Silvia Vannuccini and Federico Mecacci
Gestational diabetes mellitus: definitions and epidemiology
Diabetes is a growing global health emergency, as it is escalating worldwide, affecting already about 60 million people, and is projected to increase to 71 million people by 2040. In 2017, the International Diabetes Federation (IDF), according to the standard for estimates of diabetes prevalence and its related burden, affirmed an abrupt increase in diabetes and forecasted for doubling the current numbers in many regions by 2045 (1). Alongside other noncommunicable diseases (NCDs), diabetes is increasing most markedly in cities of low- and middle-income countries. Eight low- and middle-income countries that account for over half the global live births also contribute to more than half of the global diabetes burden: India, China, Nigeria, Pakistan, Indonesia, Bangladesh, Brazil, and Mexico.
Hyperglycemia (high blood glucose level) that is first detected during pregnancy is classified as either gestational diabetes mellitus (GDM) or hyperglycemia in pregnancy (HIP) (2). It has been estimated that most (75%–90%) cases of high blood glucose during pregnancy are GDM (3). GDM usually affects pregnant women during the second and third trimesters of pregnancy, though it can occur at any time during pregnancy. If diabetes is diagnosed in the first trimester, it likely existed before pregnancy but was undiagnosed. The overall prevalence of GDM ranges from 5% to 16% of pregnancies (1). However, the incidence markedly increases in obese and overweight women or among those aged more than 40 years, where the risk of GDM rises up to 74% (4).
Considering that obesity and overweight is an escalating problem among women of reproductive age in the United States and Europe with more than 1 in 10 pregnant women being obese, and 1 in 4 being overweight (5,6), the issue of predisposition to GDM is a major concern. Furthermore, given the interaction between HIP and poor pregnancy outcomes, a global focus on preventing, testing, diagnosing, and managing HIP should be implemented. In addition, the role of in utero imprinting in increasing the risk of diabetes and cardio-metabolic disorders in offspring of mothers with HIP, as well as increasing maternal vulnerability to future diabetes and cardiovascular disorders, should be considered (7).
Recent evidence shows that lifestyle interventions, including diet, physical activity, and lifestyle changes, either pre-pregnancy or during pregnancy, may reduce the incidence of GDM. Early prediction of women at high risk of GDM would allow for timely intervention that could limit gestational weight gain and obesity, possibly preventing the onset of GDM.
Prediction of gestational diabetes mellitus
Screening for GDM
For more than four decades, there has been a lack of international uniformity in the approach to the screening and diagnosis of GDM. Controversies include universal versus selective screening, the optimal time for screening, appropriate tests and cutoff values, and whether testing should be conducted in one or two steps (8). The first criteria for GDM were established more than 50 years ago, using a two-step approach, and they were designed to identify women at risk of developing diabetes after pregnancy (9,10). Then, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study showed a continuous relationship between the levels of hyperglycemia and the risk of adverse perinatal outcome (10–12). Therefore, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) introduced new recommendations for overt diabetes early in pregnancy and for a universal screening with the 2 hour, 75 g oral glucose tolerance test (OGTT) from 24 to 28 weeks of gestation (13). The American Diabetes Association (ADA) endorsed the IADPSG criteria; however, the U.S.-based societies such as the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) still promote the use of the two-step screening strategy with the nonfasting 50 g glucose challenge test (GCT), and if abnormal, followed by the 3 hour, 100 g OGTT using the Carpenter and Coustan criteria or the National Diabetes Data Group (NDDG) criteria (14). In 2013, the World Health Organization (WHO) and the Endocrine Society revised the guidelines and recommended to use the IADPSG criteria for the diagnosis of GDM (15). This increases GDM prevalence to 15%–20%, due both to a one-step testing policy and the requirement for only one elevated glucose value for diagnosis. Furthermore, in 2015 the International Federation of Gynecology and Obstetrics (FIGO) published a guide for the diagnosis and management of GDM advocating for universal screening using WHO shared criteria (2) (Table 6.1). Recently, the FIGO, the European Board and College of Obstetrics and Gynecology (EBCOG), and the European Association of Perinatal Medicine (EAPM) jointly recommend that all pregnant women should be tested for HIP using a one-step, 75 g OGTT procedure, rather than using a risk factor–based approach (16) (Table 6.2). In the United States, ADA, in the updated guidelines, recommends use of either the one-step or the two-step screening method (recommended by the National Institutes of Health), advising that both tests are acceptable screens (17). The recent publication of the HAPO Follow-up Study provides further evidence regarding the influence of GDM on long-term maternal and infant health. This study clearly demonstrates that HIP, untreated and identified post hoc by IADPSG criteria, carries a 41.5% risk of maternal prediabetes and 10.7% risk of type 2 diabetes after 11.4 years of follow-up (18). Thus, a universal screening should be warranted.
Table 6.1 Screening tests according to three different guidelines
3 hours, 100 g OGTT
Carpenter and Coustan
3 hours, 100 g OGTT
2 hours, 75 g OGTT
Number of abnormal values needed for the diagnosis
Abbreviations: Values in mg/dL (mmol/L). IADPSG, International Association of Diabetes and Pregnancy Study Groups; NDDG, National Diabetes Data Group; OGTT, oral glucose tolerance test.
