVITY GESTATIONAL DIABETES MELLITUS‡ FOR percent »140 mg/dl (7. To convert values for glucose to millimoles per liter. milligrams per deciliter Random‡§ After overnight fast§ One hour after test Two hours after test Three hours after test »200 »126 — — — — 95 180 155 140 *Diagnoses are based on recommendations of the Fourth International Workshop-Conference on Gestational Diabetes.nor the gestation high-risk profile Low risk (all of the following) Not required Age <25 yr Belongs to low-risk race or ethnic group‡ No diabetes in first-degree relatives Normal prepregnancy weight and weight gain during pregnancy No history of abnormal blood glucose concentrations No prior poor obstetrical outcomes *Data are from Metzger et on March 17.1 Serum or plasma glucose is measured one hour after the glucose challenge.

All rights reserved. there appears to be a weak positive correlation between the degree of maternal glycemia and birth weight3.7 mmol per liter]25). The group with the highest glucose concentrations (Positive by GDM and NDDG). hypertension. women with hypertension. polycythemia. and hypocalcemia have been reported with varying frequency in the infants of women with gestational diabetes. 50-g glucose screening test and a three-hour. who were treated to reduce their glucose concentrations.16. Accordingly. with care providers unaware of the women’s serum glucose concentrations. No other uses without permission.24.22 Careful monitoring of blood pressure.24. including pregnancies in women with untreated gestational diabetes. it is prudent to offer such women special counseling and targeted ultrasound examinations to detect fetal anomalies.. particularly during the second half of gestation. initial fasting serum glucose concentrations above 120 mg per deciliter [6.32-35 and associated complications of labor and delivery15. A simplistic view of macrosomia is that it results from the delivery of excess glucose to the fetus as a consequence of maternal hyperglycemia.16.23-25 but the increase appears to be limited to infants whose mothers have severe hyperglycemia (e.32-35 Macrosomia15. Historically. Several large clinical studies demonstrated no excess perinatal mortality when these measures were instituted at term in women with gestational diabetes and otherwise uncomplicated pregnancies who were treated by diet or at 32 to 34 weeks of gestation in women treated with insulin. maternal glycemia accounts for only a small fraction of the variance in the birth weights of the infants of mothers with gestaVol ume 341 Numb e r 23 · 4t The New England Journal of Medicine Downloaded from nejm. “Screen Negative” indicates a one-hour serum glucose value of less than 140 mg per deciliter (7. The dominant antepartum clinical risks of gestational diabetes are to the fetus.C URR ENT C ONC EP TS Macrosomia No macrosomia Cesarean No cesarean Untreated 100 Treated 100 Untreated Treated Percentage of Pregnancies 80 60 40 20 0 Percentage of Pregnancies N Sc eg re at en iv e Po Scr si ee P tiv n h os e W iti or ve ks b ho y p GD O M Po nl si y tiv e an by d G N D D M D G 80 60 40 20 0 N Sc eg re at en iv e 4t Figure 1.34. and urinary protein excretion is recommended.5 The care providers were unaware of serum glucose concentrations for all pregnancies except those complicated by gestational diabetes as defined by the NDDG. For personal use only. Macrosomia. had the lowest proportion of infants with macrosomia but the highest rate of cesarean delivery. and the women were treated.30.34 or the frequency of macrosomia.31 Whether routine cardiotocography is beneficial or leads to unnecessary interventions in pregnant women with well-controlled diabetes is not known. Rates of Macrosomia and Cesarean Delivery in Relation to Maternal Serum Glucose Classification in the Toronto TriHospital Gestational Diabetes Project. Some studies have reported an increased frequency of major congenital anomalies. stillbirth was an important complication of diabetic pregnancies. maternal monitoring of fetal movements and fetal cardiotocography are often recommended in pregnancies complicated by gestational diabetes in order to detect fetuses at risk of intrauterine death. Po Scr si ee Po tiv n h s e W iti or ve ks b ho y p GD O M Po nl si y tiv e an by d G N D D M D G 1751 . The rates of macrosomia (birth weight >4000 g) and cesarean delivery rose with increasing degrees of maternal glycemia in the three untreated groups.35 are the most frequent and serious types of morbidity. The horizontal line in each panel is the rate of the complication in the lowest glucose category. and women who had had a previous stillborn infant.36 Indeed. 2011. jaundice.8 mmol per liter) on the 50-g test. the values for women in this category were known. respiratory distress syndrome.2-4 However.27-31 The rates of induction of labor and early delivery among women with nonreassuring or suspicious fetal heart-rate tracings were in the range of 9 to 13 percent.g.16. hypoglycemia. but not the stricter criteria of the National Diabetes Data Group (NDDG). Standard diagnostic criteria and treatment of hypertensive disorders are applicable to women with gestational diabetes.24. Copyright © 1999 Massachusetts Medical Society. but only a minority of pregnant women in each group had on March 17. “Positive by GDM 4th Workshop Only” indicates that the criteria for gestational diabetes mellitus of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus1 were met (see Table 3).2 Classifications are based on the results of a one-hour. 100-g oral glucose-tolerance test in all women.15. weight gain.26 As a result.

