Diagnostic Criteria and Treatment for Gestational Diabetes Mellitus Daphne N. Voormolen, MD1 Sally K. Abell, MBBS(Hons), BMedSci, FRACP2 Rachel James, BSc, MBBS3 William M. Hague, MB BChir, MD, FRCP, FRCOG5 Ben Willem Mol, MD, PhD4,5
Utrecht, The Netherlands 2 Monash Centre for Health Research and Implementation, School of Public Health and Preventative Medicine, Monash University, Clayton, Victoria, Australia 3 Department of Obstetrics and Gynaecology, Women’s and Children’s Hospital, Adelaide, Australia 4 Department of Obstetrics and Gynaecology, South Australian Health and Medical Research Institute, Adelaide, Australia 5 The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
Address for correspondence Ben Willem Mol, MD, PhD, The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide 5000 SA, Australia (e-mail: [email protected]).
Semin Reprod Med
Abstract
Keywords
► gestational diabetes ► GDM diagnostic criteria ► treatment ► guidelines
The prevalence of gestational diabetes mellitus (GDM) is high, and the risks of maternal and perinatal complications with clear hyperglycemia are well recognized. The worldwide obesity epidemic and the consequent excess of hyperglycemia have resulted in a rising prevalence of GDM. Changing definitions and more intensive screening may also be contributing to an increased prevalence. Despite the recognized risks, much controversy surrounds the screening, diagnosis, and treatment of GDM. The more stringent diagnostic criteria, advocated in new guidelines, are based on observational studies and are not guided by interventional studies. Here, we review the evidence behind updated diagnostic criteria, stricter treatment targets, and current controversies and conclude that international consensus regarding diagnosis and treatment will only be achieved with further evidence from interventional studies.
Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance causing hyperglycemia with onset or first recognition at any time during pregnancy.1 GDM generally occurs when a pregnant woman is not able to compensate for the physiologic hormone-driven increase in insulin resistance, together with decreased insulin sensitivity, resulting in hyperglycemia. Hyperglycemia increases the risk for pregnancy complications, such as preeclampsia, still birth, and fetal macrosomia leading to slow or even obstructed labor with shoulder dystocia, requiring operative vaginal delivery or cesarean section. The neonates risk prematurity, neonatal hypoglycemia, respiratory distress syndrome, and hyperbilirubinemia.2
Issue Theme Lifestyle in Reproductive Medicine; Guest Editors, Lisa Moran, PhD, BND, BSc (Hons) and Helena Teede, MBBS, PhD, FRACP
Advanced maternal age, non-Europid ethnicity, family history of diabetes, personal history of GDM, polycystic ovary syndrome, and overweight all predispose to GDM3,4. Prepregnancy obesity5 and excessive gestational weight gain (GWG)6 are commonly seen in women with GDM and are both independently associated with adverse pregnancy outcome. The association between GDM and later onset of type 2 diabetes mellitus (T2DM) and cardiovascular disease is well established.7–9 Moreover, children born to women with GDM are at increased risk of macrosomia with higher subsequent risk of obesity, T2DM, and hypertension in early life.10–12 Body mass and lifestyle are key features in GDM etiology, treatment, and prevention. The treatment of GDM aims at
Copyright © by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0036-1572440. ISSN 1526-8004.
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1 Department of Obstetrics, University Medical Center Utrecht,
tight glycemic control, primarily by lifestyle adjustments. For the majority of patients, dietary alteration and increase in exercise are adequate therapy to improve glycemia, but 20 to 40% of women require additional treatment with pharmacotherapy, depending on treatment targets. Treatment of GDM has been shown in interventional studies to reduce perinatal complications.13,14 Following a pregnancy complicated by GDM, women have a 30% risk of recurrent GDM in a subsequent pregnancy15 as well as a sevenfold risk of developing T2DM in the longer term.16 Regular monitoring, life style adjustment, reduction of obesity, and metformin therapy have been shown to reduce the incidence of T2DM.17 This view on GDM may seem logical from a pathophysiologic point of view, but while a definition of GDM as any degree of carbohydrate intolerance causing hyperglycemia seems clear, glucose values in pregnancy are a continuum with no clear threshold at which risks increase: what constitutes hyperglycemia in pregnancy remains debatable. Worldwide, varying screening approaches and diagnostic guidelines are being used, often within single countries, due to differences in resource settings, risk factor distribution, juridical factors, and in some cases historical context. Specific diagnostic thresholds for GDM as well as intensity of glucose lowering with treatment remain controversial and the need for critical evaluation and consensus is high.
Voormolen et al.
World Health Organization (WHO) extended the recommendation to be used in pregnancy, although the test had never been investigated in pregnant women.1,20 New analytic methods to determine plasma glucose were introduced and translating old measurements into new values resulted in further variation in cutoff values. The 1999 WHO report on definition, screening, and diagnosis of GDM was the first major effort to create universal guidelines.21 These diagnostic criteria for hyperglycemia in pregnancy were based on consensus, while at the same time the urgent need for scientific evaluation of diagnosis and treatment of GDM was stressed. In 2010, the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommended new criteria,22 based on odds ratios (ORs) observed in a large-scale observational study,2 and these have since been endorsed by the WHO.20 These criteria, which include a fasting plasma glucose 5.1 mmol/L, a 1-hour plasma glucose 10.0 mmol/L, or a 2-hour plasma glucose 8.5 mmol/L, diagnose women with milder degrees of hyperglycemia as having GDM, thus increasing its prevalence. An overview of diagnostic criteria can be seen in ►Table 1.
