Gestational diabetes (GDM) is a frequent medical condition during pregnancy. It is associated with an increased risk of complications for both the mother and the baby during pregnancy and post partum. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) has proposed a new screening strategy for overt diabetes in pregnancy and screening for GDM. However, there is still 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. This review gives an update on screening for GDM and overt diabetes during pregnancy. We also give an overview on the medical and obstetrical management of GDM.
Gestational diabetes as a health problem now and later
Gestational diabetes (GDM) is a frequent medical condition during pregnancy and was historically defined as “any degree of glucose intolerance with onset or first recognition during pregnancy.” GDM has long been known to raise the risk of a large-for-gestational-age (LGA) fetus, as the maternal glucose crosses the placenta and stimulates fetal insulin secretion, which acts as a growth factor. LGA increases the risks of macrosomia, shoulder dystocia, and cesarean deliveries. GDM is also associated with pregnancy-induced hypertension, preeclampsia, and polyhydramnion. Short-term risks for the baby include neonatal hypoglycemia, hyperbilirubinemia, hypocalcemia, respiratory distress syndrome, and polycythemia . Shortly after delivery, the glucose values are generally restored to normal, but women with GDM have a sevenfold increased risk of developing type 2 diabetes mellitus (T2DM) after pregnancy . A history of GDM is also a marker for raised cardiovascular risk and early atherosclerosis .
Studies show that offspring exposed to maternal hyperglycemia are at an increased risk of being overweight in childhood and have impaired pancreatic beta-cell function as adults . By contrast, a systematic review showed that, when adjusted for maternal obesity, the associations between GDM and childhood overweight were not significant anymore . Recent findings suggest that GDM has effects on the DNA methylation of genes involved in energy metabolism, anti-inflammatory processes, and insulin resistance, which could partially explain the increased risk of cardio-metabolic morbidities later in life . When the baby is female, exposure to maternal hyperglycemia in utero might increase her own risk of subsequently developing GDM in her own pregnancies. Compelling evidence for the role of epigenetic transmission has come from comparison of siblings born before and after the development of maternal diabetes, exposure to this intrauterine diabetic environment being shown to cause alterations in fetal growth patterns . This metabolic programming by in utero exposure to hyperglycemia might therefore be a transgenerational effect contributing to the expected huge increase in the prevalence of T2DM worldwide .
Screening for GDM
Lack of uniformity in the guidelines for screening for GDM
Since long, 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. Various large surveys completed by respondents from many different countries highlighted the strong variability that exists internationally in the screening, diagnosis, and management of women with GDM .
The initial criteria for the diagnosis of GDM were established nearly 50 years ago . These criteria were chosen to identify women at a high risk of developing diabetes after pregnancy and not to identify pregnancies with an increased risk of adverse perinatal outcome . Progressively more data have shown that the risk of adverse perinatal outcomes is also associated with degrees of hyperglycemia less severe than overt diabetes during pregnancy. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study showed a continuous and graded relationship between maternal hyperglycemia and the risk of an adverse perinatal outcome, independent of other risk factors . After reviewing the results of the HAPO study, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) developed a new consensus that recommends screening for overt diabetes early in pregnancy and for a universal screening with the 2-h 75-g oral glucose tolerance test (OGTT) from 24–28 weeks of gestation using more stringent diagnostic criteria for GDM . Furthermore, one abnormal value is now enough for the diagnosis of GDM ( Table 1 ). These criteria are the first diagnostic criteria for GDM based on perinatal outcome and therefore unique.
| NDDG 3-h 100-g OGTT | Carpenter and Coustan 3-h 100-g OGTT | IADPSG 2-h 75-g OGTT | |
|---|---|---|---|
| Fasting | ≥105 (5.8) | ≥95 (5.3) | ≥92 (5.1) |
| 1 h | ≥190 (10.6) | ≥180 (10.0) | ≥180 (10.0) |
| 2 h | ≥165 (9.2) | ≥155 (8.6) | ≥153 (8.5) |
| 3 h | ≥145 (8.0) | ≥140 (7.8) | |
| The number of abnormal values needed for the diagnosis of GDM | ≥2 | ≥2 | ≥1 |
Internationally, the IADPSG recommendation for screening for GDM remains controversial, as in most populations this will lead to a significant increase in the number of women labeled and treated as GDM . Other comments raised include the paucity of data on the cost-effectiveness of such a screening strategy, the uncertainty in the clinical relevance of treatment of mild GDM based on the IADPSG criteria, and the uncertainty in the risk of women who have had mild GDM to develop T2DM post partum .
