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Although the term ‘gestational diabetes’ was coined by Carrington in 1957 (ref.^1 ), it only gained wider recog- nition after the publications of John O’Sullivan in 1961 (ref.^2 ) and 1964 (ref.^3 ). However, the phenomenon of hyperglycaemia that develops during pregnancy (gen- erally detected in the late second trimester (13–26 com- pleted weeks of gestation) or early in the third trimester (27–40 weeks)) and resolves following delivery, was noted some time before^4. Complexity and controversy have shadowed the diagnosis of gestational diabetes mellitus (GDM) ever since, partly owing to the very broad definition that was initially promoted 5 , which allowed for “any degree of hyperglycaemia first recognized in pregnancy”, irrespec- tive of the treatment required or the extent of postpar- tum resolution of hyperglycaemia. Consequently, ‘GDM’ encompassed a broad range of hyperglycaemia, from mild impaired glucose tolerance (IGT) or impaired fast- ing glucose (IFG) detected in late pregnancy to glucose levels characteristic of overt diabetes (or, rarely, even new-onset type 1 diabetes mellitus (T1DM)) detected in early pregnancy (<20 weeks of gestation). Although more severe hyperglycaemia was initially uncommon, it has become much more prominent with the expanding worldwide epidemics of diabetes and obesity and the
societal trend for childbearing at a later age, especially in regions in which obesity and early-onset diabetes are also common. For example, in the USA, the reported prevalence of overt diabetes in adults 20–22 years of age is 4.5%, and a further 29.3% of these individuals have detectable pre-diabetes (IFG, IGT or impaired glycated haemoglobin (HbA1c))^6. In the context of this epidemic of hyperglycaemia outside pregnancy, it is highly likely that many cases diagnosed as GDM actually repre- sent undiagnosed pre- pregnancy hyperglycaemia of varying severity. Globally, no single diagnostic protocol or set of diag- nostic criteria for GDM has gained universal accept- ance, making international comparisons difficult. However, the International Association of Diabetes in Pregnancy Study Groups (IADPSG) 2010 criteria 7 , which were endorsed by the WHO in 2013 (ref.^8 ), clas- sify women who are first diagnosed during pregnancy but who would be diagnosed with diabetes if hyper- glycaemia were detected outside of pregnancy as distinct from women who have ‘standard’ GDM. IADPSG described these women as having ‘overt dia- betes’ whereas the WHO preferred the term ‘diabetes in pregnancy’. However, both groups recognized that these women had severe hyperglycaemia that merited
Gestational diabetes mellitus
H. David McIntyre^1 *, Patrick Catalano 2 , Cuilin Zhang 3 , Gernot Desoye 4 ,
Elisabeth R. Mathiesen 5 and Peter Damm 6
Abstract | Hyperglycaemia that develops during pregnancy and resolves after birth has been recognized for over 50 years, but uniform worldwide consensus is lacking about threshold hyperglycaemic levels that merit a diagnosis of ‘gestational diabetes mellitus’ (GDM) and thus treatment during pregnancy. GDM is currently the most common medical complication of pregnancy, and prevalence of undiagnosed hyperglycaemia and even overt diabetes in young women is increasing. Maternal overweight and obesity, later age at childbearing, previous history of GDM, family history of type 2 diabetes mellitus and ethnicity are major GDM risk factors. Diagnosis is usually performed using an oral glucose tolerance test (OGTT), although a non-fasting, glucose challenge test (GCT) is used in some parts of the world to screen women for those requiring a full OGTT. Dietary modification and increased physical activity are the primary treatments for GDM, but pharmacotherapy, usually insulin, is used when normoglycaemia is not achieved. Oral hypoglycaemic agents, principally metformin and glibenclamide (glyburide), are also used in some countries. Treatment improves immediate pregnancy outcomes, reducing excess fetal growth and adiposity and pregnancy-related hypertensive disorders. GDM increases the risk of long-term complications, including obesity, impaired glucose metabolism and card iovascular disease, in both the mother and infant. Optimal management of mother and infant during long-term follow-up remains challenging, with very limited implementation of preventive strategies in most parts of the world.
*e-mail: David.McIntyre@ mater.org.au https://doi.org/10.1038/ s41572-019-0098-
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immediate treatment and might also have established microvascular complications of diabetes that require timely intervention^9. Thus, these women are at high risk and are clinically distinct from women with less marked hyperglycaemia. However, in this Primer, we consider primarily those women who are classified as having GDM using the IADPSG or WHO 2013 criteria (that is, hyperglycaemia that is first diagnosed during pregnancy, with glucose levels below those considered diagnostic of overt diabetes outside of pregnancy) (Table 1). Irrespective of diagnostic criteria or temporal trends, GDM is important for two reasons. First, GDM increases the risk of complications during pregnancy for both the mother (especially hypertensive disorders of pregnancy) and the fetus (especially those related to excessive fetal growth and adiposity). Second, a GDM diagnosis identifies a group of women and their offspring who are at higher risk of diabetes, obesity and premature cardiovascular disease in the long term10–12. In this Primer, we explore the clinical definition of gestational diabetes and examine its underlying mol- ecular and clinical pathophysiology. We consider the epidemiology and relationship of gestational diabetes to immediate adverse perinatal outcomes, including mater- nal quality of life (QOL). We also discuss the treatment of gestational diabetes during pregnancy and evolv- ing trends in risk factors, prevention and longer-term follow- up of affected mothers and offspring. Finally, we outline future perspectives for treating and under- standing gestational diabetes, including areas requiring further research across the translational spectrum.
