Version May 2024
INTRODUCTION — Pregnancy is generally a state of both enhanced beta-cell function and insulin resistance, mediated primarily by placental secretion of diabetogenic hormones including growth hormone, corticotropin-releasing hormone, placental lactogen (chorionic somatomammotropin), prolactin, and progesterone. These and other metabolic changes, which are most prominent in the third trimester, ensure that the fetus has an ample supply of nutrients.
Gestational diabetes mellitus (GDM) develops in pregnant people whose pancreatic beta-cell function is insufficient to overcome the insulin resistance associated with the pregnant state. Among the main consequences of GDM are increased risks of preeclampsia, large for gestational age (LGA) newborns, and cesarean birth, and their associated morbidities. Patients with GDM are at high risk of developing type 2 diabetes later in life, which is not surprising since both disorders are characterized by inadequate insulin secretion in the setting of insulin resistance. In contrast to diabetes that develops pregestationally, GDM is not generally associated with an increased risk for congenital anomalies since hyperglycemia develops after organ formation is complete.
There is no universally accepted standard regarding screening for or diagnosis of GDM. Practitioners tend to follow the guidance of their national medical organizations. Approaches to screening and diagnosis will be reviewed here. Medical and obstetric management and prognosis are discussed separately:
●(See "Gestational diabetes mellitus: Glucose management and maternal prognosis".)
●(See "Gestational diabetes mellitus: Obstetric issues and management".)
TERMINOLOGY
●Gestational diabetes traditionally referred to any pregnant person in whom abnormal glucose tolerance was first recognized at any time during pregnancy [1]. A more contemporary definition, and that used by the American Diabetes Association (ADA), is diabetes diagnosed in the second or third trimester that was not clearly overt diabetes prior to conception [2]. This definition excludes patients diagnosed in the first trimester because they likely have previously undiagnosed type 2 diabetes. The term "overt diabetes" is sometimes used to describe the diabetes status of these individuals during pregnancy; a formal diagnosis of type 2 diabetes can be made when the diagnosis is confirmed in the nonpregnant state.
The American College of Obstetricians and Gynecologists (ACOG) continues to define GDM as "a condition in which carbohydrate intolerance develops during pregnancy" [3].
●Preexisting or pregestational diabetes refers to type 1 or 2 diabetes diagnosed before pregnancy.
BACKGROUND
Prevalence — The prevalence of GDM by the traditional Carpenter and Coustan criteria (table 3B) [4] was 7.8 percent of births in the United States in 2020 [5] and ranged from 2 to 38 percent of pregnant people in other countries [6]. Worldwide prevalence varies because of differences in population characteristics (eg, average maternal age and body mass index [BMI]) and choice of screening and diagnostic criteria. Using the 2010 International Association of Diabetes and Pregnancy Study Groups (IADPSG) screening and diagnostic criteria for diabetes in pregnancy (table 3C) [7], the global prevalence of GDM has been estimated to be 17 percent, with regional estimates of 10 percent in North America and 25 percent in Southeast Asia [8].
Prevalence has been increasing over time, likely due to increases in mean maternal age and BMI, particularly increasing obesity, and changes in screening practices and methods [9-16].
Significance — GDM has been associated with increased risks of several adverse outcomes. (See "Gestational diabetes mellitus: Obstetric issues and management", section on 'Consequences of GDM'.)
Although treatment of GDM can reduce the risk of some short-term outcomes (eg, preeclampsia, macrosomia), a favorable effect on the long-term outcomes described below is unclear. (See "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Rationale for treatment'.)
●Short-term – GDM has been associated with increased risks of the following problems, some of which are interdependent [17-21]:
•Hypertensive disorders of pregnancy (preeclampsia, gestational hypertension)
•Large for gestational age (LGA) or macrosomic newborn
•Polyhydramnios
•Medically-indicated preterm birth
•Operative birth (cesarean, forceps- or vacuum-assisted vaginal)
•Shoulder dystocia
•Maternal and/or newborn birth trauma
•Fetal/neonatal cardiomyopathy
•Neonatal respiratory problems and metabolic complications (eg, hypoglycemia, hyperbilirubinemia, hypocalcemia, hypomagnesemia, polycythemia and hyperviscosity syndrome)
•Stillbirth
Importantly, the risks of these outcomes increase as maternal fasting plasma glucose levels increase above 75 mg/dL (4.2 mmol/L) and as the one- and two-hour oral glucose tolerance test (GTT) values increase from the lowest septile to the highest. This is a continuous effect; there is no clear threshold that defines patients at increased risk of adverse obstetric outcome [19-22].
The small increase in congenital anomalies observed in some population-based studies of GDM (odds ratio [OR] 1.18 [23]) is likely related to undiagnosed preexisting type 2 diabetes mellitus or maternal obesity [24,25]. (See "Obesity in pregnancy: Complications and maternal management", section on 'Congenital anomalies'.)
●Long-term – GDM has also been associated with increased long-term risks:
•Maternal – Development of diabetes mellitus (primarily type 2), metabolic syndrome, and cardiovascular disease. (See "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Long-term risk'.)
•Adolescent and adult offspring – Obesity, abnormal glucose tolerance, hypertension, and metabolic syndrome. An increased risk of adverse neurodevelopmental outcomes has also been reported and may be related to shared environmental and genetic factors; however, evidence is circumstantial and requires further study [26-31]. (See "Infants of mothers with diabetes (IMD)", section on 'Long-term outcome'.)
Risk factors
Individuals at increased risk of GDM — Pregnant people with any of the following characteristics appear to be at increased risk of developing GDM. The risk varies across these characteristics and is additive when multiple risk factors are present [3,32-39]:
●Personal history of any of the following:
•GDM in a previous pregnancy (associated with a 40 percent risk of recurrence [40])
•Impaired glucose tolerance
•A1C ≥5.7 percent
•Elevated fasting glucose
●Family history of diabetes, especially in a first-degree relative.
●Prepregnancy BMI ≥30 kg/m2, significant weight gain in early adulthood or between pregnancies, or excessive gestational weight gain during the first 18 to 24 weeks of pregnancy.