While the American Diabetes Association (ADA) has adopted the IADPSG recommendations since December 2010, the American College of Obstetricians and Gynecologists (ACOG) and an independent expert panel assigned by the National Institute of Health (NIH) continue to promote the use of the two-step screening strategy with the non-fasting 50-g glucose challenge test (GCT) and, if abnormal, followed by the 3-h 100-g OGTT using the Carpenter and Coustan criteria or the National Diabetes Data Group criteria ( Table 1 ). Recently, both the World Health Organization (WHO) and the Endocrine Society revised their guidelines and now advise the use of the IADPSG criteria for the diagnosis of GDM . The latest 2014 ADA recommendations specify that further research is needed to establish a uniform approach to diagnosing GDM and now leave the option open between the one-step IADPSG recommendation and the two-step screening strategy ( Table 2 ).
| WHO |
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| Endocrine society |
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| ADA | Option between:
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| NIH |
|
| ACOG |
|
Meanwhile, the European Board and College of Obstetrics and Gynecology (EBCOG) has appointed a steering committee, including members of EBCOG and representatives of the Diabetic Pregnancy Study Group, to prepare a proposal for the use of uniform diagnostic criteria for GDM in Europe. The proposal is currently under review by the national societies (presentation at the EBCOG conference in May 2014 by Benhalima K).
Screening for overt diabetes and GDM in early pregnancy
Women with unknown overt diabetes in pregnancy are at an increased risk of congenital anomalies due to their greater degree of hyperglycemia earlier in pregnancy . As the frequency of obesity and T2DM in young adults is increasing worldwide and as the use of a simple screening test will lead to more women being diagnosed with overt diabetes in time, most guidelines now recommend screening for overt diabetes at the first prenatal visit, especially in high-risk groups . The cutoffs for tests used to detect diabetes in the nonpregnant population are recommended in early pregnancy (fasting plasma glucose ≥126 mg/dl (7.0 mmol/l), random plasma glucose ≥200 mg/dl (11.1 mmol/l), or HbA1c ≥ 6.5% (47 mmol/mol)). However, the WHO does not consider HbA1c for the diagnosis of overt diabetes .
It is generally considered that there is not enough evidence to recommend the screening and treatment of GDM before 24 weeks of gestation . However, the IADPSG recommends that a fasting plasma glucose (FPG) ≥92 mg/dl (5.1 mmol/l) in early pregnancy be classified as GDM . This is now also endorsed by the WHO and the Endocrine Society , but remains highly debatable as this recommendation was merely based on data extrapolated from the cutoff value used on the 75-g OGTT later in pregnancy. A recent evaluation of the FPG in the first prenatal visit to diagnose GDM in China showed that an FPG level between 110 and 125 mg/dl (6.1–6.9 mmol/l) was a much better predictor of the development of GDM and that, for their population, an FPG level ≥92 mg/dl (5.1 mmol/l) at the first prenatal visit could not be supported as the criterion for the diagnosis of GDM .
The value of the 50-g GCT to screen for GDM
The GCT has the advantage that it can be performed throughout the day without the need to be in fasting conditions. A systematic review showed that, for universal screening, the sensitivity of the GCT was 0.74 for a specificity of 0.85 . A recent study comparing an FPG and GCT for screening for GDM showed an overall sensitivity and specificity of 75.0% and 92.0% for the GCT and 88.8% and 95.2% for the FPG, respectively . A recent study showed that, among women with a positive GCT, those tested in the afternoon have better metabolic function and a lower risk of GDM on subsequent OGTT . This suggests that the time of day of testing may lead to misclassification of patients with markedly elevated GCT results when a threshold is applied at which GDM can be diagnosed without proceeding to the OGTT. Altogether, these findings show that the GCT is acceptable for screening for GDM, but it cannot replace the OGTT.