Management of Gestational Diabetes Mellitus Principles of Treatment
Developing Diagnostic Criteria Diagnosing GDM has long been the subject of considerable controversy, and creating GDM diagnostic guidelines has often been consensus driven. In the 1960s, O’Sullivan reported adverse pregnancy outcome in women with GDM.18 They formulated diagnostic criteria based on a 3-hour 100-g oral glucose tolerance test (OGTT) and thresholds were set in relation to the risk of development of future T2DM.19 In 1980, the 2-hour 75-g OGTT was established as the diagnostic test for diabetes in the general population, and the
Lifestyle intervention through optimal nutrition is the preferred initial treatment of GDM, involving optimal nutrition and regular physical exercise.23 Effectiveness of interventions can be monitored by self-monitoring blood glucose.23 The majority of women can be managed with lifestyle intervention alone. However, if glycemic targets are not achieved, management is escalated by introduction of pharmacotherapy.
Lifestyle Interventions The American Diabetes Association (ADA) recommends nutritional counselling by a registered dietician with a
Table 1 Guidelines on glucose values for the diagnosis of GDM Guideline
Glucose load
Fasting plasma glucose (mmol/L)
WHO 1999
75 g OGTTa
7.0
a
6.1
Modified WHO 1999
75 g OGTT
WHO 2013
75 g OGTTa
5.1–6.9
1-h plasma glucose (mmol/L)
2-h plasma glucose (mmol/L) 7.8 7.8
10.0
8.5–11.0
75 g OGTT
a
7.0
NICE 2015
75 g OGTT
a
5.6
IADPSG 2013, ADA 2014, ADIPS 2014
75 g OGTTa
5.1
10.0
8.5
ACOG 2013
100 g OGTTb
5.3
10.0
8.6
CDA 2013
75 g OGTTa
5.3
10.6
9.0
NICE 2008
3-h plasma glucose (mmol/L)
7.8 7.8
7.8
Abbreviations: ACOG, American Congress of Obstetricians and Gynecologists; ADA, American Diabetes Association; ADIPS, Australasian Diabetes in Pregnancy Society; CDA, Canadian Diabetes Association; GDM, gestational diabetes mellitus; IADPSG, International Association of Diabetes and Pregnancy Study Groups; NICE, National Institute for Health and Care Excellence (UK); OGTT, oral glucose tolerance test; WHO, World Health Organization. a Requires one abnormality for diagnosis. b Requires two abnormalities for diagnosis. Seminars in Reproductive Medicine
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Diagnostic Criteria and Treatment for Gestational Diabetes Mellitus
Diagnostic Criteria and Treatment for Gestational Diabetes Mellitus
Pharmacotherapy Glibenclamide (glyburide) and metformin are increasingly used in the management of GDM, with their use now recommended by several organisations.23,26,31,32 Langer et al found equivalent perinatal outcomes in 404 women randomly assigned to glibenclamide or insulin, with only 4% of women in the glibenclamide group requiring additional insulin.33 The Metformin in GDM (MiG) trial found similar perinatal outcomes in 751 women randomized to metformin versus insulin.34 However, metformin was associated with a slight increase in preterm birth rate, while at the doses used, 46% of the women required supplemental insulin.34 Metformin crosses the placenta, but to date, no long-term ill effects have been reported in offspring exposed to metformin in utero.35,36 Insulin is often the preferred therapy for women who fail dietary intervention. Short-acting insulin is used to cover glucose excursions following the meal and intermediate- or long-acting insulin for hepatic glucose production in the fasting state. Rapid-acting insulin analogs lispro and aspart are safe in pregnancy, do not cross the placenta, and are superior to regular insulin for reducing postprandial glucose excursions.24,25,37 The long-acting insulin analog detemir has recently been approved in pregnancy and there appear to be no major safety concerns with glargine, although data are limited.37 A recent systematic review and meta-analysis of 15 randomized controlled trials (RCTs), including 2,509 women with GDM, compared the use of glibenclamide, metformin, and insulin.38 Glibenclamide compared with insulin was associated with increased birthweight, macrosomia, and neonatal hypoglycemia. Metformin was associated with less
maternal weight gain, earlier gestational age at delivery, more preterm birth, and a trend for reduced neonatal hypoglycemia compared with insulin. Metformin was associated with less maternal weight gain, lower birth weight, less macrosomia, and LGA offspring compared with glibenclamide, but treatment failure rates were higher with metformin. Overall, the authors concluded that metformin (plus insulin where required) was the most effective therapy with regard to pregnancy outcomes. Despite short-term efficacy, longer-term effects of oral hypoglycemic agents on offspring remain largely unknown and require more research. Long-term follow-up of the MiG trial demonstrated that offspring at age 2 years who had been exposed to metformin in utero showed no difference in total body fat but had greater measures of subcutaneous fat, suggesting a decrease in visceral fat.39 While glibenclamide is thought to be safe and minimally crosses the placenta, little is known about its long-term effects on maternal and fetal β cells.23,26