●Medical condition/setting associated with development of diabetes (eg, polycystic ovary syndrome [PCOS]).
●Older maternal age (≥35 years of age).
●Member of one of the following groups, which have a high prevalence of type 2 diabetes: Hispanic American; Native American, Alaska native, or Native Hawaiian; South or East Asian, Pacific Islander. The prevalence is less in non-Hispanic White and non-Hispanic Black people [5].
●Previous birth of an infant ≥4000 g (approximately 9 pounds).
Individuals at low risk of GDM — By comparison, the risk of developing GDM is low in younger (<25 years of age) non-Hispanic White people, with normal BMI (<25 kg/m2 [<23 kg/m2 in Asian people]), no history of previous glucose intolerance or adverse pregnancy outcomes associated with GDM, and no first-degree relative with diabetes [41]. Only 10 percent of the general obstetric population in the United States meets all of these criteria for low risk of developing GDM, which is the basis for universal rather than selective screening [42]. (See 'Candidates' below.)
Lifestyle interventions for risk reduction — Lifestyle interventions (eg, diet modification, exercise) are targeted at individuals at increased risk for developing GDM, particularly those who are overweight or obese and those with a history of GDM in a previous pregnancy. The primary target of lifestyle interventions is weight loss leading to less insulin resistance and impaired insulin secretion.
●Diet modification and increased exercise – In a meta-analysis of randomized trials, lifestyle interventions targeted at individuals with a higher baseline risk of GDM (eg, 20 percent incidence of GDM) reduced the risk of GDM by approximately 20 percent compared with standard care [43]. The interventions included diet modification, increased exercise, or both, ideally initiated before pregnancy and continuing across gestation; exercising at the proper intensity and frequency (eg, moderate intensity for 50 to 60 minutes at least twice a week throughout pregnancy); and managing gestational weight gain so as to not exceed standard recommendations (table 1).
Individuals who are overweight or obese appear to benefit from weight loss before conception [44,45], whereas beginning a modest unsupervised exercise program in the second trimester appears to be inadequate to impact the risk of GDM [46-48]. (See "Exercise during pregnancy and the postpartum period".)
●Type of diet – The optimum diet is unclear. There is limited evidence (none from randomized trials) that a diet favoring fruit, vegetables, whole grains, and fish and low in red and processed meat, refined grains, and high-fat dairy reduces the risk of developing GDM [49,50]. The effect of a low glycemic index diet on risk of GDM is unclear as only a few small randomized trials have been performed. A meta-analysis of these trials did not demonstrate a clear benefit, but the confidence interval was wide (risk ratio [RR] 0.91, 95% CI 0.61-1.31; four trials, 912 participants) [51].
●Smoking cessation – Smoking cessation should be encouraged in all patients. The association between smoking and GDM is uncertain [32,52] and cessation is often associated with weight gain; cessation has multiple maternal and fetal benefits and may reduce GDM. (See "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options".)
These interventions overlap with those utilized for prevention of type 2 diabetes and are discussed in detail separately. (See "Prevention of type 2 diabetes mellitus".)
Investigational risk reduction measures of uncertain benefit
●Metformin has not reduced the risk for GDM in randomized trials. Metformin has been proposed as a medication to "prevent" GDM, based in part on evidence of its effectiveness in reducing the risk for type 2 diabetes in nonpregnant individuals with prior GDM [53] and observations that it reduced the risk for GDM in patients with PCOS [54,55]. However, in a randomized trial of 273 pregnancies among 257 patients with PCOS who were assigned to receive metformin (2000 mg/day) or placebo from the first trimester until delivery, the prevalence of GDM was similar in both groups (metformin: 17.6 percent versus placebo: 16.9 percent) [56]. Two randomized trials comparing metformin with placebo in pregnant people with obesity also showed no significant reduction in the rate of GDM [57,58]. In most other metformin trials, patients in the metformin group gained less weight during pregnancy than those in the placebo group.
●Probiotics do not appear to be useful and may be harmful. In a meta-analysis of randomized trials, probiotics did not clearly reduce the risk of GDM compared with placebo (mean RR 0.80, 95% CI 0.54-1.20; 6 trials, 1440 participants) but increased the risk of preeclampsia (RR 1.85, 95% CI 1.04-3.29; 4 studies, 955 participants) [59].
●Myoinositol is a naturally occurring sugar in fruits, beans, grains, and nuts that can improve insulin resistance. A meta-analysis reported a reduction in GDM with supplementation (RR 0.53, 95% CI 0.31-0.90; 6 trials, 1140 participants), but limitations include individual small studies, lack of generalizability, and inconsistency, which may be related to different doses, timing, and combinations of myoinositol supplementation [60]. Before this intervention can be recommended, a large multicenter, blinded, randomized trial is needed to confirm safety and demonstrate improvement in clinically important maternal and/or neonatal outcomes.
BENEFITS AND HARMS OF SCREENING
●Potential benefits – A 2021 systematic review by the United States Preventive Services Task Force (USPSTF) found that screening for GDM at 24 weeks of gestation or after was associated with some favorable maternal and fetal/newborn outcomes (eg, reduction in cesarean births, birth injuries, neonatal intensive care unit admissions, stillbirth) compared with historical unscreened controls [61,62]. These findings were largely derived from two observational studies [63,64]. In addition, randomized trials have shown that treatment of GDM can reduce some fetal, neonatal, and maternal morbidities, particularly macrosomia and shoulder dystocia, and possibly preeclampsia [61,62]. These data are described separately. (See "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Rationale for treatment'.)
●Potential harms – The commonly used screening and diagnostic tests for diabetes involve drinking a glucose-containing beverage followed by blood glucose measurement. None of the screening or diagnostic tests are associated with serious harmful maternal or fetal effects, but the hyperosmolar drinks are poorly tolerated by some individuals since they may cause nausea and vomiting.