Epidemiology Prevalence The documented prevalence of GDM varies substan- tially worldwide, ranging from 1% to >30%. Owing to a lack of consensus and uniformity in the screening stan- dards and diagnostic criteria for GDM, it is challenging to compare the prevalence across countries and regions. Furthermore, historical definitions of GDM make it dif- ficult to differentiate between undiagnosed diabetes and GDM, and GDM diagnostic criteria have changed over the years. To capture the contemporary burden of GDM with the consideration of variations due to these factors, a review of the global prevalence of GDM was carried out on the basis of studies between 2005 and 2015 (ref.^13 ). Using the same methods, we have expanded this
review by including studies published between August 2015 and December 2018. The overall updated GDM prevalence map by WHO regions and country-specific estimates of GDM prevalence are illustrated in figs 1 and 2. The prevalence of GDM is highest in the Middle East and some North African countries, with a median of 15.2% (interquartile range 8.8–20.0%), followed by South-East Asia (median 15.0%; range 9.6–18.3%), the Western Pacific (median 10.3%; range 4.5–20.3%), South and Central America (median 11.2%; range 7.1–16.6%), sub-Saharan Africa (median 10.8%; range 8.5–13.1%) and North America and the Caribbean (median 7.0%; range 6.5–11.9%). The lowest GDM prevalence and widest variation in prevalence is observed in Europe (median 6.1%; range 1.8–31.0%). Even within each region, considerable variation is observed, both within and between countries. For example, in the Western Pacific region, the prevalence ranges from 4.5% in Japan to 18.0% in Singapore. By contrast, among countries in North America, GDM prevalence is relatively consistent. As few studies are available to estimate GDM prevalence in Africa and South and Central America, more studies are clearly warranted in these regions.
Risk factors Epidemiological studies have identified a number of GDM risk factors (box 1), such as advanced maternal age, ethni- city, previous history of gestational diabetes and family history of type 2 diabetes mellitus (T2DM). Although the traditional focus has been on risk factors detected during pregnancy, data support the important role of risk factors during the periconception and preconception periods in the development of GDM14,15.
Age. Advanced maternal age has been related to increased risk of GDM. In a large prospective study in the USA (>95% white ethnicity), women >40 years of age had a more than twofold increased risk of GDM compared with women <30 years of age (prevalence 9.8% versus 4.1%, respectively), even after adjustment for other major risk factors 16. Women carrying a male fetus seem to have a higher risk of developing GDM 17 , and some reports 18 suggest a higher risk of GDM in twin pregnancies, although this is not a universal finding^19.
Geography and ethnicity. It should be noted that even when the same diagnostic criteria were applied, consid- erable variability in prevalence estimates of GDM was observed between different countries (fig. 2), which indicates that variations in the distributions of inherent characteristics of study populations may contribute to the variability. Furthermore, in countries with multi-ethnic populations (such as Australia, the USA and Canada), notable differences in the prevalence of GDM between ethnicities have been observed. For example, in northern California, GDM prevalence was highest among women from the Philippines (10.9%) and Asians (10.2%) and lowest among non-Hispanic white (4.5%) and African- American (4.4%) women 20. In Australia 21 , women of South Asian origin had more than fourfold higher risk of GDM than women of Australian or New Zealand origin, which is consistent with the higher prevalence
Author addresses (^1) Mater Research and University of Queensland, Brisbane, Queensland, Australia. (^2) Mother Infant Research Institute, Department of Obstetrics and Gynecology, Tufts University School of Medicine, Friedman School of Nutrition Science and Policy, Boston, MA, USA. (^3) Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA. (^4) Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria. (^5) Department of Endocrinology, Center for Pregnant Women with Diabetes, Rigshospitalet and The Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. (^6) Department of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet and The Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Genetic factors. Although genetic heritability is impli- cated in the aetiology of GDM, studies that have examined associations of specific genetic factors with GDM are limited and findings are inconsistent. A sys- tematic review and meta- analysis suggested that the minor alleles of nine single-nucleotide polymorphisms (SNPs) in seven genes (such as rs7903146 (in TCF7L2), rs12255372 (in TCF7L2), rs1799884 (−30G/A, in GCK) and rs5219 (E23K, in KCNJ11)), most of which are involved in regulating insulin secretion, are associated with increased risk of GDM, which supports an impor- tant role of pancreatic islet β-cell compensation in the pathogenesis of GDM^44. In the only genome-wide associ- ation study of GDM in an Asian population, two genetic variants, rs10830962 (near MTNR1B) and rs (in CDKAL1) were associated with GDM^45. Subsequently, rs10830962 was associated with β-cell compensation for insulin resistance in Hispanic women with prior GDM^46. In a study of 112 SNPs among 8,722 white women (2, with GDM and 6,086 without GDM) from two inde- pendent populations 47 , 8 novel GDM-associated SNPs were identified. Larger genetic studies of GDM that included information about the fetal and/or paternal genome, gene–gene and gene–environmental inter- actions and in non-white populations are rare. Future studies with larger sample sizes, likely through consor- tium efforts, are warranted to improve understanding of genetic contributions to the aetiology of GDM.