Intervention Studies Two landmark studies have provided valuable insight in the treatment of GDM. The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) randomized women diagnosed with GDM (75 g OGTT at 24–34 weeks: fasting plasma glucose 4,000 g, and preeclampsia. There were increased neonatal nursery admissions and induction of labor, but similar rates of cesarean section. The NICHD maternal–fetal medicine unit (MFMU) in the United States randomized women with mild GDM (3-hour OGTT at 24–31 weeks: fasting glucose 5.3 mmol/L, 2 hours >6.7 mmol/L). There was no difference in the primary composite perinatal outcome (perinatal death, neonatal hypoglycemia, increased cord C-peptide, or birth trauma), but a reduction in the secondary outcomes: LGA, birth weight >4,000 g, neonatal fat mass, shoulder dystocia, hypertensive complications, and cesarean delivery. While the two largest studies showed benefit of treatment of GDM, the treatment effect in the ACHOIS study was mainly established by shoulder dystocia not resulting in injury, while the NICHD study did not show a difference in the primary endpoint. In addition, the NICHD study achieved its effect in Seminars in Reproductive Medicine
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personalized plan based on the individual’s body mass index (BMI).24,25 Generally, a diet where carbohydrate intake is limited to 35 to 40% of calories spread throughout the day, with preference for complex carbohydrates and low glycemic index foods, minimizes postprandial hyperglycemia.26 Regular physical activity promotes healthy lifestyle and behaviors, reduces insulin resistance, and improves insulin sensitivity. Daily moderate exercise is recommended for 30 minutes.26 Overweight and obesity increase the risks for GDM, hypertensive complications of pregnancy, stillbirth, and delivery complications. Pre-pregnancy overweight and obesity account for a high proportion of babies who were large for gestational age (LGA), even in the absence of GDM.27,28 The Institute of Medicine has published recommendations for GWG based on pre-pregnancy BMI. However, many women have reached or exceeded such recommendations when a diagnosis of GDM is made and there are no recommendations specific to women with GDM.29 Dietary and lifestyle interventions in pregnancy may reduce maternal GWG, which may in turn improve maternal pregnancy outcomes, but they may have little effect on the fetus/neonate. This will be discussed elsewhere in this special issue of Seminars in Reproductive Endocrinology.30 Further research is required to determine how to optimize pre-pregnancy weight and limit excess GWG to minimize adverse pregnancy outcomes.
Voormolen et al.
women pregnant with a male fetus.14,40 Finally, it is uncertain whether the benefits described in these two RCTs may be extended to the additional women identified by the criteria from the IADPSG.24 The IADPSG criteria include a group of women with GDM that is milder than that of the women in the ACHOIS and NICHD studies. Emerging studies using IADPSG criteria are showing rates of poor pregnancy outcomes similar to those seen in women diagnosed by old criteria, suggesting the benefits may translate.41–43 However, this should be the topic of new randomized clinical trials. A recent meta-analysis by the U.S. Preventative Services Task Force44 summarized evidence from five RCTs and six cohort studies and found that treating GDM (with dietary modification, glucose monitoring, and insulin as needed) resulted in significantly less preeclampsia (pooled risk ratio: 0.62 [95% confidence interval (CI): 0.43–0.89]), shoulder dystocia (0.42 [0.23–0.77]), and macrosomia (0.50 [0.35– 0.71]). They did not find an effect on neonatal hypoglycemia or jaundice, and evidence was insufficient regarding maternal weight gain and birth injury. In addition, it remains unclear whether long-term benefits to women and their offspring will result from treatment of GDM regardless of diagnostic criteria.24,44
Recent Studies Examining Diagnostic Criteria While uncertainty remains on which women should be treated for GDM, more recent research has focused on reexamining diagnostic criteria. A landmark study in the field of GDM is the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study.2 This international multicenter prospective observational study of 25,505 women in 15 centers in nine countries, conducted between July 2000 and April 2006, studied the risk of adverse outcomes associated with various degrees of maternal glucose intolerance. A universal screening strategy was applied for all consenting women, who received a 75-g OGTT between 24 and 32 weeks of gestation. Patients and caregivers were unaware of the test results unless the post-load glucose value was diagnostic of diabetes (2-hour plasma glucose >11.1 mmol/L) or if the fasting glucose was >5.8 mmol/L or a random plasma glucose was 8.9 mmol/L. Women who had any glucose testing before recruitment or had a previous diagnosis of diabetes were excluded. A total of 23,316 women were included with a mean age of 29.2 5.8 years and a mean BMI of 27.7 5.1 kg/m2 (range of means among centers: 24.4–29.9). There was a continuous linear association between maternal glucose and adverse pregnancy outcomes, with no threshold for increased risk. With increasing maternal glucose values, the incidence of all primary outcome measures (birth weight >90th percentile, primary cesarean section, clinical neonatal hypoglycemia, and fetal hyperinsulinemia as measured by a cord-blood serum C-peptide >90th percentile) increased. Several secondary outcome measures, including preeclampsia, shoulder dystocia, premature delivery, need for neonatal intensive care, and neonatal hyperbilirubinemia, were also associated with increased maternal glucose. Seminars in Reproductive Medicine
Voormolen et al.