measurements of insulin in the amniotic fluid identify the minority of fetuses with hyperinsulinism. 19 9 9 nancies complicated by preexisting diabetes.44 and reducing the total intake for overweight women to 25 kcal per kilogram.7 mmol per liter) one and two hours. With each of these two approaches. Postprandial hyperglycemia is more closely related to fetal macrosomia than preprandial hyperglycemia in preg1752 · Decem b er 2 .3 Other maternal factors that may contribute to fetal macrosomia include obesity2.8 mmol per liter) while receiving dietary therapy. Copyright © 1999 Massachusetts Medical Society.17.46 Once nutritional therapy has been initiated.39. 2011. Dietary approaches that lower maternal serum glucose concentrations include limiting carbohydrate intake to 40 percent of total calories.45 One study found that women who obtained less than 40 percent of their total calories from carbohydrates had infants with lower birth weights and fewer cesarean deliveries than women with higher intakes. The American Diabetes Association42 recommends the provision of adequate calories and nutrients to meet the needs of pregnancy and to minimize maternal hyperglycemia. but that affects only a minority of infants overall (approximately 20 to 30 percent of infants whose mothers have gestational diabetes). No other uses without permission. One such approach uses serum fructosamine concentrations to identify women with low-risk pregnancies.33-35.3 and high serum concentrations of amino acids37. The rates of macrosomia and perinatal complications are low with both of these fetus-based approaches.4 Home blood glucose monitoring with memorycapable meters appears superior to monitoring with visually read strips in identifying women whose blood glucose concentrations remain elevated while they are receiving dietary therapy. .52 Measurements of the fetal abdominal circumference early in the third trimester are then used to identify the minority of fetuses at risk for macrosomia at term. some investigators have combined simple measures of maternal glycemia with fetal measurements to identify pregnancies at risk for perinatal morbidity.4.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne tional diabetes.16 Antepartum Metabolic Treatment Antepartum treatment of women with gestational diabetes should be focused on the prevention of fetal complications.40 Fetal responses to maternal diabetes vary as well. excessive fetal growth in pregnancies complicated by gestational diabetes should be viewed as the result of a multifaceted maternal metabolic disturbance superimposed on varied fetal responses to that disturbance.24.50 although overly aggressive treatment without preselection for mothers with large fetuses51. after meals.49 Nonetheless. respectively. The net result is a frequency of macrosomia that is greater than in infants of nondiabetic pregnant women. and many of them require insulin therapy.2. Another approach uses measurements of fasting serum glucose obtained every one to two weeks to identify the majority of women who maintain glucose concentrations of less than 105 mg per deciliter (5.1.41 The excess rate of macrosomia associated with gestational diabetes is likely to decrease as the cutoff levels are lowered to include more on March 17.53 Treatment based on maternal hyperglycemia alone has been estimated to be cost effective. Virtually all approaches have as their foundation a program of nutritional education and dietary treatment. the Fourth International WorkshopConference on Gestational Diabetes Mellitus1 recommended maintaining blood glucose concentrations at less than 95 mg per deciliter (5. Since there is not a maternal glycemic threshold for fetal risk. The most common approach and the one backed by the greatest clinical experience uses intensive monitoring to detect blood glucose concentrations that are indicative of increased fetal risk. although that practice has not been proved to be superior to preprandial monitoring alone.43 providing carbohydrates that have a low glycemic index. as evidenced by the differences in the frequency of macrosomia in the infants of women with gestational diabetes who belong to different racial and ethnic groups.15-17. Women in whom there are signs of fetal morbidity (according to approaches based on the characteris- The New England Journal of Medicine Downloaded from nejm. For personal use only.47.54 even though all women being treated must monitor their blood glucose concentrations.55 Since only a minority of fetuses of women with gestational diabetes are at risk for hyperglycemiarelated morbidity (Fig.38 and lipids.41 Thus.3 mmol per liter) before meals and less than 140 and 120 mg per deciliter (7.51. Some clinicians have used more strict glycemic targets.2-4 recommendations have focused on maintaining blood glucose concentrations in the normal range for pregnancy in all women. but neither approach has been compared directly with treatment based on maternal hyperglycemia alone for efficacy or cost effectiveness.56 In the remainder. two general approaches can be used to identify women whose fetuses are at sufficiently high risk to warrant more intensive treatment: frequent measurement of maternal blood glucose concentrations and assessments of fetal development. All rights reserved.8 and 6. Daily caloric needs for women of normal weight in the second half of pregnancy are 30 to 32 kcal per kilogram of body weight. blood glucose monitoring by patients and treatment with insulin are used only in the minority of pregnancies that have some evidence of fetal hyperinsulinism (20 percent of pregnancies complicated by gestational diabetes in one study56) or macrosomia (one third of pregnancies complicated by gestational diabetes in another study51).48 That observation led to recommendations for both preprandial and postprandial blood glucose monitoring in women with gestational diabetes. 1).52 may increase the rate of delivery of small-for-gestational-age infants.