Mechanisms/pathophysiology The metabolic abnormalities underlying GDM include increased insulin resistance and β-cell defects. These defects most likely exist before conception in many cases, especially in populations with high rates of dia- betes and obesity. However, these defects are almost entirely asymptomatic and are generally detected only because of widespread testing of glucose levels during
pregnancy. The metabolic adaptations during preg- nancy place additional stress on β-cells (figs 3,4). The increased risk of T2DM in the years after pregnancy in women with a history of GDM is related both to pre- existing (often undiagnosed) baseline abnormalities and to further, progressive β-cell dysfunction after the index GDM pregnancy, which are associated with factors such as retention of excessive gestational weight gain and increases in insulin resistance. Only a small proportion of women with GDM (2–13%) have antibodies against specific β-cell antigens^48 , whereas approximately 5% of women with GDM have monogenic variants of diabetes mellitus, which most commonly involve mutations in GCK (encoding glucokinase) in white populations 49. As glucokinase phosphorylates glucose to produce glucose-6-phosphate in the pancreas and liver, a hetero- zygous GCK mutation in the mother often results in mildly elevated fasting glucose levels with the attendant risk of excess fetal growth if the fetus does not have the GCK mutation. Interestingly, if the GCK mutation is pres- ent in both the mother and the fetus, then fetal growth is normal, whereas if only the fetus has the GCK muta- tion, there is an increased risk of fetal growth restriction because of altered glucose sensing by the fetal pancreas^50.
Metabolic changes during normal pregnancy To understand the pathophysiology of GDM, one needs to recognize the metabolic alterations that occur in a normal pregnancy. To meet the fasting energy needs of pregnancy, basal endogenous glucose production (primarily hepatic) increases by 30% in healthy preg- nant women by the end of gestation, despite a substantial increase in fasting insulin levels^51. However, circulating fasting glucose concentrations decrease during preg- nancy, most likely because of an increase in plasma vol- ume in early pregnancy and increased glucose utilization in later gestation by the feto-placental unit. Peripheral
North America and Caribbean 7.0 (6.5–11.9)
South and Central America 11.2 (7.1–16.6)
South-East Asia 15.0 (9.6–18.3)
Western Pacific 10.3 (4.5–20.3)
Europe 6.1 (1.8–31.0)
Sub-Saharan Africa 10.8 (8.5–13.1)
Middle East and North Africa 15.2 (8.8–20.0)
Fig. 1 | Global prevalence of GDM in 2005–2018. Median (interquartile range) prevalence (%) of gestational diabetes mellitus (GDM) by WHO region, 2005–2018 (map generated from WHO website). A literature search was conducted in PubMed supplemented by cross-checking relevant references of eligible studies on the prevalence of GDM from 1 January 2005 to 1 December 2018 to capture the contemporary burden of GDM. Among the eligible studies that met the search criteria^13 , data from countries reported in the studies were included to derive country-specific estimates for GDM prevalence. The region-specific prevalence of GDM was estimated by calculating the median prevalence of country-specific estimates within each WHO region.
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insulin sensitivity (defined as the ability of insulin to increase glucose uptake in skeletal muscle and adipose tissue) decreases by approximately 50% by late gesta- tion 52. In women with normal glucose tolerance, there is a 2–3-fold increase in insulin secretion in response to the decreased insulin sensitivity that maintains eugly- caemia. Maternal amino acid and lipid metabolism are also affected by the decreased insulin sensitivity during pregnancy and are also related to the increased risk of increased fetal growth and adiposity but are not discussed owing to space considerations.
Pathophysiology of GDM Insulin resistance. In women who are normoglycae- mic before pregnancy but go on to develop GDM in late gestation, there is evidence of decreased peripheral insulin sensitivity before conception 53 (fig. 5). These women initially adaptively maintain normoglycaemia in early pregnancy because of the ability of the pancreatic β-cells to increase their insulin response. However, by late pregnancy, as insulin resistance increases, the insu- lin response is inadequate. This defect in β-cell function exists before pregnancy in many cases but only clinically manifests with the increased insulin resistance of preg- nancy, resulting in hyperglycaemia 54 (fig. 6). Although endogenous glucose production is increased by 30% in women with normal glucose tolerance in pregnancy, it is almost completely suppressed during insulin infu- sion with a hyperinsulinaemic–euglycaemic clamp in women with normoglycaemia before conception. However, suppressed endogenous glucose production may contribute to fasting hyperglycaemia in women with (again often undetected) IFG before pregnancy,
who are later diagnosed with GDM 53. By contrast, women who develop GDM have less suppression (by 80–85% compared with almost 100%) of endogenous glucose production, thus contributing to postprandial hyperglycaemia in this population. In non-pregnant women with normal glucose toler- ance, the binding of insulin to the cell surface insulin receptor in peripheral tissues, such as skeletal muscle, results in glucose uptake by cells. This interaction acti- vates then results in autophosphorylation by the tyro- sine kinase domain of the insulin receptor β-subunit (IRβ), which activates a signalling cascade that induces redistribution of glucose transporter type 4 (GLUT4) to the cell surface to enable glucose uptake by the cell. As noted previously, there is a decrease in sensitivity with advancing gestation during pregnancy, and this is further decreased in women who develop GDM, both before and during pregnancy^55 (see fig. 7 for the defects in the insulin signalling cascade during pregnancy and known defects associated with GDM). In late pregnancy, skeletal muscle content of one of the signalling molecules, insulin receptor substrate 1 (IRS1), is lower than in non-pregnant women. In addition to the decrease in IRS1 levels, auto- phosphorylation of IRβ is lower in women with GDM than in pregnant women with normal glucose tolerance, which results in 25% lower glucose uptake in biopsied skeletal muscle^56. Historically, insulin resistance during pregnancy has been ascribed to the effects of hormones released by the placenta, such as human placental lactogen (HPL; also known as choriomammotropin) and placental growth hormone (PGH)^57. Although concentrations of these hormones are higher in later gestation, a specific
Prevalence of GDM (%)
35
15
10
0
Singapore
25
20
New Zealand
ThailandVietnamChinaAustraliaJapan BangladeshSri Lanka
India Malaysia
CubaBrazil Canada
Trinidad and Tobago
USA Barbados
United Arab Emirates
QatarBahrainIsraelIranNorway
UK BelguimHungarySpainFranceTurkeyGreenland Switzerland
GermanySwedenIrelandNigeriaTanzania
30
WHO NDDG C&C IADPSG Other
Western Pacific
South-East Asia
South and Central America
North America and Caribbean
Middle East and North Africa Europe
Sub- Saharan Africa
Fig. 2 | Country-specific prevalence of GDM according to different diagnostic criteria. Graph of prevalence of gestational diabetes mellitus (GDM) in selected countries according to the Carpenter–Coustan criteria (C&C), International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria, National Diabetes Data Group (NDDG) criteria, WHO 2013 criteria and International Classification of Diseases codes and local guidelines or criteria (other). A literature search was conducted in PubMed, supplemented by cross-checking relevant references of eligible studies on the prevalence of GDM from 1 January 2005 to 1 December 2018 to capture the contemporary burden of GDM. Among the eligible studies that met the search criteria^13 , data from countries reported in the studies were included to derive country-specific estimates of GDM prevalence on the basis of different diagnostic criteria. The median of all available source data was used if more than one estimate of GDM prevalence was available for a country.