The HAPO study results provided the basis for the IADPSG consensus panel recommendations in 2010.22 New, lower, diagnostic cutoff values for GDM were formulated, based on the HAPO data. In contrast to previous thresholds set at glucose values that related to a doubling of risks of subsequent maternal T2DM, the threshold values here related to the mean fasting, 1 hour, and 2 hour post-load glucose values with an OR of an arbitrarily determined 1.75 for birth weight >90th percentile, cord C-peptide >90th percentile, and neonatal percent body fat >90th percentile, compared with the risk of these outcomes at the mean glucose values at these time points across the whole HAPO study population. Both the WHO and the ADA followed the IADPSG recommendations. However, the new “milder” criteria have not been adopted by either the American National Institutes of Health (NIH) or the British National Institute for Health and Care Excellence (NICE), due to concerns about the lack of robust evidence on treatment benefit and costs.32,45 An updated NICE guideline was published in 2015, advocating yet different diagnostic criteria. The ADA has since acknowledged that the evidence is limited and that various criteria could be justified. An overview of the various diagnostic criteria presented by different guidelines can be seen in ►Table 1. Despite new insights presented by clinical studies and several expert panels, international consensus has still not been reached.
Critical Consideration of New Gestational Diabetes Mellitus Criteria While many have welcomed the new stricter IADPSG/WHO criteria, others have expressed concerns. The WHO 2013 criteria will greatly extend the GDM population with a group of pregnant women with mild “hyperglycemia.” Depending on the background population, the screening strategy (universal vs. selective), and the timing of the screening (gestational age when tested), the new criteria will result in up to 15 to 35% of all pregnant women being diagnosed with GDM.46 This has immediate major consequences, both for pregnant women and for the available resources in health facilities. Therefore, adopting the new criteria must be critically considered. Wilson and Jungner formulated in 1968 their general principles of screening.47 The disease should be medically relevant, clearly defined, and have a relatively high prevalence. Furthermore, the natural course of disease must be known, and an effective treatment must be available. The screening strategy must be cost-effective, and facilities for testing and treating must be readily available. Test-specific requisites are good sensitivity (the ability to give a positive result when the subject has the disease) and specificity (the ability to give a negative result when the subject is free from the disease) and it must be safe, inexpensive, and patient friendly.48,49 Screening can improve health, but inappropriate screening is potentially harmful and wastes valuable resources. When considering the earlier-mentioned screening principles, several critical concerns are present in relation to recent IADPSG/WHO GDM screening guidelines.
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Diagnostic Criteria and Treatment for Gestational Diabetes Mellitus
GDM fulfils many of these criteria of a disease worth screening for: it is a medically relevant condition, and treatment is effective in reducing pregnancy complications, although this applies to GDM as defined by older criteria.50 The IADPSG/WHO criteria redefine GDM by incorporating a large group of mild cases, and the previous shown treatment benefits cannot be automatically translated to the new GDM population. Reevaluation of treatment effects in the appropriate patient group, for example, including the mild cases, is required. Several retrospective analyses have been done, calculating the potential treatment benefit in untreated populations, but this is methodologically weak. Furthermore, treating this new mild patient group might even have harmful effects that must be considered: treatment of these women might expose the fetus to relative undernutrition, which could interfere with programing for future metabolic disease.51 This overtreatment/undernutrition paradigm has been shown to be an issue with excess numbers of small for gestational age (SGA) classified babies in studies of GDM.52 As there is a linear relation between hyperglycemia and adverse pregnancy outcome, any diagnostic cutoff value will be arbitrary. It might be better to introduce a multivariable approach that incorporates other patient characteristics in overall risk assessment.53 Nevertheless, before implementing new threshold values for the diagnosis of GDM, empirical studies on treatment effectiveness are indispensable.32 Welldesigned RCTs including cost-effectiveness should serve as a basis for such rigorous guideline adaptations.32
Glucose Treatment Targets and Controversies in Gestational Diabetes Mellitus Goals of Therapy in GDM The new lower IADPSG diagnostic targets have also raised controversy about glucose treatment targets in women with a diagnosis of GDM. Historically, the treatment goal in pregnancies complicated by diabetes has been to mimic patterns of glycemia in normal pregnancy, to “normalize” maternal and fetal outcomes.54 Current recommended glucose targets have improved, but arguably not normalized, perinatal outcomes. Furthermore, fetal macrosomia still occurs with excellent glycemic control, and there have been calls to reexamine critically the patterns of “normal” maternal glycemia and their effect on fetal growth.55 Other nutrients than glucose, such as free fatty acids and triglycerides, influence fetal growth,56 and pre-pregnancy BMI and excess GWG have major roles.27 However, tight glycemic control remains the focus of management strategies until sufficient evidence accumulates to recommend lipid goals appropriate to women with GDM. Self-monitoring of plasma glucose is recommended at least four times daily, fasting and either 1 or 2 hours postprandial, and the frequency of monitoring is modified depending on glucose goals.26
Evidence for Glucose Treatment Targets The evidence for optimal glucose targets in women with GDM is limited and of variable quality. The two key RCTs in treatment of GDM outlined earlier (ACHOIS and the NICHD
Voormolen et al.
studies) utilized different glucose targets and thresholds for insulin commencement.13,14 Targets recommended by the 2007 Fifth International Workshop on GDM are 5.3 mmol/L (95 mg/dL) fasting,
Utrecht, The Netherlands 2 Monash Centre for Health Research and Implementation, School of Public Health and Preventative Medicine, Monash University, Clayton, Victoria, Australia 3 Department of Obstetrics and Gynaecology, Women’s and Children’s Hospital, Adelaide, Australia 4 Department of Obstetrics and Gynaecology, South Australian Health and Medical Research Institute, Adelaide, Australia 5 The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
Address for correspondence Ben Willem Mol, MD, PhD, The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide 5000 SA, Australia (e-mail: [email protected]).