If GDM is diagnosed, management involves medical nutrition therapy; an increased frequency of prenatal visits; frequent blood glucose monitoring; and the possibility of pharmacologic therapy, antenatal fetal monitoring, and induction because of diabetes status. Most of these interventions are not associated with serious harm, but antihyperglycemic drugs can be costly and can have side effects, which vary by drug and dose. Screening and diagnosis of GDM may lead to over- or undertreatment (treatment without a favorable effect on outcome) and heighten maternal anxiety, but long-term psychological harm is unlikely.
The cost implications of screening versus not screening are not clear [65-67].
SCREENING FOR OVERT DIABETES IN EARLY PREGNANCY — Diabetes diagnosed early in pregnancy has been called overt diabetes and is assumed to be previously undiagnosed type 2 diabetes.
Rationale — An increasing proportion of pregnant patients have unrecognized type 2 diabetes due to the increasing prevalence of obesity and lack of routine glucose/diabetes screening in reproductive-age individuals [68]. Approximately 30 percent of females aged 18 to 44 years in the United States are estimated to have some degree of abnormal glucose metabolism including impaired glucose tolerance and/or impaired fasting glucose (26 percent) or type 2 diabetes (4 percent) [69].
Unrecognized, untreated hyperglycemia in early pregnancy is important because it is associated with an increased risk of miscarriage and congenital anomalies [70-72]. In addition, unrecognized maternal comorbidity (eg, nephropathy, retinopathy) can have serious maternal and obstetric consequences. If these individuals are identified early in pregnancy, they could benefit from receiving the diagnostic and therapeutic interventions routinely provided to pregnant patients with preexisting (pregestational) diabetes mellitus. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management".)
Our approach to early pregnancy screening (universal screening by A1C) — Given the increasing frequency of type 2 diabetes and evidence of a reduced risk of large for gestational age (LGA) newborns with universal early maternal screening and treatment [73], the author of this topic checks an A1C level to screen for diabetes as part of the routine prenatal laboratory studies of all patients at the initial prenatal visit.
●A1C ≥6.5 percent (≥48 mmol/mol) – In nonpregnant people, an A1C ≥6.5 percent (≥48 mmol/mol) is one of the criteria used to diagnose diabetes (table 2). Therefore, an A1C ≥6.5 percent early in pregnancy, when A1C levels are generally slightly lower than in the nonpregnant state [74], strongly suggests previously undiagnosed type 2 diabetes. These patients are managed similar to those with preexisting diabetes mellitus. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management" and "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control" and "Pregestational (preexisting) diabetes mellitus: Obstetric issues and management".)
●A1C <6.5 percent (<48 mmol/mol) – This is a negative test for diabetes in nonpregnant people. At 24 to 28 weeks of gestation, the author screens these patients for GDM with the two-step test. Approximately one-quarter of pregnant people with A1C 5.7 to 6.4 percent (39 to 47 mmol/mol) suggestive of impaired glucose intolerance in early pregnancy are diagnosed with GDM when screened with a two-step test later in pregnancy compared with <10 percent of those with A1C <5.7 percent (39 mmol/mol) [75]. (See 'One- and two-step approaches' below.)
The author acknowledges that an A1C <6.5 percent (<48 mmol/mol) is not sufficiently sensitive to detect mildly impaired glucose tolerance, especially if the A1C is ≥5.7 (which is above the upper limit of normal in nonpregnant individuals), but the overall value of detecting and treating mildly impaired glucose tolerance in early pregnancy has not been established in randomized trials [76].
Other approaches to early pregnancy screening
Targeted screening of individuals at high risk — The International Association of Diabetes and Pregnancy Study Groups (IADPSG) [7], the American Diabetes Association (ADA) [2], and the American College of Obstetricians and Gynecologists (ACOG) [3] suggest targeting early pregnancy screening to individuals at increased risk of undiagnosed type 2 diabetes. However, the ADA also suggests that clinicians consider testing all individuals for undiagnosed diabetes at the first prenatal visit (or preconceptionally) [2]. In contrast, a United States Preventive Services Task Force (USPSTF) guideline concluded that available evidence was insufficient to assess the balance of benefits and harms of screening asymptomatic pregnant people for glucose intolerance before 24 weeks of gestation [61,62].
The ADA and ACOG define patients at increased risk of type 2 diabetes based on [2,3]:
●GDM in a previous pregnancy.
●Body mass index (BMI) ≥25 kg/m2 (≥23 kg/m2 in Asian Americans) plus one or more of the following:
•First-degree relative with diabetes.
•High-risk race/ethnicity (eg, African American, Latino, Native American, Asian American, Pacific Islander).
•History of cardiovascular disease.
•Hypertension (≥130/80 mmHg prepregnancy) or on therapy for hypertension.
•High-density lipoprotein cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL (2.82 mmol/L).
•Polycystic ovary syndrome (PCOS).
•Physical inactivity.
•Other clinical condition associated with insulin resistance (eg, severe obesity, acanthosis nigricans).
●Glycated hemoglobin ≥5.7 percent (39 mmol/mol), impaired glucose tolerance (two-hour glucose level 140 to 199 mg/dL), or impaired fasting glucose (glucose level 100 to 125 mg/dL) on a previous 75-gram oral glucose tolerance test (GTT) in the nonpregnant state.
●HIV infection, exposure to high-risk medicines, history of pancreatitis.
●Age ≥35 years.
In a randomized trial, early pregnancy diabetes screening because of obesity alone (BMI ≥30 kg/m2) did not demonstrate a reduction in a composite of adverse outcomes (eg, macrosomia, primary cesarean delivery, hypertensive disease of pregnancy, shoulder dystocia, neonatal hyperbilirubinemia, or hypoglycemia) [77]. Screening was done using a 50-gram one-hour GTT followed by a 100-gram, three-hour GTT if the initial screen was ≥135 mg/dL. The trial findings were limited by the small number of participants diagnosed with early GDM (n = 29) and the timing of the early screening, which was between 14 and 20 weeks.