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cord blood concentrations of docosahexaenoic acid. The reduced placental NLS1 levels may explain the lower cord blood levels of docosahexaenoic acid in women with GDM than in healthy women. At the end of pregnancy, only ~9–10% of the placen- tal surface is involved in mediating nutrient transfer to the fetus 74 , and this proportion is unaltered in GDM. Nutrients taken up across the vast majority of the placen- tal surface instead enter metabolic pools in the placenta to sustain placental functions^65. Collectively, at the end of a GDM pregnancy, the pla- centa does not actively enhance the quantum of mater- nal nutrients reaching the fetal circulation and thus does not directly contribute to excessive fat accretion that leads to the characteristic phenotype of fetuses in GDM pregnancies.
Buffering capacity of the placenta. Many of the changes in the placenta of women with GDM are adaptive responses to protect both the placenta and fetus, of which placental hypervascularization is the best stud- ied example. Fetal aerobic metabolism is stimulated by hyperinsulinaemia in GDM pregnancies, and ele- vated cord blood concentrations of erythropoietin and
red blood cells reflect some degree of fetal hypoxia. The placenta responds to the increased fetal oxygen demand by increasing its capillary surface^75. Low oxygen, hyperinsulinaemia and changes in the levels of several other angiogenic factors in the fetal circulation in GDM stimulate placental angiogenesis 76,77^. Whereas these regulatory signals are derived from the fetus, others may come from the trophoblast and macrophages, both of which are essential cell types for placental function78,79. The number and function of these cell types may also be altered in GDM, including changes in the molecules they secrete, which contribute to regulation of placental vascularization. Overall, multiple signals give rise to placental hypervascularization in GDM. Other examples of placental adaptations that ‘buffer’ the potentially adverse effects of the maternal environ- ment in GDM on fetal growth and development include an enhanced placental capacity to cope with increased cholesterol synthesis in placental endothelial cells. Multiple cellular and molecular mechanisms that facili- tate cholesterol removal from the feto-placental circu- lation to avoid the formation of pre-atherosclerotic lesions (which would reduce blood flow) are upregulated in GDM80,81. The placenta seems to have evolved some capacity to buffer the intrauterine environment by adapting its functions to altered conditions in this environment, although this adaptive capacity is likely to be limited 82. Thus, extreme perturbations of the maternal milieu, as in untreated GDM or GDM combined with obesity, may override the placental buffering capacity and thereby contribute to pathological effects in the fetus^83. Some evi- dence exists to suggest that placental adaptive responses are more pronounced in female fetuses84–87. As a fetal tissue, the placenta is under fetal con- trol, especially in the second half of gestation, when fetal organs have formed. Consequently, the placenta is less vulnerable to an adverse maternal environment in this period than in early pregnancy, when the pla- centa is mostly under maternal control 88. For example, the placenta has poor antioxidative defences (such as lower levels of the antioxidant enzyme catalase) in the first 10–12 weeks of pregnancy^89 , resulting in the pla- centa being especially sensitive to oxidative and meta- inflammatory stress, which often occurs in women with hyperglycaemia, obesity and/or GDM 90,91^. Future studies should investigate whether and how early hyper- glycaemic events in women who will develop GDM later in pregnancy affect the growth and developmental trajectories of the placenta and, subsequently, the fetus^92.
Fetal phenotype and long-term effects. Maternal glucose is the main macronutrient that sustains fetal growth (fig. 8). In pregnant women with T1DM, prolonged expo- sure of the fetal pancreas to hyperglycaemia from the early stages of pregnancy, which may also occur in GDM (but remain undetected until diagnosis), accelerates mat- uration of the stimulus–secretion coupling mechanism in pancreatic β-cells and results in early hyperinsulinaemia, with ensuing fetal hyperglycaemia. Some amino acids, such as arginine, also stimulate the fetal pancreas and contribute to hyperinsulinaemia. Free fatty acids (FFAs)
Hyperglycaemia and hyperinsulinaemia
- Short-term consequences (e.g. macrosomia and neonatal hypoglycaemia)
- Long-term consequences (e.g. T2DM and obesity)
Excessive peripheral insulin resistance
Insufficient insulin production
Pre-pregnancy risk factors (e.g. obesity and inflammatory cytokines (such as TNF))
- Short-term consequences (e.g. pre-eclampsia)
- Long-term consequences (e.g. T2DM)
Hyperglycaemia
↑ Glucose production
Excessive endogenous glucose production
↓ Glucose uptake
Excessive peripheral insulin resistance
Placental- related hormones
Mother Fetus
Fig. 3 | Pathophysiology of GDM. Women who develop gestational diabetes mellitus (GDM) during pregnancy have evidence of metabolic dysfunction before conception, such as pancreatic β-cell defects and increased insulin resistance. In high-income countries, many women who develop GDM are overweight or obese, which is associated with an inflammatory milieu. With the onset of pregnancy and associated metabolic changes (increased insulin resistance and demand for increased β-cell response because of placental factors), insulin is less effective in suppressing endogenous (primarily hepatic) glucose production and glucose uptake by peripheral skeletal muscle and adipose tissue, which results in clinical hyperglycaemia. Maternal hyperglycaemia results in increased placental transfer of glucose and (fetal) β-cell secretagogues, such as amino acids, to the fetus, leading to fetal hyperinsulinaemia. Fetal hyperinsulinaemia then results in fetal metabolic reprogramming that leads to short-term problems, such as fetal overgrowth and/or adiposity, and long-term problems, such as metabolic dysfunction in later life. T2DM, type 2 diabetes mellitus; TNF, tumour necrosis factor.