Semin Reprod Med
Abstract
Keywords
► gestational diabetes ► GDM diagnostic criteria ► treatment ► guidelines
The prevalence of gestational diabetes mellitus (GDM) is high, and the risks of maternal and perinatal complications with clear hyperglycemia are well recognized. The worldwide obesity epidemic and the consequent excess of hyperglycemia have resulted in a rising prevalence of GDM. Changing definitions and more intensive screening may also be contributing to an increased prevalence. Despite the recognized risks, much controversy surrounds the screening, diagnosis, and treatment of GDM. The more stringent diagnostic criteria, advocated in new guidelines, are based on observational studies and are not guided by interventional studies. Here, we review the evidence behind updated diagnostic criteria, stricter treatment targets, and current controversies and conclude that international consensus regarding diagnosis and treatment will only be achieved with further evidence from interventional studies.
Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance causing hyperglycemia with onset or first recognition at any time during pregnancy.1 GDM generally occurs when a pregnant woman is not able to compensate for the physiologic hormone-driven increase in insulin resistance, together with decreased insulin sensitivity, resulting in hyperglycemia. Hyperglycemia increases the risk for pregnancy complications, such as preeclampsia, still birth, and fetal macrosomia leading to slow or even obstructed labor with shoulder dystocia, requiring operative vaginal delivery or cesarean section. The neonates risk prematurity, neonatal hypoglycemia, respiratory distress syndrome, and hyperbilirubinemia.2
Issue Theme Lifestyle in Reproductive Medicine; Guest Editors, Lisa Moran, PhD, BND, BSc (Hons) and Helena Teede, MBBS, PhD, FRACP
Advanced maternal age, non-Europid ethnicity, family history of diabetes, personal history of GDM, polycystic ovary syndrome, and overweight all predispose to GDM3,4. Prepregnancy obesity5 and excessive gestational weight gain (GWG)6 are commonly seen in women with GDM and are both independently associated with adverse pregnancy outcome. The association between GDM and later onset of type 2 diabetes mellitus (T2DM) and cardiovascular disease is well established.7–9 Moreover, children born to women with GDM are at increased risk of macrosomia with higher subsequent risk of obesity, T2DM, and hypertension in early life.10–12 Body mass and lifestyle are key features in GDM etiology, treatment, and prevention. The treatment of GDM aims at
Copyright © by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0036-1572440. ISSN 1526-8004.
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1 Department of Obstetrics, University Medical Center Utrecht,
tight glycemic control, primarily by lifestyle adjustments. For the majority of patients, dietary alteration and increase in exercise are adequate therapy to improve glycemia, but 20 to 40% of women require additional treatment with pharmacotherapy, depending on treatment targets. Treatment of GDM has been shown in interventional studies to reduce perinatal complications.13,14 Following a pregnancy complicated by GDM, women have a 30% risk of recurrent GDM in a subsequent pregnancy15 as well as a sevenfold risk of developing T2DM in the longer term.16 Regular monitoring, life style adjustment, reduction of obesity, and metformin therapy have been shown to reduce the incidence of T2DM.17 This view on GDM may seem logical from a pathophysiologic point of view, but while a definition of GDM as any degree of carbohydrate intolerance causing hyperglycemia seems clear, glucose values in pregnancy are a continuum with no clear threshold at which risks increase: what constitutes hyperglycemia in pregnancy remains debatable. Worldwide, varying screening approaches and diagnostic guidelines are being used, often within single countries, due to differences in resource settings, risk factor distribution, juridical factors, and in some cases historical context. Specific diagnostic thresholds for GDM as well as intensity of glucose lowering with treatment remain controversial and the need for critical evaluation and consensus is high.
Voormolen et al.
World Health Organization (WHO) extended the recommendation to be used in pregnancy, although the test had never been investigated in pregnant women.1,20 New analytic methods to determine plasma glucose were introduced and translating old measurements into new values resulted in further variation in cutoff values. The 1999 WHO report on definition, screening, and diagnosis of GDM was the first major effort to create universal guidelines.21 These diagnostic criteria for hyperglycemia in pregnancy were based on consensus, while at the same time the urgent need for scientific evaluation of diagnosis and treatment of GDM was stressed. In 2010, the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommended new criteria,22 based on odds ratios (ORs) observed in a large-scale observational study,2 and these have since been endorsed by the WHO.20 These criteria, which include a fasting plasma glucose 5.1 mmol/L, a 1-hour plasma glucose 10.0 mmol/L, or a 2-hour plasma glucose 8.5 mmol/L, diagnose women with milder degrees of hyperglycemia as having GDM, thus increasing its prevalence. An overview of diagnostic criteria can be seen in ►Table 1.