The value of HbA1c to screen for GDM
A recent study showed that women with an HbA1c level of 5.7–6.4% (39–46 mmol/mol) in early pregnancy had a threefold increased risk of progression to GDM compared to women with a normal Hba1c level . A study in India showed that, by using different ranges of Hba1c for the IADPSG criteria and the old ADA criteria, an OGTT could be avoided in approximately 40% (IADPSG) and 60% (ADA) of women, respectively . Recent data from a New Zealand population show that pregnant women with a normal OGTT but Hba1c >5.8% (40 mmol/mol) are likely to require pharmacotherapy . However, the HAPO study showed that associations with adverse outcomes were significantly stronger with glucose measures than with Hba1c . Altogether, these findings suggest that an Hba1c measurement is not a useful alternative to an OGTT in pregnant women. Additionally, Hba1c is not reimbursed for screening in many countries.
Selective screening versus universal screening for GDM
Recent studies confirm that selective screening would lead to missing one-third of women with GDM, who, even without risk factors, had more events than women without GDM and this was irrespective of ethnicity . Applying selective screening guidelines for GDM to a large pregnant cohort from Ireland showed that the ADA guidelines would result in the lowest number of missed cases compared to the Irish and the National Institute for Health and Clinical Excellence guidelines . On the other hand, several studies have shown that a two-step screening algorithm, including an FPG measurement and a risk estimation model, can increase sensitivity >90% for predicting GDM . In 2008, the U.S. Preventive Services Task Force Recommendation (USPSTF) concluded that the evidence was insufficient to assess the balance of the benefits and harms of screening for GDM before or after 24 weeks of gestation . In the update of 2014, USPSTF now recommends screening for GDM in asymptomatic pregnant women after 24 weeks of gestation . This change in recommendation is based on evidence from several systematic reviews showing that a GCT and a FPG are effective in identifying women who do not have GDM and that the diagnostic criteria used for GDM identify pregnancies at an increased risk of adverse feto-maternal outcomes .
The impact of the IADPSG criteria on pregnancy outcomes
Data on the impact of implementing the IADPSG criteria are currently based on retrospective analysis comparing the two-step screening strategy or the former WHO screening strategy with the IADPSG criteria. Several studies show that women classified as normal glucose tolerant (NGT) but considered to have GDM according to the IADPSG criteria have impaired pregnancy outcomes compared to NGT women, while some studies show similar pregnancy outcomes as NGT women . Analyses of the Israeli HAPO study showed that screening with FPG and BMI may be a practical alternative as this detected proportions of adverse outcomes similar to IADPSG criteria . Moreover, one-third of IADPSG-positive women were at a low risk of adverse outcomes and could be managed less intensively. A systematic review showed that associations with pregnancy outcomes were of similar magnitude for the IADPSG criteria and the WHO criteria, but a high inconsistency was seen for those with the IADPSG criteria . A recent systematic review assessing different diagnostic thresholds for GDM on outcomes showed that higher glucose thresholds did not consistently demonstrate a greater risk, possibly because studies did not compare mutually exclusive groups of women .
In their present form, the IADPSG recommendations are not simple enough to implement in low-resource settings. Options that can be used in different settings such as measuring FPG alone to either diagnose or screen for GDM, using non-fasting glucose testing or using a GCT, need to be offered.
Thus far, two studies have addressed the cost-effectiveness of GDM screening according to the IADPSG criteria using decision analysis models for a US population . One study showed that the IADPSG recommendations are cost-effective only when postdelivery care reduces the incidence of diabetes . In the second study, treatment according to IADPSG would be cost-effective if treatment would result in decreased preeclampsia >0.55% and decreased cesarean delivery >2.7% . It is, however, highly doubtful to assume that the treatment of GDM would lead to a decreased cesarean delivery rate in routine care as intervention randomized controlled trials (RCTs) have been conflicting and recent analyses showed that women with GDM had significantly higher levels of cesarean deliveries and neonatal unit admissions, leading to a 34% higher cost of care compared to women without GDM . Analyses from the UAE showed that switching from a two-step to a one-step strategy would increase cost by 42% but decrease the laboratory workload by 36% . For their population, an initial screen by FPG would avoid about 50% of OGTTs and would therefore be the ideal strategy, in terms of both cost and workload.