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are released from maternal lipoproteins by lipolysis, but only a small proportion crosses the placenta and contrib- utes to the fetal FFA pool. This pool mainly comprises FFAs produced by de novo lipogenesis in the fetal liver, using glucose as a precursor, which is present in excess in maternal overnutrition. Fetal insulin stimulates tri- glyceride synthesis and, thus, fat storage in white adipo- cytes in the fetus in a sex-dependent manner, which is reflected by a stronger association of cord blood insulin with neonatal fat deposition in males than in females^93. GDM also leads to long-term metabolic effects in offspring. The pathogenetic mechanisms underlying these abnormal metabolic characteristics are not known, but maternal hyperglycaemia-induced changes in DNA methylation and microRNA (miRNA) content in fetal blood, skeletal muscle and adipose tissue94–96^ and other factors are most likely involved.
Clinical consequences The first description of GDM arose from the observation that parous pregnant women with overt diabetes often had the same complications in pregnancies antedating their own diagnosis of diabetes as those in pregnant women with diabetes, which was speculated to be due to undetected prediabetic hyperglycaemia in previous pregnancies. The GDM diagnostic criteria were based on the long-term risk of maternal diabetes rather than the short-term risks of poor perinatal outcomes^3.
Short-term consequences for mother and offspring. Later retrospective and prospective observational studies using these and similar diagnostic criteria clearly indicated that GDM was indeed associated with poor maternal and offspring outcomes. The short-term complications
included pre- eclampsia, polyhydramnios, operative delivery, shoulder dystocia, birth canal lacerations, fetal overgrowth (also called macrosomia), neonatal hypo- glycaemia, jaundice and, in some studies of untreated GDM, perinatal mortality 97–102^. Furthermore, a graded increase in the risk of maternal, fetal and neonatal com- plications occurs with rising maternal glucose, even within what is generally considered the normal plasma glucose range103–106. However, women with GDM often have other risk factors for poor outcomes, including maternal over- weight, increasing age, reduced physical activity or belonging to an ethnic minority. Thus, for many years it was intensely debated whether the poor outcomes asso- ciated with GDM were due to maternal hyperglycaemia per se or other risk factors^107. Subsequently, the large multinational landmark Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study 108 clearly docu- mented that maternal hyperglycaemia independently and in a graded linear way (without obvious cut-off points) increases the risk of pre-eclampsia, preterm delivery, cae- sarean section, large for gestational age (LGA) infants, shoulder dystocia, neonatal hypoglycaemia, hyperbiliru- binaemia and admission to neonatal special care units^108. The absolute risk of these complications in women with GDM diagnosed using the IADPSG criteria ranges from 1.8% for shoulder dystocia to 16.6% for neonatal adi- posity (absolute outcome frequencies are summarized in Table 2). Overall, fasting plasma glucose values from the OGTT were more strongly associated with poor out- comes than were the 1-hour and 2-hour values. Two large randomized controlled trials have clearly shown that treatment of GDM is effective in reducing or preventing maternal and fetal short-term complications, in particu- lar with reduction in LGA frequency to within the normal expected range and of pre-eclampsia by ~50%109,110.
Long-term maternal consequences. It has been known since the original diagnostic criteria for GDM by O’Sullivan 3 that women with elevated glucose levels in pregnancy are at an increased risk of subsequently developing diabetes (primarily T2DM). Risk estimates have been obtained for different populations and vary depending on the population studied and the GDM criteria used. A meta-analysis found a more than sev- enfold increased risk of T2DM in women with GDM compared with women with normoglycaemic preg- nancies 111. Thus, GDM is the best- known risk factor for T2DM 112. Increasing BMI, GDM diagnosis early in pregnancy, higher glucose levels at the time of diag- nosis during pregnancy, need for insulin treatment during pregnancy and IGT in the postpartum OGTT are some of the risk factors for subsequent diabetes in women with previous GDM 113–115^. In 2018, the HAPO Follow-Up Study (HAPO-FUS) 116 provided long-term data about maternal and infant outcomes in women who were diagnosed with GDM post hoc using IADPSG cri- teria but who were untreated in the index pregnancy. This study provided data about the natural history of untreated GDM (outcomes in the immediate perinatal period and after a mean of 11.4 years follow-up are summarized in Table 2). Untreated GDM clearly has
Insulin resistance and
β-cell
dysfunction (%)
20 40 60 Lifespan (years and increasing weight)
0
T2DM
100
60
40
20
0
80
GDM
Normal glucose tolerance
Fig. 4 |^ Pregnancy as a metabolic stress test for future metabolic disorders. Schematic representation of the risk of type 2 diabetes mellitus (T2DM) in women with normal glucose tolerance and gestational diabetes mellitus (GDM), based on pregravid metabolic status of insulin sensitivity and β-cell dysfunction, with increasing age and body weight. Higher insulin resistance and β-cell dysfunction preceding pregnancy in women who develop GDM increases risk of T2DM in later life (that is, exceeding the glycaemic threshold for T2DM (dashed line)), whereas women with normal glucose tolerance (that is, no insulin resistance and normal β-cell function) who undergo the metabolic changes in pregnancy but return to their normal trajectory of metabolic changes (that occur owing to increasing age and weight) are at lower risk of T2DM in later life.