Management of Gestational Diabetes Mellitus Principles of Treatment
Developing Diagnostic Criteria Diagnosing GDM has long been the subject of considerable controversy, and creating GDM diagnostic guidelines has often been consensus driven. In the 1960s, O’Sullivan reported adverse pregnancy outcome in women with GDM.18 They formulated diagnostic criteria based on a 3-hour 100-g oral glucose tolerance test (OGTT) and thresholds were set in relation to the risk of development of future T2DM.19 In 1980, the 2-hour 75-g OGTT was established as the diagnostic test for diabetes in the general population, and the
Lifestyle intervention through optimal nutrition is the preferred initial treatment of GDM, involving optimal nutrition and regular physical exercise.23 Effectiveness of interventions can be monitored by self-monitoring blood glucose.23 The majority of women can be managed with lifestyle intervention alone. However, if glycemic targets are not achieved, management is escalated by introduction of pharmacotherapy.
Lifestyle Interventions The American Diabetes Association (ADA) recommends nutritional counselling by a registered dietician with a
Table 1 Guidelines on glucose values for the diagnosis of GDM Guideline
Glucose load
Fasting plasma glucose (mmol/L)
WHO 1999
75 g OGTTa
7.0
a
6.1
Modified WHO 1999
75 g OGTT
WHO 2013
75 g OGTTa
5.1–6.9
1-h plasma glucose (mmol/L)
2-h plasma glucose (mmol/L) 7.8 7.8
10.0
8.5–11.0
75 g OGTT
a
7.0
NICE 2015
75 g OGTT
a
5.6
IADPSG 2013, ADA 2014, ADIPS 2014
75 g OGTTa
5.1
10.0
8.5
ACOG 2013
100 g OGTTb
5.3
10.0
8.6
CDA 2013
75 g OGTTa
5.3
10.6
9.0
NICE 2008
3-h plasma glucose (mmol/L)
7.8 7.8
7.8
Abbreviations: ACOG, American Congress of Obstetricians and Gynecologists; ADA, American Diabetes Association; ADIPS, Australasian Diabetes in Pregnancy Society; CDA, Canadian Diabetes Association; GDM, gestational diabetes mellitus; IADPSG, International Association of Diabetes and Pregnancy Study Groups; NICE, National Institute for Health and Care Excellence (UK); OGTT, oral glucose tolerance test; WHO, World Health Organization. a Requires one abnormality for diagnosis. b Requires two abnormalities for diagnosis. Seminars in Reproductive Medicine
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Diagnostic Criteria and Treatment for Gestational Diabetes Mellitus
Diagnostic Criteria and Treatment for Gestational Diabetes Mellitus
Pharmacotherapy Glibenclamide (glyburide) and metformin are increasingly used in the management of GDM, with their use now recommended by several organisations.23,26,31,32 Langer et al found equivalent perinatal outcomes in 404 women randomly assigned to glibenclamide or insulin, with only 4% of women in the glibenclamide group requiring additional insulin.33 The Metformin in GDM (MiG) trial found similar perinatal outcomes in 751 women randomized to metformin versus insulin.34 However, metformin was associated with a slight increase in preterm birth rate, while at the doses used, 46% of the women required supplemental insulin.34 Metformin crosses the placenta, but to date, no long-term ill effects have been reported in offspring exposed to metformin in utero.35,36 Insulin is often the preferred therapy for women who fail dietary intervention. Short-acting insulin is used to cover glucose excursions following the meal and intermediate- or long-acting insulin for hepatic glucose production in the fasting state. Rapid-acting insulin analogs lispro and aspart are safe in pregnancy, do not cross the placenta, and are superior to regular insulin for reducing postprandial glucose excursions.24,25,37 The long-acting insulin analog detemir has recently been approved in pregnancy and there appear to be no major safety concerns with glargine, although data are limited.37 A recent systematic review and meta-analysis of 15 randomized controlled trials (RCTs), including 2,509 women with GDM, compared the use of glibenclamide, metformin, and insulin.38 Glibenclamide compared with insulin was associated with increased birthweight, macrosomia, and neonatal hypoglycemia. Metformin was associated with less
maternal weight gain, earlier gestational age at delivery, more preterm birth, and a trend for reduced neonatal hypoglycemia compared with insulin. Metformin was associated with less maternal weight gain, lower birth weight, less macrosomia, and LGA offspring compared with glibenclamide, but treatment failure rates were higher with metformin. Overall, the authors concluded that metformin (plus insulin where required) was the most effective therapy with regard to pregnancy outcomes. Despite short-term efficacy, longer-term effects of oral hypoglycemic agents on offspring remain largely unknown and require more research. Long-term follow-up of the MiG trial demonstrated that offspring at age 2 years who had been exposed to metformin in utero showed no difference in total body fat but had greater measures of subcutaneous fat, suggesting a decrease in visceral fat.39 While glibenclamide is thought to be safe and minimally crosses the placenta, little is known about its long-term effects on maternal and fetal β cells.23,26
Intervention Studies Two landmark studies have provided valuable insight in the treatment of GDM. The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) randomized women diagnosed with GDM (75 g OGTT at 24–34 weeks: fasting plasma glucose 4,000 g, and preeclampsia. There were increased neonatal nursery admissions and induction of labor, but similar rates of cesarean section. The NICHD maternal–fetal medicine unit (MFMU) in the United States randomized women with mild GDM (3-hour OGTT at 24–31 weeks: fasting glucose 5.3 mmol/L, 2 hours >6.7 mmol/L). There was no difference in the primary composite perinatal outcome (perinatal death, neonatal hypoglycemia, increased cord C-peptide, or birth trauma), but a reduction in the secondary outcomes: LGA, birth weight >4,000 g, neonatal fat mass, shoulder dystocia, hypertensive complications, and cesarean delivery. While the two largest studies showed benefit of treatment of GDM, the treatment effect in the ACHOIS study was mainly established by shoulder dystocia not resulting in injury, while the NICHD study did not show a difference in the primary endpoint. In addition, the NICHD study achieved its effect in Seminars in Reproductive Medicine