Postpartum screening for glucose intolerance
The best postpartum screening strategy for glucose intolerance among women with a history of GDM is also still under debate. The ADA and the Endocrine Society recommend screening women with a history of GDM at 6–12 weeks post partum using the 2-h 75-g OGTT with nonpregnancy diagnostic criteria . It is acknowledged that this recommendation is mostly based on expert consensus or clinical experience. Studies evaluating the use of HbA1c alone or in combination with FPG to diagnose glucose intolerance in women who have had GDM show conflicting results with the sensitivity rates of HbA1c and FPG combined ranging from 83.0% to 90.0% . Measurement of Hba1c alone does not seem to perform properly in this setting .
Women with a history of GDM should undergo lifelong screening for the development of glucose intolerance, at least every 3 years . Currently, there is insufficient evidence to recommend one test over the other and, therefore, HbA1C, FPG, or 75-g 2-h OGTT are appropriate to test for glucose intolerance. Women with a history of GDM found to have prediabetes should receive lifestyle interventions with or without metformin as this has been shown to delay or prevent diabetes in >50% of women .
Screening for GDM
Lack of uniformity in the guidelines for screening for GDM
Since long, 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. Various large surveys completed by respondents from many different countries highlighted the strong variability that exists internationally in the screening, diagnosis, and management of women with GDM .
The initial criteria for the diagnosis of GDM were established nearly 50 years ago . These criteria were chosen to identify women at a high risk of developing diabetes after pregnancy and not to identify pregnancies with an increased risk of adverse perinatal outcome . Progressively more data have shown that the risk of adverse perinatal outcomes is also associated with degrees of hyperglycemia less severe than overt diabetes during pregnancy. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study showed a continuous and graded relationship between maternal hyperglycemia and the risk of an adverse perinatal outcome, independent of other risk factors . After reviewing the results of the HAPO study, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) developed a new consensus that recommends screening for overt diabetes early in pregnancy and for a universal screening with the 2-h 75-g oral glucose tolerance test (OGTT) from 24–28 weeks of gestation using more stringent diagnostic criteria for GDM . Furthermore, one abnormal value is now enough for the diagnosis of GDM ( Table 1 ). These criteria are the first diagnostic criteria for GDM based on perinatal outcome and therefore unique.
| NDDG 3-h 100-g OGTT | Carpenter and Coustan 3-h 100-g OGTT | IADPSG 2-h 75-g OGTT | |
|---|---|---|---|
| Fasting | ≥105 (5.8) | ≥95 (5.3) | ≥92 (5.1) |
| 1 h | ≥190 (10.6) | ≥180 (10.0) | ≥180 (10.0) |
| 2 h | ≥165 (9.2) | ≥155 (8.6) | ≥153 (8.5) |
| 3 h | ≥145 (8.0) | ≥140 (7.8) | |
| The number of abnormal values needed for the diagnosis of GDM | ≥2 | ≥2 | ≥1 |
Internationally, the IADPSG recommendation for screening for GDM remains controversial, as in most populations this will lead to a significant increase in the number of women labeled and treated as GDM . Other comments raised include the paucity of data on the cost-effectiveness of such a screening strategy, the uncertainty in the clinical relevance of treatment of mild GDM based on the IADPSG criteria, and the uncertainty in the risk of women who have had mild GDM to develop T2DM post partum .
While the American Diabetes Association (ADA) has adopted the IADPSG recommendations since December 2010, the American College of Obstetricians and Gynecologists (ACOG) and an independent expert panel assigned by the National Institute of Health (NIH) continue to promote the use of the two-step screening strategy with the non-fasting 50-g glucose challenge test (GCT) and, if abnormal, followed by the 3-h 100-g OGTT using the Carpenter and Coustan criteria or the National Diabetes Data Group criteria ( Table 1 ). Recently, both the World Health Organization (WHO) and the Endocrine Society revised their guidelines and now advise the use of the IADPSG criteria for the diagnosis of GDM . The latest 2014 ADA recommendations specify that further research is needed to establish a uniform approach to diagnosing GDM and now leave the option open between the one-step IADPSG recommendation and the two-step screening strategy ( Table 2 ).
| WHO |
|
| Endocrine society |
|
| ADA | Option between:
|
| NIH |
|
| ACOG |
|
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