Targeting screening to symptomatic patients is not useful because many patients are asymptomatic or have unrecognized mild symptoms. However, those with random blood glucose values ≥200 mg/dL (11.1 mmol/L) may have symptoms of hyperglycemia (eg, increased thirst, polyuria, weight loss, blurry vision). (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)
Choice of screening test — No approach has been validated for diagnosis of diabetes in the first or early second trimester. Clinical practice varies by institution and clinician preference. Screening practice varies from a hemoglobin A1C alone, fasting glucose alone, a two-hour 75-gram oral GTT, or two-step test (one-hour 50-gram GTT followed by a three-hour 100-gram GTT if the 50-gram GTT is positive). (See 'One- and two-step approaches' below.)
●If a two-step test is used, ACOG criteria for diabetes are shown in the tables (table 3A-B). These criteria are the same as those used for diagnosis of GDM later in pregnancy.
●If a one-step test is used:
•ADA criteria for diabetes are shown in the table (table 2). These thresholds are the same as those used by the ADA for diagnosis of diabetes in nonpregnant people and were chosen because they correlate with development of adverse vascular events, such as retinopathy and coronary artery disease, in these individuals over time [2].
ADA criteria for "early abnormal glucose metabolism" are fasting glucose 110 to 125 mg/dL (6.1 to 6.9 mmol/L) or A1C 5.9 to 6.4 percent (41 to 47 mmol/mol).
•IADPSG criteria for diabetes are similar to ADA criteria: A1C ≥6.5 percent, fasting blood glucose ≥126 mg/dL (7.0 mmol/L), or random plasma glucose ≥200 mg/dL (11.1 mmol/L) confirmed by fasting blood glucose or A1C at these levels.
These criteria for diagnosis of diabetes in early pregnancy are different from those used by the ADA and IADPSG for diagnosis of GDM later in pregnancy (table 3C).
Management of patients after an early pregnancy GTT
●Abnormal GTT – If a patient in early pregnancy (before significant insulin resistance) meets ADA (table 2) or IADPSG criteria for diagnosis of diabetes in the nonpregnant state, they are assumed to have had the disorder prior to the pregnancy and their management is similar to those with documented preexisting diabetes mellitus in pregnancy. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management" and "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control" and "Pregestational (preexisting) diabetes mellitus: Obstetric issues and management".)
The benefit of treating a patient whose early pregnancy GTT meets ADA and IADPSG criteria for GDM (table 3C) has not been established. A randomized trial including over 800 pregnant participants with an abnormal two-hour 75-gram oral GTT (defined as fasting glucose level ≥92 mg/dL [≥5.1 mmol/L], one-hour glucose level ≥180 mg/dL [≥10.0 mmol/L], or a two-hour glucose level ≥153 mg/dL [≥8.5 mmol per liter]) before 20 weeks of gestation compared immediate treatment versus retesting at 24 to 28 weeks and starting treatment at that time if results were abnormal [76]. Those discovered to have overt diabetes at early testing were excluded from randomization (overt diabetes: fasting glucose level ≥110 mg/dL [≥6.1 mmol/L] or two-hour glucose level ≥200 mg/dL [11.1 mmol/L]) and treated.
Immediate treatment of patients who meet diagnostic criteria for GDM early in pregnancy did not result in a clear or substantial reduction in LGA births (16.8 versus 19.6 percent; RR 0.77, 95% CI 0.51-1.17), composite adverse neonatal outcome (24.9 versus 30.5 percent; RR 0.82, 95% CI 0.68-0.98), or pregnancy-related hypertension (10.6 versus 9.9 percent; RR 1.08, 95% CI 0.85-1.38). The modest reduction in adverse neonatal outcome was largely due to a reduction in neonatal respiratory distress, which was unexpected. In addition, one-third of participants in the untreated early abnormal test group had normal results when retested at 24 to 28 weeks. These findings have prompted stakeholders to review their early pregnancy diabetes screening protocols, but revised guidelines from major medical organizations have not been published.
●Normal GTT – Patients with normal 75- or 100-gram oral GTT in early pregnancy are screened for GDM at 24 to 28 weeks of gestation.
•Those who were screened early in pregnancy by the one-step approach are rescreened using the 75-gram oral GTT.
•Those who were screened early in pregnancy by the two-step approach can omit the first step (50-gram oral glucose solution with glucose testing after one hour) at 24 to 28 weeks as it is likely to be abnormal; these patients can be rescreened using the three-hour 100-gram oral GTT alone [78,79] .
SCREENING FOR GDM AT 24 TO 28 WEEKS
Candidates — In the United States, universal screening appears to be the most practical approach because:
●90 percent of pregnant people have at least one risk factor for glucose impairment during pregnancy, so limiting testing to those with risk factors would not substantially reduce testing [42] (see 'Risk factors' above).
●20 percent of pregnant people with GDM have no risk factors, so limiting testing to those with risk factors would miss most cases of GDM [80-82].
One- and two-step approaches — Screening is performed at 24 to 28 weeks of gestation since 24 weeks is the gestational age when insulin resistance is significantly increasing, leading to hyperglycemia in those with insufficient insulin secretory capacity to maintain euglycemia [2,3]. It can be performed as a one- or two-step process. There is no consensus among national and international organizations for the optimal approach, and the choice generally depends on local customs.
One-step test — The one-step approach simplifies screening by performing only a diagnostic test, typically a fasting 75-gram oral glucose tolerance test (GTT), in all patients. The criteria for diagnosis of GDM are shown in the table (table 3C). The International Association of Diabetes and Pregnancy Study Groups (IADPSG) prefers this approach, which has been widely adopted internationally, and the American Diabetes Association (ADA) considers it an acceptable alternative to the two-step approach [2]. The procedure is described below. (See 'Procedures and laboratory issues' below and 'Validation of the 75-gram GTT' below.)
Two-step test — In the United States, the two-step test is the most widely used approach for identifying pregnant people with GDM. It is endorsed by American College of Obstetricians and Gynecologists (ACOG) [3] and the ADA considers it an acceptable option [2]. We prefer the two-step approach because fewer patients are diagnosed and managed as GDM, without incurring an increase in adverse outcome (see 'Evidence for choosing the two-step versus one-step approach' below). The first step has the practical advantages that fasting is unnecessary and only one blood sample is required. A minority of patients need to undergo the second step (16 percent at the ≥140 mg/dL threshold in a large series [83]).