org on March as children and young adults. To minimize such iatrogenic morbidity. usually with insulin. For personal use only.72.57-59 and perinatal morbidity. The associations have been reported not only in the offspring of women with type 1 or type 2 diabetes.90. This observation suggests that the two approaches are clinically equivalent with regard to the most serious types of perinatal morbidity. No other uses without permission. but that waiting allows more time for accelerated fetal growth.81.1 Moreover.72.63-65 Some of the increase may be due to an increase in the number of infants with macrosomia.85.50. The observation that weight gain and an additional pregnancy increase the risk of diabetes after gestational diabetes102 suggests that insulin resistance may accelerate the decline in beta-cell function that leads to diabetes.4 mmol per liter) in women whose fetuses have been identified as being at risk for macrosomia by fetal ultrasonography. treatment of women with a history of gestational diabetes should include Vol ume 341 Numb e r 23 · 1753 The New England Journal of Medicine Downloaded from nejm. the rates of cesarean delivery among women with gestational diabetes are more than double those for nondiabetic women.71.66 However.74 No interventions to prevent these longterm complications have been tested.60 The preprandial target of 105 mg per deciliter is higher than currently recommended. Nonetheless.1 Women with gestational diabetes have a 17 to 63 percent risk of nongestational diabetes within 5 to 16 years after the index pregnancy. 23 percent) than did waiting for labor to begin spontaneously by 41 completed weeks of gestation.95-101 but its cause is unknown in the majority. Other options for intensifying treatment include the dietary modifications mentioned above and aerobic exercise. and fetal growth characteristics should all be considered in designing insulin treatment.62 Route and Timing of Delivery women whose labor was induced.61. and blood glucose concentrations and appropriate diet and physical activity to minimize the likelihood that obesity will develop.83. All rights reserved.59 Optimal insulin regimens have not been determined. 2011. the route of delivery in well-treated women should be based on the same maternal and fetal considerations that apply to nondiabetic pregnant women. the target glucose concentrations.94 The beta-cell defect may be due to pancreatic autoimmunity in a small minority of women. In that regard.80-83 or soon after 80.12. Copyright © 1999 Massachusetts Medical Society. and tailoring of regimens to achieve blood glucose targets in individual patients is recommended.C URR ENT C ONC EP TS tics of the fetus) or in whom blood glucose concentrations exceed targets (according to glucose-based or fetus-based approaches) are treated more intensively.67 routine induction of labor at 38 completed weeks of gestation resulted in earlier delivery (39 vs.53. unblinded study of women with insulin-treated diabetes (93 percent of whom had gestational diabetes).84.68. excess macrosomia has been eliminated with insulin by reducing preprandial blood glucose concentrations to approximately 80 mg per deciliter (4.76-83 The risk of diabetes is particularly high in women who have marked hyperglycemia during9.80. testing of fetal lung maturation is not recommended after 38 weeks of gestation in cases in which there are reliable estimates of gestational age and good maternal glycemic control.58.51.86 Physiologic testing of women with gestational diabetes has revealed a limited capacity of pancreatic beta cells to increase insulin secretion in compensation for insulin resistance. 31 percent among women in whom labor was not induced) nor the frequency of shoulder dystocia (0 percent vs. the strength of the indication for preterm delivery should determine whether assessment of pulmonary maturity would alter the clinical management of individual cases. knowledge that the mother has gestational diabetes16 or has been treated with insulin51 can increase the chances of cesarean section.51 Thus. 3 percent) was higher. AFTER THE PREGNANCY Gestational diabetes is not in itself an indication for cesarean delivery.87-93 Poor insulin secretion during pregnancy is predictive of diabetes after delivery. neither the rate of cesarean delivery (25 percent.84 and women whose gestational diabetes was diagnosed before 24 weeks of gestation.1 Before 38 weeks.81. The timing of delivery.69 Accordingly. the timing of measurements of blood glucose. vs. 40 weeks) and a smaller proportion of infants who were large for gestational age (10 percent vs. insulin treatment to achieve postprandial blood glucose concentrations of less than 140 mg per deciliter resulted in a lower average level of glycemia and better perinatal outcomes than treatment to maintain preprandial blood glucose concentrations of less than 105 mg per deciliter in women who were not selected according to fetal characteristics.16.83 pregnancy.62 which was associated with perinatal outcomes similar to the outcomes in insulintreated women in one small study. Surfactant-deficient respiratory distress syndrome is rare in term infants of mothers with gestational diabetes.76. who have no circulating antibodies to islet-cell antigens. women who are obese. weight. but also in the offspring of women with gestational diabetes. Accordingly. should take into account fetal growth patterns as well as the risks associated with the induction of labor and premature delivery. . Among There is epidemiologic evidence that persons exposed to maternal diabetes in utero have an increased risk of obesity70-74 and abnormal glucose tolerance71. Insulin therapy decreases the frequency of fetal macrosomia50. in the absence of maternal or fetal jeopardy.74. Recommendations for the care of the children include regular evaluations of height. In one randomized.79.

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