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personalized plan based on the individual’s body mass index (BMI).24,25 Generally, a diet where carbohydrate intake is limited to 35 to 40% of calories spread throughout the day, with preference for complex carbohydrates and low glycemic index foods, minimizes postprandial hyperglycemia.26 Regular physical activity promotes healthy lifestyle and behaviors, reduces insulin resistance, and improves insulin sensitivity. Daily moderate exercise is recommended for 30 minutes.26 Overweight and obesity increase the risks for GDM, hypertensive complications of pregnancy, stillbirth, and delivery complications. Pre-pregnancy overweight and obesity account for a high proportion of babies who were large for gestational age (LGA), even in the absence of GDM.27,28 The Institute of Medicine has published recommendations for GWG based on pre-pregnancy BMI. However, many women have reached or exceeded such recommendations when a diagnosis of GDM is made and there are no recommendations specific to women with GDM.29 Dietary and lifestyle interventions in pregnancy may reduce maternal GWG, which may in turn improve maternal pregnancy outcomes, but they may have little effect on the fetus/neonate. This will be discussed elsewhere in this special issue of Seminars in Reproductive Endocrinology.30 Further research is required to determine how to optimize pre-pregnancy weight and limit excess GWG to minimize adverse pregnancy outcomes.
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women pregnant with a male fetus.14,40 Finally, it is uncertain whether the benefits described in these two RCTs may be extended to the additional women identified by the criteria from the IADPSG.24 The IADPSG criteria include a group of women with GDM that is milder than that of the women in the ACHOIS and NICHD studies. Emerging studies using IADPSG criteria are showing rates of poor pregnancy outcomes similar to those seen in women diagnosed by old criteria, suggesting the benefits may translate.41–43 However, this should be the topic of new randomized clinical trials. A recent meta-analysis by the U.S. Preventative Services Task Force44 summarized evidence from five RCTs and six cohort studies and found that treating GDM (with dietary modification, glucose monitoring, and insulin as needed) resulted in significantly less preeclampsia (pooled risk ratio: 0.62 [95% confidence interval (CI): 0.43–0.89]), shoulder dystocia (0.42 [0.23–0.77]), and macrosomia (0.50 [0.35– 0.71]). They did not find an effect on neonatal hypoglycemia or jaundice, and evidence was insufficient regarding maternal weight gain and birth injury. In addition, it remains unclear whether long-term benefits to women and their offspring will result from treatment of GDM regardless of diagnostic criteria.24,44
Recent Studies Examining Diagnostic Criteria While uncertainty remains on which women should be treated for GDM, more recent research has focused on reexamining diagnostic criteria. A landmark study in the field of GDM is the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study.2 This international multicenter prospective observational study of 25,505 women in 15 centers in nine countries, conducted between July 2000 and April 2006, studied the risk of adverse outcomes associated with various degrees of maternal glucose intolerance. A universal screening strategy was applied for all consenting women, who received a 75-g OGTT between 24 and 32 weeks of gestation. Patients and caregivers were unaware of the test results unless the post-load glucose value was diagnostic of diabetes (2-hour plasma glucose >11.1 mmol/L) or if the fasting glucose was >5.8 mmol/L or a random plasma glucose was 8.9 mmol/L. Women who had any glucose testing before recruitment or had a previous diagnosis of diabetes were excluded. A total of 23,316 women were included with a mean age of 29.2 5.8 years and a mean BMI of 27.7 5.1 kg/m2 (range of means among centers: 24.4–29.9). There was a continuous linear association between maternal glucose and adverse pregnancy outcomes, with no threshold for increased risk. With increasing maternal glucose values, the incidence of all primary outcome measures (birth weight >90th percentile, primary cesarean section, clinical neonatal hypoglycemia, and fetal hyperinsulinemia as measured by a cord-blood serum C-peptide >90th percentile) increased. Several secondary outcome measures, including preeclampsia, shoulder dystocia, premature delivery, need for neonatal intensive care, and neonatal hyperbilirubinemia, were also associated with increased maternal glucose. Seminars in Reproductive Medicine
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The HAPO study results provided the basis for the IADPSG consensus panel recommendations in 2010.22 New, lower, diagnostic cutoff values for GDM were formulated, based on the HAPO data. In contrast to previous thresholds set at glucose values that related to a doubling of risks of subsequent maternal T2DM, the threshold values here related to the mean fasting, 1 hour, and 2 hour post-load glucose values with an OR of an arbitrarily determined 1.75 for birth weight >90th percentile, cord C-peptide >90th percentile, and neonatal percent body fat >90th percentile, compared with the risk of these outcomes at the mean glucose values at these time points across the whole HAPO study population. Both the WHO and the ADA followed the IADPSG recommendations. However, the new “milder” criteria have not been adopted by either the American National Institutes of Health (NIH) or the British National Institute for Health and Care Excellence (NICE), due to concerns about the lack of robust evidence on treatment benefit and costs.32,45 An updated NICE guideline was published in 2015, advocating yet different diagnostic criteria. The ADA has since acknowledged that the evidence is limited and that various criteria could be justified. An overview of the various diagnostic criteria presented by different guidelines can be seen in ►Table 1. Despite new insights presented by clinical studies and several expert panels, international consensus has still not been reached.