●The first step is a one-hour 50-gram oral GTT administered without regard to time of day/previous meals. Screen-positive individuals (table 3A) are at increased risk for GDM so all but those with very high (≥200 mg/dL [11.1 mmol/L]) glucose values go on to have the more cumbersome second step. We use ≥135 mg/dL (7.5 mmol/L) as the cutoff for a positive test because our patient population is at high risk for developing GDM. Although there are limited data regarding the clinical benefit of this cutoff, we believe that it offers the optimum combination of sensitivity and specificity for our population. Some institutions use a cut-off of ≥130 based on their higher-risk population. A cut-off of ≥140 mg/dL (7.8 mmol/L) is another commonly used cut-off. The procedure and supporting evidence are described below. (See 'Screening: 50-gram one-hour GTT' below.)
●The second step is a three-hour 100-gram oral GTT performed after an overnight fast; the GTT is the diagnostic test for GDM (table 3B). We use Carpenter and Coustan criteria for an abnormal GTT as the lower, more stringent criteria for diagnosis identifies patients with glucose intolerance at the most risk of adverse perinatal outcomes.
Although the three-hour 100-gram oral GTT is typically performed as the second step of the two-step approach, this is arbitrary and in some countries (eg, Canada) a two-hour 75-gram oral GTT is performed as the second step in the screening/diagnostic process [84]. The procedure and supporting evidence are described below. (See 'Procedures and laboratory issues' below and 'Validation of the 100-gram GTT' below.)
Evidence for choosing the two-step versus one-step approach — The body of evidence may favor the two-step approach. In a 2022 meta-analysis of randomized trials comparing outcomes of the one- versus the two-step approach:
●The one-step approach diagnosed twice as many patients with GDM (16.3 versus 8.3 percent; RR 2.13, 95% CI 1.61-2.82) and resulted in twice as many patients receiving antihyperglycemic pharmacotherapy (7.1 versus 3.8 percent; RR 2.24, 95% CI 1.21-4.15), without a clear benefit in outcome.
●Most maternal and neonatal outcomes were similar for both groups:
•Large for gestational age (LGA; 8.8 versus 9.2 percent; RR 0.95, 95% CI 0.88-1.04)
•Hypertensive disorder of pregnancy (13.6 percent versus 13.6 percent; RR 1.00, 95% CI 0.94-1.07)
•Primary cesarean birth (24.0 versus 24.7 percent; RR 0.98, 95% CI 0.93-1.02)
•Macrosomia (>4000 grams, 11.2 versus 11.3 percent; RR 0.99, 95% CI 0.92-1.07)
•Shoulder dystocia (2.1 versus 2.0 percent; RR 1.06, 95% CI 0.89-1.28)
•Small for gestational age (SGA; 8.6 versus 8.3 percent; RR 1.04, 95% CI 0.95-1.13)
•Stillbirth (0.5 versus 0.6 percent; RR 0.90, 95% CI 0.64-1.28)
●Neonatal hypoglycemia was more common in the one-step group (9.3 versus 7.6 percent; RR 1.23, 95% CI 1.13-1.34)
Results were similar in high-quality observational studies, except for LGA (RR 0.97, 95% CI 0.95-0.98) where the confidence interval was consistent with a modest reduction.
Based on these findings, it appears that using the one-step method increases the number of patients who receive a diagnosis of GDM and thus has the potential for increased patient and medical system burden (eg, more prenatal visits, fetal and maternal surveillance, lifestyle changes, and intervention) with economic, personal, and psychological consequences [85-87], but without a clear direct benefit over the two-step approach in maternal and newborn outcomes. Therefore, we believe it is prudent to use the two-step approach to diagnose GDM followed by treatment of affected patients according to standard guidelines. Nevertheless, because of limitations of the available trials, the best approach remains controversial [88]. (See 'One- and two-step approaches' above.)
The potential long-term consequences of increasing the number of patients who receive a diagnosis of GDM is another issue. Increased identification of glucose intolerance in pregnancy might lead to improved long-term maternal outcomes. Theoretically, if individuals with GDM are identified and make postpartum lifestyle changes (with or without metformin), this may prevent or delay development of type 2 diabetes later in life [53]. Data are lacking due to the low percentage of patients with GDM who complete the recommended postpartum follow-up. Counseling regarding long-term risk, adherence to a risk-reduction program, and long-term glucose monitoring for diabetes would be essential to assess this issue.
Procedures and laboratory issues
Screening: 50-gram one-hour GTT — A 50-gram oral glucose solution is given without regard to the time elapsed since the last meal/beverage and venous plasma glucose is measured one hour later (sometimes called a glucose challenge test [GCT] or glucose loading test [GLT]). Glucose concentration should be measured using an accurate and precise enzymatic method. The majority of patients (70 to 80 percent) screen negative at this step and thus do not undergo diagnostic testing [4].
The following thresholds have been proposed to define a positive screen: ≥130 mg/dL, ≥135 mg/dL, or ≥140 mg/dL (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L). The original threshold for an elevated test (equivalent to 143 mg/dL [7.9 mmol/L] with current methodology) was arbitrary, used whole blood and a nonspecific glucose assay, and was validated by its ability to predict an abnormal 100-gram oral GTT [89]. Using a lower threshold (≥130 mg/dL [7.2 mmol/L] with current methodology) increases sensitivity, but results in more false positives and would require administering a three-hour 100-gram oral GTT to more patients. In a systematic review of cohort studies of screening tests for GDM by the USPSTF, using Carpenter and Coustan criteria, sensitivity and specificity at the ≥130 mg/dL threshold was 100 and 25 percent, respectively, in one study; 90 and 81 percent in a second study; and 75 and 86 percent in a third study [90]. The pooled sensitivity and specificity at ≥135 mg/dL was 93 and 79 percent, respectively; at ≥140 mg/dL pooled sensitivity and specificity were both 82 percent.
The precise composition of the glucose solution (other than the 50 grams of glucose) can vary among manufactures. No studies have compared products.