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Pharmacological interventions Pharmacological interventions during pregnancy for GDM prevention are rare, with most studies testing metformin in high- risk populations, such as over- weight and obese women156,157^ or women with a history of polycystic ovary syndrome 158,159^. Overall, data from existing studies do not demonstrate a protective role of metformin in the prevention of GDM. Large-scale, multiple-arm inter vention studies, in which the inter- vention is initiated early in or even before pregnancy, among multi- ethnic populations are sorely needed. Ideally, these studies should be sufficiently powered to detect effects on maternal and neonatal outcomes and should obtain long-term follow-up data for both mother and child.
Screening and diagnosis Historical definition of GDM. The prevailing defini- tions of GDM are based on the landmark 1964 paper by O’Sullivan and Mahan 3. These authors reported on an unselected cohort of 986 women from Boston (USA) who were enrolled over a 4-month period. A subgroup (752 women) completed both a 50 g non-fasting glucose challenge test (GCT) at their first antenatal presentation and later a formal 3-hour, 100 g oral glucose tolerance test (OGTT), and their results are the historical basis for the diagnosis of GDM in the USA. Their OGTT values were used to derive 97.7 percentile levels (2 s.d. above the cohort mean) for the 100 g OGTT in pregnancy. After rounding of the 2-hour and 3-hour values, these results provided the initial threshold whole blood glucose values for GDM (fasting 90 mg dl–1^ ; 1 hour 165 mg dl–1^ ; 2 hour 145 mg dl –1^ ; 3 hour 125 mg dl –1^ ), with the equally arbi- trary decision (noted as “it was considered expedient…”)
that two elevated values would be required for a GDM diagnosis. Using this definition, GDM prevalence in the cohort was 1.9% and was predictive of risk of later developing T2DM. These original ‘O’Sullivan criteria’ for a GDM diag- nosis were subsequently modified in the late 1980s and early 1990s (to account for changes in laboratory methodology) by Carpenter and Coustan 160 and the National Diabetes Data Group (NDDG)^161. The NDDG criteria erroneously failed to correct for the measure- ment of substances other than glucose in the original O’Sullivan studies and thereby produced higher diagnos- tic threshold glucose levels for GDM. However, both the Carpenter–Coustan and NDDG criteria are still recog- nized by the American College of Obstetricians and Gynecologists (ACOG)^162 , despite the fact that they were derived from an empirical analysis of a small cohort of women in Boston in the late 1950s and developed as pre- dictors of later T2DM, without consideration of their relationship to pregnancy outcomes (despite these short- comings and owing to their widespread use in the USA, we include these criteria in Table 1). The HAPO study 108,163–165^ provided large- scale blinded data of the association between mild hyper- glycaemia in pregnancy and maternal and fetal out- comes. In a cohort of 23,316 women (>30-fold larger than the O’Sullivan cohort) who completed a blinded 75 g OGTT at 24–32 weeks of gestation, fasting, 1-hour and 2-hour glucose values in the OGTT were linearly associated with a broad range of pre-defined, carefully ascertained and adjudicated adverse clinical and bio- chemical outcomes of pregnancy. These independent associations of hyperglycaemia with pregnancy out- comes remained strong after extensive adjustment for potential confounders, including maternal BMI, age, height, mean arterial pressure and parity.
Current screening and diagnostic criteria. Following the HAPO study, it was evident that there are no ‘natural inflection points’ in the associations between glycaemia and adverse outcomes that readily identify a ‘natural’ set of diagnostic thresholds for GDM. After an exten- sive consensus process, taking into consideration the results of both the HAPO study and other published studies, the IADPSG published recommendations in 2010 for the identification and classification of hyper- glycaemia in pregnancy^166. The underlying principles of the IADPSG consensus process were that women with equivalent levels of glycaemia-associated risk of adverse pregnancy outcomes should be classified in a similar manner and that threshold blood glucose values should be standardized internationally. The IADPSG recom- mended a ‘one- step’ method involving an OGTT at 24–28 weeks of gestation and proposed GDM diagnos- tic thresholds (Table 1) that were based on an adjusted odds ratio threshold of 1.75 (compared with the odds at the HAPO cohort mean) of delivering an infant affected by key fetal complications of maternal hyperglycaemia, namely, increased size at birth, increased adiposity and elevated cord blood C- peptide levels. The IADPSG also recognized that undiagnosed T2DM in pregnant women is increasingly prevalent in certain populations
Insulin secretion rate
1,
700 600 500 400 300 200 100 0 0.1 0.2 0.3 0. Insulin sensitivity index
900 800
Normoglycaemic GDM Third trimester Postpartum
Fig. 6 |^ Insulin sensitivity–secretion relationships in normoglycaemic women and women with GDM. Prehepatic insulin secretion was assessed during steady-state hyperglycaemia using measurement of plasma insulin and C-peptide concentrations and kinetics in individual patients during the third trimester and postpartum. The disposition index depicts the relationship of changes of insulin secretion together with insulin sensitivity. In women who developed gestational diabetes mellitus (GDM) during pregnancy, when not pregnant (postpartum, yellow circles) there is decreased insulin sensitivity and slightly lower insulin secretion than in postpartum women with normal glucose tolerance. In the third trimester of pregnancy (blue circles), however, although there is a further decrease in insulin sensitivity in both groups, in women who develop GDM there is a less marked increase in insulin secretion to match the decreased insulin sensitivity, which then results in hyperglycaemia. Adapted with permission from ref.^54 , Oxford University Press.