Table 6.2 Risk assessment for gestational diabetes mellitus according to National Institute for Health and Care Excellence (NICE) and American Diabetes Association (ADA) guidelines
•BMI above 30 kg/m2
•Previous macrosomic baby weighing 4.5 kg or above
•Family history of diabetes (first-degree relative with diabetes)
•Minority ethnic family origin with a high prevalence of diabetes:
•South Asia: India, Pakistan, or Bangladesh
•Middle Eastern: Saudi Arabia, United Arab Emirates, Iraq, Jordan, Syria, Oman, Qatar, Kuwait, Lebanon, or Egypt
•Overweight or obese (BMI above 25 kg/m2 or above 23 kg/m2 in Asian Americans) adults who have one or more of the following risk factors
•First-degree relative with diabetes
•High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)
•History of CVD
•Hypertension (≥140/90 mmHg or on therapy for hypertension)
•HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL (2.82 mmol/L)
•Women with polycystic ovary syndrome
•Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)
Abbreviations: BMI, body mass index; CVD, cardiovascular disease; GDM, gestational diabetes mellitus; HDL, high-density lipoprotein.
Risk factors for GDM
GDM has well-defined risk factors, including personal and medical history (age greater than or equal to 35 years at delivery, nonwhite ethnicity, maternal overweight and obesity, hypertension, metabolic syndrome, polycystic ovarian syndrome [PCOS], chronic use of steroids, glycosuria, known impaired glucose metabolism), family history of diabetes mellitus and obstetric history (history of GDM, prior unexplained stillbirth, prior infant with congenital anomaly—if not screened during that pregnancy—prior macrosoma) (16,19).
Regarding nonmodifiable risk factors, age, ethnicity, and parity play a major role. After 35 years, the risk of GDM increases from 2% to 7%, and women older than 40 years have an OR 3.8 to develop GDM (20–22). Belonging to an ethnic group such as South Asian or Middle Eastern nationalities, as well as having a low socioeconomic background, exposes to a higher risk of GDM than the general population (23). The recurrence of GDM in a subsequent pregnancy is significantly high, around 48% according to a recent systematic review (24), but varying between 30% and 80% (25,26). However, in recurrent GDM, ethnicity and parity also play a key role, as those who are primiparous and non-Hispanic white have a lower recurrence rate than that observed (24). A recent meta-analysis revealed that family history of diabetes is also an important factor to predict GDM (27). Concerning the mode of conception, assisted reproductive technology (ART) pregnancies have been associated with a 28% increased likelihood of GDM compared with non-ART pregnancies, maybe due also to advanced maternal age and multiple pregnancies (28).
Among modifiable risk factors, obesity and metabolic syndrome are crucial determinants of GDM (29). It has been shown that in women trying to conceive, even a reduction of 10% in body mass index (BMI) made the risk of GDM 10% lower (30). Increased pre-pregnancy BMI and excessive weight gain in pregnancy, in fact, have in common the same metabolic milieu with insulin resistance and chronic inflammation, favoring GDM onset. Furthermore, women who are obese are twice as likely to develop GDM compared to an overweight cohort (31), and in this group pre-pregnancy counseling on diet change, physical exercise, and lifestyle changes is crucial in order to reduce the risk of GDM later in pregnancy. In PCOS, a hormonal and metabolic dysfunction, the presence of associated obesity, insulin resistance, and hyperandrogenism contributes to the threefold increased risk of GDM (32).
Risk factors assessment based on maternal demographic and medical characteristics is easy to apply, and it has been proposed in early pregnancy to improve protocols for diagnostic testing. Baseline maternal characteristics (race, age, height, weight) in conjunction with obstetric history (previous GDM, mode of conception) integrated in the scoring system had a 83% prediction of GDM (33). However, results of a meta-analysis on risk factors screening to identify those women to test for GDM observed that the prediction model based on risk factors showed modest screening performance (34).
Several biomarkers have been tested for GDM, especially during the first trimester, in order to perform an early diagnosis of the disease (35,36). These include markers of glucose metabolism, insulin resistance, inflammation, fat tissue activity, and placental function. In the last years, novel markers have been investigated, such as vitamin D, soluble (pro)renin receptor, glycosylated fibronectin, and microRNAs (37) (Table 6.3). However, their role should be further investigated in prospective studies, also evaluating their relevance when integrating with clinical predictive models. Furthermore, the recent introduction of omics technologies, such as proteomics and metabolomics, will open the opportunity to understand the flow of information that underlies diseases (38).
Table 6.3 Biochemical markers of gestational diabetes mellitus
Fasting plasma glucose
Random plasma glucose
Postload plasma glucose
Insulin resistance markers
Sex hormone-binding globulin (SHBG)
C-reactive protein (CRP)
Tumor necrosis factor-α
Placental growth factor
Soluble (pro)renin receptor