Management of patients with results ≥200 mg/dL — For patients with one-hour 50-gram glucose concentration ≥200 mg/dL (11.1 mmol/L), the author makes a presumptive diagnosis of GDM, unless the patient prefers to undergo a three-hour 100-gram oral GTT for definitive diagnosis. The GTT can be performed safely, as the 100-gram glucose load would rarely, if ever, lead to a hyperglycemic emergency or other serious adverse events in patients with GDM or unrecognized type 2 diabetes. It has been performed in thousands of patients with no reports of serious adverse events.
The basis for this approach is that patients who have a very high glucose level on their one-hour 50-gram oral GTT have a high likelihood of an abnormal three-hour 100-gram oral GTT; the positive predictive value (PPV) varies depending on the prevalence of GDM in the population tested and the GTT criteria used for diagnosis. For example, Carpenter and Coustan found that patients whose one-hour 50-gram oral GTT plasma glucose concentration was >182 mg/dL (10.1 mmol/L) had >95 percent probability of an abnormal three-hour 100-gram oral GTT [4]. At glucose levels ≥200 mg/dL (11.1 mmol/L), others have reported PPVs of 47 to 80 percent for an abnormal three-hour 100-gram oral GTT [83,91,92].
Diagnostic testing: 75- and 100-gram GTT
Pretest preparation — Fasting for 8 to 10 hours is required before the test. Carbohydrate loading for three days before the test is unnecessary if the patient is not on a very-low-carbohydrate diet [93-96]. (See 'Options for patients unable to tolerate hyperosmolar oral glucose' below.)
●Role of fasting glucose level – A fasting glucose level is rarely determined before administering the GTT. This approach would require asking the patient to have blood drawn for their fasting glucose level and then wait for the results before going ahead with the GTT later the same day (and remain fasting) or on another day (and fasting again), which is cumbersome. Excluding fasting hyperglycemia before a GTT is unnecessary to safely perform the test. However, identifying fasting hyperglycemia can reduce testing for some patients.
•If a 75-gram oral GTT is planned and the fasting glucose level is ≥92 mg/dL (5.1 mmol/L), then the diagnosis of GDM is made and the GTT is cancelled.
•If a 100-gram oral GTT is planned, no data support a particular fasting cutoff for diagnosing GDM and an abnormal fasting glucose level alone is not diagnostic of GDM. However, a glucose level ≥126 mg/dL (7 mmol/L) is a reasonable threshold for cancelling the GTT as it is diagnostic of diabetes in the general population.
Diagnostic criteria — The diagnosis of GDM is based on plasma glucose values during the two-hour GTT using a 75-gram oral glucose load or during the three-hour GTT using a 100-gram oral glucose load. Thresholds for a positive test are shown in the tables (table 3B-C).
The GTT is an imprecise test with poor reproducibility [97].
●In a study that performed two 100-gram oral GTTs one to two weeks apart in 64 pregnant people whose one-hour 50-gram oral GTT was ≥135 mg/dL, 48 had normal/normal, 11 had normal/abnormal, three had abnormal/normal, and two had abnormal/abnormal results [98]. Thus, only 50 of 64 (78 percent) had reproducible test results.
●In a trial that performed a two-hour 75-gram oral GTT before 20 weeks and repeated the test at 24 to 28 weeks, one-third of participants had abnormal followed by normal results [76].
Nevertheless, the 100-gram oral GTT is a practical and widely utilized means of diagnosing GDM, and the 75-gram oral GTT is a widely utilized means of diagnosing diabetes in both pregnant and nonpregnant individuals. Proper handling and processing of blood samples are important for accurate results [99].
Options for patients unable to tolerate hyperosmolar oral glucose — The highly concentrated hyperosmolar glucose solution used for the GTT can cause gastric irritation, delayed emptying, and gastrointestinal osmotic imbalance, leading to nausea and, in a small percentage of patients, vomiting [100-102]. Options in these cases include:
●Serving over ice – Serving the hyperosmolar glucose drink on ice may reduce nausea and vomiting.
●Antiemetic premedication – If the patient vomited during the oral GTT and is willing to come back another day for repeat testing, premedication with an antiemetic drug may allow the test to be completed. In one study, 8 percent of patients could not complete the 100-gram oral GTT because of vomiting [100]. It is possible that fewer patients vomit with the 75-gram oral GTT.
●Intravenous GTT – The GTT can be performed intravenously instead of orally, although this is rarely done because it is onerous, expensive, and unvalidated in pregnancy [103]. Considering these limitations, we recommend not using it.
●Structured postprandial glucose assessment – Periodic fasting and one- or two-hour postprandial blood glucose tests can be obtained in pregnant people at high risk for GDM. For example, they can be asked to keep a weekly log of self-monitored glucose values from 24 to 28 weeks (the gestational age when screening would be performed) and at 32 weeks (the gestational age of peak insulin resistance).
This approach is also useful for pregnant people who have dumping syndrome after a Roux-en-Y gastric bypass procedure; these individuals are unlikely to tolerate a hyperosmolar glucose solution [104]. Monitoring glucose values will only identify those cases of GDM that might require intervention for hyperglycemia and not all cases of GDM. (See "Fertility and pregnancy after bariatric surgery".)
●Other – Other approaches have been tried in patients who do not tolerate or decline to have an oral GTT, but are not recommended because they have not been validated or they perform poorly.
•Candy, a predefined meal, or commercial soft drinks with 75 or 100 grams of glucose have been used instead of a standard glucose monomer or polymer solution [105-110]. These oral glucose loads are better tolerated but appear to be less sensitive and have not been validated in large studies. None have been endorsed by the ADA or ACOG.
•A1C – In a USPSTF systematic review, no threshold for glycated hemoglobin (A1C) in the second and third trimesters had both good sensitivity and specificity as a screening test for GDM [90].
•Fasting glucose alone – The USPSTF review also found that a fasting plasma glucose threshold of 79 mg/dL was required to achieve high (96 percent) sensitivity but specificity was poor (35 percent) [90]. A fasting plasma glucose threshold of 95.5 mg/dL was required to achieve high specificity (98 percent) but sensitivity was 58 percent at this level.