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and recommended that these cases should ideally be detected early in pregnancy and classified as ‘overt diabetes’ (also termed ‘diabetes in pregnancy’ in the subsequent WHO adaptation of the IADPSG criteria) 8 to both identify them as a particularly high-risk group and ensure rapid treatment (see Table 1 for a summary of the recommended classification). Subsequently, the IADPSG recommendations were widely endorsed as the preferred diagnostic criteria by major national bodies167–171^ and international bodies8, but were disputed by others162,173,174. The IADPSG crite- ria are largely followed in Australia^169 and Japan 170 and are officially endorsed in Europe^175 and globally by the International Federation for Gynecology and Obstetrics (FIGO) and the International Diabetes Federation172,176. However, they are not widely used in the USA or Canada, although the 2018 ACOG guidelines^177 and 2018 Canadian guidelines 178 include the IADPSG process as one (not the preferred) option. The UK guidelines issued by the National Institute for Clinical Excellence (NICE) remain at variance with other countries in their contin- ued support for selective risk-factor-based testing^179. The principal points of contention relate to increased num- bers of women potentially diagnosed with GDM owing to the change in thresholds and from a ‘two-step’ method (screening test followed by a diagnostic test) to a one-step method (a diagnostic test only, the 75 g glucose 2-hour test). In most settings, the two-step method involves a non-fasting GCT in which plasma glucose is tested 1 hour after ingestion of a 50 g or 75 g glucose load, which is fol- lowed by a full fasting OGTT if the GCT falls above a pre- defined threshold. The other issue, principally relevant to the USA, is the change from a requirement that two values on the OGTT should meet or exceed the threshold value to make a GDM diagnosis^177 to the acceptance by IADPSG that only a single elevated value on the OGTT is sufficient to make a GDM diagnosis^7.
The two-step method imposes less of a diagnostic burden on many women than the one-step method but, depending on the thresholds used to determine the need for a full diagnostic OGTT, requires that up to 30% of women complete a second test. However, a systematic review demonstrated that the two-step method misses approximately 25% of women with GDM on a formal OGTT^180 , whereas another systematic review concluded that the one-step method is associated with improved pregnancy outcomes 181. Ensuring reliable follow- up after a positive GCT result is also important; only 36% of women in a study from eastern Canada received appropriate further testing after a positive GCT result^182 , whereas 75% of women in a study from western Canada received appropriate follow-up testing within 2 weeks^183. Insistence on two or more elevated values on the OGTT to make a GDM diagnosis is essentially a histor- ical quirk related to the empirical decision in favour of this approach by O’Sullivan and Mahan in their land- mark 1964 publication^3. The two-step method limits the number of women who are diagnosed with GDM but not in a logical manner, as demonstrated in multiple case series (reviewed in ref.^184 ). In summary, GDM is diagnosed by the detection of hyperglycaemia in pregnancy, which, although less severe than overt diabetes, is associated with increased pregnancy complications, particularly those related to excessive fetal growth. In the absence of natural thresh- olds, the precise numeric cut-off values of maternal glycaemia used for diagnosis are the subject of ongoing debate. Overall consensus currently favours the IADPSG and WHO criteria (outlined in Table 1), which are based on a consensus overview of available large-scale epidemio- logical data and randomized controlled trials and relate the diagnostic thresholds to the risk of hyperglycaemia- related pregnancy complications. However, they may not be suitable for uniform worldwide application, as a
Normal glucose tolerance (non-pregnant)
Normoglycaemic pregnancy
GDM
IRS
pSer pTyr
Insulin receptor
GLUT
Insulin
P P P P P
Insulin PI3K action
Glucose
IRS
pSer pTyr
P P P P P
Insulin PI3K action
Glucose
IRS
pSer pTyr
P
P
P
Insulin PI3K action
Glucose
Fig. 7 | Changes in insulin signalling in normoglycaemic and GDM pregnancies. Schematic representation of pregnancy- related changes in insulin signalling. Insulin signalling during pregnancy in women with normal glucose tolerance requires tyrosine autophosphorylation of the insulin receptor in skeletal muscle. This is the initial step in the insulin signalling cascade, allowing recruitment and activation of downstream effectors, such as insulin receptor substrate 1 (IRS1) and phosphatidylinositol 3-kinase (PI3K), resulting in translocation of glucose transporter type 4 (GLUT4) to the plasma membrane and thereby leading to increased glucose uptake into skeletal muscle^55. In late pregnancy, skeletal muscle IRS content is lower (red arrow) than in non-pregnant women. In gestational diabetes mellitus (GDM) pregnancies, in addition to the decrease in IRS1, tyrosine autophosphorylation in the intracellular domain of the insulin receptor β-subunit is reduced, which results in 25% lower in vitro glucose uptake than in pregnant women with normal glucose tolerance^56.