Critical Consideration of New Gestational Diabetes Mellitus Criteria While many have welcomed the new stricter IADPSG/WHO criteria, others have expressed concerns. The WHO 2013 criteria will greatly extend the GDM population with a group of pregnant women with mild “hyperglycemia.” Depending on the background population, the screening strategy (universal vs. selective), and the timing of the screening (gestational age when tested), the new criteria will result in up to 15 to 35% of all pregnant women being diagnosed with GDM.46 This has immediate major consequences, both for pregnant women and for the available resources in health facilities. Therefore, adopting the new criteria must be critically considered. Wilson and Jungner formulated in 1968 their general principles of screening.47 The disease should be medically relevant, clearly defined, and have a relatively high prevalence. Furthermore, the natural course of disease must be known, and an effective treatment must be available. The screening strategy must be cost-effective, and facilities for testing and treating must be readily available. Test-specific requisites are good sensitivity (the ability to give a positive result when the subject has the disease) and specificity (the ability to give a negative result when the subject is free from the disease) and it must be safe, inexpensive, and patient friendly.48,49 Screening can improve health, but inappropriate screening is potentially harmful and wastes valuable resources. When considering the earlier-mentioned screening principles, several critical concerns are present in relation to recent IADPSG/WHO GDM screening guidelines.
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Diagnostic Criteria and Treatment for Gestational Diabetes Mellitus
GDM fulfils many of these criteria of a disease worth screening for: it is a medically relevant condition, and treatment is effective in reducing pregnancy complications, although this applies to GDM as defined by older criteria.50 The IADPSG/WHO criteria redefine GDM by incorporating a large group of mild cases, and the previous shown treatment benefits cannot be automatically translated to the new GDM population. Reevaluation of treatment effects in the appropriate patient group, for example, including the mild cases, is required. Several retrospective analyses have been done, calculating the potential treatment benefit in untreated populations, but this is methodologically weak. Furthermore, treating this new mild patient group might even have harmful effects that must be considered: treatment of these women might expose the fetus to relative undernutrition, which could interfere with programing for future metabolic disease.51 This overtreatment/undernutrition paradigm has been shown to be an issue with excess numbers of small for gestational age (SGA) classified babies in studies of GDM.52 As there is a linear relation between hyperglycemia and adverse pregnancy outcome, any diagnostic cutoff value will be arbitrary. It might be better to introduce a multivariable approach that incorporates other patient characteristics in overall risk assessment.53 Nevertheless, before implementing new threshold values for the diagnosis of GDM, empirical studies on treatment effectiveness are indispensable.32 Welldesigned RCTs including cost-effectiveness should serve as a basis for such rigorous guideline adaptations.32
Glucose Treatment Targets and Controversies in Gestational Diabetes Mellitus Goals of Therapy in GDM The new lower IADPSG diagnostic targets have also raised controversy about glucose treatment targets in women with a diagnosis of GDM. Historically, the treatment goal in pregnancies complicated by diabetes has been to mimic patterns of glycemia in normal pregnancy, to “normalize” maternal and fetal outcomes.54 Current recommended glucose targets have improved, but arguably not normalized, perinatal outcomes. Furthermore, fetal macrosomia still occurs with excellent glycemic control, and there have been calls to reexamine critically the patterns of “normal” maternal glycemia and their effect on fetal growth.55 Other nutrients than glucose, such as free fatty acids and triglycerides, influence fetal growth,56 and pre-pregnancy BMI and excess GWG have major roles.27 However, tight glycemic control remains the focus of management strategies until sufficient evidence accumulates to recommend lipid goals appropriate to women with GDM. Self-monitoring of plasma glucose is recommended at least four times daily, fasting and either 1 or 2 hours postprandial, and the frequency of monitoring is modified depending on glucose goals.26
Evidence for Glucose Treatment Targets The evidence for optimal glucose targets in women with GDM is limited and of variable quality. The two key RCTs in treatment of GDM outlined earlier (ACHOIS and the NICHD
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studies) utilized different glucose targets and thresholds for insulin commencement.13,14 Targets recommended by the 2007 Fifth International Workshop on GDM are 5.3 mmol/L (95 mg/dL) fasting,