However, in low-resource settings where universal screening with a GTT is not feasible, use of fasting plasma glucose at 24 to 28 weeks to screen pregnant people may be a practical approach, a reasonable trade-off between cost savings and adverse outcomes in missed cases. In a study from 15 Chinese hospitals, if performance of the GTT was restricted to pregnant people with fasting glucose from 79 mg/dL (4.4 mmol/L) to 90 mg/dL (5.0 mmol/L), then 50 percent of pregnant people could avoid a GTT since 38 percent of this population had fasting glucose <79 mg/dL (4.4 mmol/L) and 12 percent had fasting glucose >90 mg/dL (5.0 mmol/L), diagnostic of GDM in this system; 12 percent of patients with GDM were missed [111]. These findings may not be generalizable to other low-resource populations since Asian females have a higher incidence of type 2 diabetes and GDM than White females, and fasting hyperglycemia among Asian females with GDM is less prominent than in non-Asian populations [112]. In non-Asian populations, 50 to 75 percent of patients with GDM have fasting glucose levels ≥92 mg/dL (5.1 mmol/L) on an oral GTT [112].
•Testing for glucosuria – A positive urine dipstick for glycosuria is not very predictive of GDM, and a negative urine dipstick for glycosuria is not very predictive of absence of GDM, so should not be used for ruling the diagnosis in or out [113-115]. Glycosuria with a normal blood glucose level is common in pregnant people as pregnancy is associated with reductions in fractional reabsorption of glucose, which results in higher rates of urinary excretion.
Validation of the 100-gram GTT — The three-hour 100-gram oral GTT is diagnostic of GDM when two glucose values are elevated. The most commonly used thresholds for defining elevated values were proposed by Carpenter and Coustan (table 3B) [4], which is a modification of thresholds proposed by O’Sullivan and Mahan [116], originally based on venous whole blood samples. The Carpenter and Coustan values are based on newer enzymatic assays performed on plasma samples and reflect current laboratory practices.
The requirement for two abnormal values on the GTT was an arbitrary decision made by O’Sullivan and Mahan in 1964 [116]. Treatment of patients who meet these diagnostic criteria for GDM improves some pregnancy outcomes (eg, pregnancy-induced hypertension, macrosomia, shoulder dystocia) [117]. However, a 2016 systematic review including 25 studies noted that pregnant people with one abnormal value on the 100-gram oral GTT generally had increased risks for the same poor outcomes as those with two abnormal values (ie, GDM) [118]. This subset of patients may warrant closer monitoring for fetal overgrowth and other adverse outcomes of GDM, as well as closer monitoring for future development of type 2 diabetes [119]. Whether they would benefit from treatment is unknown. The author of this topic obtains a third-trimester fetal growth scan on these patients. If fetal overgrowth or polyhydramnios is present, she discusses the option of home glucose monitoring.
Validation of the 75-gram GTT — The two-hour 75-gram oral GTT is diagnostic of GDM when one glucose value is elevated. The most commonly used thresholds for defining elevated values have been proposed by the IADPSG (table 3C). The 75-gram oral GTT is generally more sensitive for identifying the pregnancy at risk for adverse outcome (eg, gestational hypertension, preeclampsia, LGA) than the 100-gram oral GTT [120]. Increased sensitivity is primarily related to the need for only one elevated glucose value for a positive test [112], as well as slightly lower glucose thresholds.
●Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study – The IADPSG-defined thresholds for the 75-gram oral GTT are primarily based on outcome data reported in the HAPO study, a prospective observational study of more than 23,000 pregnancies in nine countries evaluated with a 75-gram oral GTT at 24 to 32 weeks of gestation [7,19]. These thresholds represent the glucose values at which the odds of neonatal birth weight, cord C-peptide (surrogate for fetal insulin level), and percent body fat >90th percentile were 1.75 times the estimated odds of these outcomes at mean glucose levels, based on fully adjusted logistic regression models. Compared with participants in the HAPO study with all glucose values below the thresholds, those who exceeded one or more of these thresholds had a twofold higher frequency of LGA newborns and preeclampsia and >45 percent increase in preterm birth and primary cesarean birth. Using an odds ratio (OR) of 2 for the thresholds defined a population with a higher frequency of these outcomes, but the difference was modest and resulted in failure to identify many pregnant people who were at almost similar risk of these outcomes but had all glucose values below the thresholds. IADPSG-defined thresholds are also predictive of a more than threefold increased long-term risk of diabetes and metabolic syndrome [121,122]. In a post hoc analysis of data from the HAPO Study, 52 percent of pregnant people who would meet IADPSG criteria for GDM developed a disorder of glucose metabolism by 10 to 14 years postpartum, compared with 20 percent of those without GDM (OR 3.44, 95% CI 2.85-4.14 [122]). Among pregnant people who met IADPSG criteria for GDM, rates of type 2 diabetes and prediabetes were 10.7 and 41.5 percent, respectively, versus rates of 1.6 and 18.4 percent, respectively, in those without GDM. The children of these individuals were more likely to be “overweight or obese” (39.5 versus 28.6 percent in children of mothers without GDM, OR 1.21, 95% CI 1.00-1.46) after adjustment for maternal body mass index (BMI) during pregnancy, and the difference in prevalence of obesity was statistically significant (19 versus 10 percent in children of mothers without GDM, OR 1.58, 95% CI 1.24-2.01).
●Post-HAPO data – In 2022, the IADPSG-defined thresholds for the 75-gram oral GTT were reassessed in a trial that randomly assigned 4061 pregnant patients undergoing GDM screening to the standard glycemic threshold criteria for diagnosis (table 3C) or higher thresholds (ie, fasting plasma glucose ≥99 mg/dL [≥5.5 mmol/L] or two-hour glucose ≥162 mg/dL [≥9.0 mmol/L]) [123]. Patients who met the threshold criteria for GDM for their assigned group received usual care for patients with GDM (per New Zealand Ministry of Health clinical practice guideline on GDM). Major findings were:
•Use of lower glycemic threshold criteria resulted in more patients diagnosed with GDM (15.3 versus 6.1 percent), but this was not accompanied by a significant reduction in birth of LGA (8.8 versus 8.9 percent) or macrosomic newborns (11.8 versus 12.3 percent).
•Use of the lower glycemic threshold criteria resulted in more inductions of labor (33.7 versus 30.2 percent), use of health services, and use of pharmacotherapy (10.9 versus 4.6 percent). The lower glycemic threshold group also had a higher rate of neonatal hypoglycemia warranting treatment (10.7 versus 8.4 percent), which was likely related to hospital protocols requiring screening for hypoglycemia in infants of diabetic mothers.
•Rates of preeclampsia, preterm birth, shoulder dystocia, cesarean birth, and SGA newborn were similar in the two trial groups.
Interestingly, about half of the patients with glucose test results that fell between the lower and higher glycemic threshold criteria were considered by their providers to have a mild degree of GDM and were treated for GDM. These patients had maternal and infant health benefits, including fewer LGA newborns, compared with those who did not receive a diagnosis of a mild degree of GDM and therefore not treated.
The results of this trial suggest that the optimum glucose thresholds for diagnosis of GDM by the 75-gram oral GTT still need to be determined.
SHOULD TESTING BE REPEATED LATER IN PREGNANCY? — We recommend not repeating a glucose tolerance test (GTT) later in pregnancy after an initially normal GTT. Although some studies have reported that repeating the test after an initially normal GTT (defined as the absence of at least two glucose values above threshold) will identify additional cases in 4 to 29 percent of cases depending on the timing and indication for repeat testing [124-127], the value of identifying these individuals versus nondiagnosis of GDM is unproven. Furthermore, patients with a normal GTT and sonographic signs of fetal overgrowth or with one abnormal value on the GTT can be given the option of insulin therapy in an attempt to improve pregnancy outcome.
RECOMMENDATIONS OF NATIONAL AND INTERNATIONAL ORGANIZATIONS — The optimum strategy for diagnosis of GDM to improve maternal and infant health is unclear [128]. Many organizations have published recommendations for screening and diagnosis of diabetes in pregnancy:
●American College of Obstetricians and Gynecologists (ACOG, two-step approach (table 3A and table 3B)) [3]
●International Association of Diabetes and Pregnancy Study Groups (IADPSG, one-step approach (table 3C)) [7]
●American Diabetes Association (ADA, one- or two-step approach) [2]
●World Health Organization (WHO, one-step approach (table 4)) [129]
●Canadian Diabetes Association (CDA, two-step [preferred] or one-step approach) [84]
●Australasian Diabetes in Pregnancy Society (WHO approach) [41]
●National Institute for Health and Care Excellence (NICE, United Kingdom, one-step approach)
●International Federation of Gynecology and Obstetrics (FIGO, one-step approach) [130]
POSTDELIVERY FOLLOW-UP — Although pregnancy-related maternal insulin resistance returns to prepregnancy levels within a few days of giving birth, individuals with GDM should be screened again 4 to 12 weeks postpartum and periodically (at least every three years) thereafter because they are at increased risk for developing type 2 diabetes mellitus. Postdelivery follow-up is described separately. (See "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Follow-up'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in pregnancy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Gestational diabetes (The Basics)")
●Beyond the Basics topics (see "Patient education: Gestational diabetes (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Terminology and significance – Gestational diabetes mellitus (GDM) typically refers to diagnosis of diabetes at 24 to 28 weeks of gestation. Diagnosis of diabetes early in pregnancy (sometimes called overt diabetes) is more consistent with previously undiagnosed type 2 diabetes. (See 'Terminology' above.)
GDM has been associated with increased risks of several adverse outcomes (table 5). The association between hyperglycemia and adverse pregnancy outcomes is dose-dependent and continuous. (See 'Significance' above.)
●How to screen
•Overall approach – An overall approach to screening for diabetes in pregnancy and after delivery is shown in the algorithm (algorithm 1). (See 'Screening for overt diabetes in early pregnancy' above and 'Screening for GDM at 24 to 28 weeks' above.)
•Early pregnancy screening for previously undiagnosed type 2 diabetes – There is no standard approach to early pregnancy screening for undiagnosed type 2 diabetes. The author obtains an A1C level at the initial prenatal visit in all patients as part of the initial prenatal blood work; a value ≥6.5 percent (≥48 mmol/mol) is diagnostic of diabetes and the patient is managed accordingly. If the A1C is <6.5 percent (<48 mmol/mol), the author performs standard screening for GDM at 24 to 28 weeks. Alternatively, several national organizations have suggested a targeted approach that limits screening to patients at high risk. (See 'Screening for overt diabetes in early pregnancy' above.)
•Screening for GDM at 24 to 28 weeks – We suggest screening for GDM at 24 to 28 weeks of gestation (Grade 2C). In the United States, universal rather than selective screening appears to be the most practical approach because 90 percent of pregnant people have at least one risk factor for glucose impairment during pregnancy and 20 percent of individuals with GDM have no risk factors. In pregnant people with GDM, treatment (medical nutritional therapy, and then pharmacotherapy if glycemic goals are not achieved) can reduce the rate of some adverse pregnancy outcomes, particularly macrosomia and shoulder dystocia, and possibly preeclampsia. (See 'Candidates' above and 'Significance' above and 'Benefits and harms of screening' above and "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Rationale for treatment'.)
•One- and two-step testing approaches – We use a two-step approach for screening/diagnosis of GDM (table 3A-B), but a one-step approach is also acceptable (table 3C). (See 'One- and two-step approaches' above and 'Procedures and laboratory issues' above.)
●Postpartum follow-up – Individuals with GDM should be screened for diabetes postpartum and periodically thereafter because they are at increased risk for developing type 2 diabetes mellitus. (See "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Follow-up'.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Lois Jovanovic, MD, Donald R Coustan, MD, and Michael Greene, MD, who contributed to earlier versions of this topic review.
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