NATURE REvIEWS |^ DiSeASe PRiMeRS |^ Article citation ID: (2019) 5:47 11
led to recommendations for weekly gestational weight- gain goals that are dependent on maternal BMI before pregnancy. For obese, overweight and healthy-weight women, the IOM 189 recommends a maximum weekly weight gain of 220 g, 280 g and 420 g, respectively. There is some evidence that even lower targets for obese women may be safe and are associated with more appropriate fetal growth 194. Many clinicians will therefore accept a diet aimed at weight stability, and some clinicians even recommend some weight loss in obese women after diagnosis of GDM. To follow the recommendations for weekly weight gain, the weight of the mother should be monitored carefully at frequent intervals after diagnosis of GDM. Both caregivers and patients should be aware of both the blood glucose targets and the weight-gain goals.
Medical treatment of GDM When glycaemia remains elevated after ≥1–2 weeks of lifestyle interventions, daily glucose testing should be continued and pharmacological treatment should be initiated. Ultrasonography- based assessment of fetal growth may also assist in guiding the intensity of glu- cose control that is needed in an individual woman. If the baby is growing appropriately, in particular if fetal abdominal circumference is <75th percentile, it may be
safe to postpone initiation of pharmacological treat- ment. Conversely, excessive fetal growth may lead to intensification of treatment with lower glycaemia goals^195.
Insulin. Traditionally, insulin has been the primary med- ical treatment if the glycaemic treatment goals are not achieved with lifestyle intervention within 1–2 weeks. Insulin is effective and safe for the fetus, as it does not cross the placenta. Human insulin and several insulin analogues (for example, insulin aspart, insulin lispro and insulin detemir) have been formally tested and are considered safe to use in pregnancy^191. Insulin glargine is also often used and, although there are no randomized trials supporting the use of insulin glargine, a synthesis of published cohort studies has not raised specific concerns about its use in pregnancy196,197. The main issue with insulin therapy is the burden for the women, which can include discomfort, fear of needles, the cost of treatment and the risk of hypo- glycaemia. Episodes of mild hypoglycaemia occur often, whereas episodes of severe hypoglycaemia (that require help from a third party) are rare. During medical treatment, the goals for glucose con- trol and weight gain are the same as those for lifestyle interventions alone. The insulin treatment can be a basal–bolus regimen using intermediate-acting or long- acting insulin once daily and a rapid-acting insulin before main meals. Twice-daily injections of a mixture of fast- acting and long-acting insulin are also effective^198. Insulin detemir has been associated with less hyperglycaemia and hypoglycaemia than slow- acting human neutral protamine Hagedorn (NPH) insulin^199. However, when choosing the type of insulin, the cost of the insulin must also be considered. An initial dose of 0.3 international units (IU) per kg (body weight) per 24 hours can be used when initiating the insulin treatment, and a final insulin dose close to 1 IU per kg (body weight) is often needed^198. Insulin treatment is time consuming for caregivers and requires training and education of the pregnant women, and patient contact is frequently needed to adjust the insulin dose. Consequently, oral glucose- lowering medications, such as two well-established oral agents, metformin and the sulfonylurea glibenclamide, have been studied in women with GDM. Other glucose- lowering agents are generally not advocated for use in pregnancy owing to documented complications, such as neonatal hypoglycaemia, fear of unexpected fetal com- plications and possible metabolic or epigenetic changes in the developing fetus.
Metformin. Metformin acts mainly by suppressing hepatic glucose production, leading to a reduction in fasting plasma glucose levels and HbA (^) 1c. Metformin is the first-line treatment in non-pregnant patients with T2DM 200. Although it is inexpensive and easy to use, metformin commonly causes gastrointestinal symptoms, may cause low vitamin B 12 and, rarely, may increase the risk of lactic acidosis. Perhaps more importantly, met- formin crosses the placenta and thus can potentially affect the developing fetus. In randomized clinical trials, metformin seems to be comparable to insulin in glycae- mic control and immediate neonatal outcomes 201,^. At least one-third of women with GDM who are treated
Table 2 |^ Outcomes from the HAPO study and the HAPO-FUS Outcome GDMa (%)
Non- GDM (%)
Statistical significance Perinatal outcomes b Pre-eclampsia 9.1 4.5 (^) P < 0. Preterm delivery (<37 weeks) 9.4 6.4 P < 0. Primary caesarean delivery 24.4 16.8 P < 0. Shoulder dystocia or birth injury 1.8 1.3 P < 0. Birthweight greater than ninetieth percentile 16.2 8.3 P < 0. Neonate percentage body fat greater than ninetieth percentile
16.6 8.5 P < 0.
Cord blood C-peptide level greater than ninetieth percentile
17.5 6.7 P < 0.
Clinical neonatal hypoglycaemia 2.7 1.9 P < 0. Admission to newborn intensive care 9.1 7.8 (^) P < 0. Long- term outcomes c Maternal diabetes 10.7 1.6 (^) P < 0. Maternal pre-diabetes 41.5 18.4 (^) P < 0. Offspring overweight or obesity 39.5 28.6 P < 0. Offspring obesity 19.1 9.9 P < 0. Offspring percentage body fat greater than eighty-fifth percentile
21.7 13.9 P < 0.
Offspring impaired fasting glucose (ADA threshold of ≥5.6 mmol l–1)
9.2 7.4 Not significant
Offspring impaired glucose tolerance 10.6 5.0 P < 0. Offspring diabetes 0.3 0.2 Not significant ADA, American Diabetes Association; GDM, gestational diabetes mellitus; HAPO, Hyperglycemia and Adverse Pregnancy Outcomes; HAPO-FUS, HAPO Follow-Up Study. aWomen classified post hoc as having GDM by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria were compared to women without GDM. Women with GDM were not treated during or after the index pregnancy. bOutcomes are from the HAPO study^108. cOutcomes are from the HAPO-FUS^116.
NATURE REvIEWS |^ DiSeASe PRiMeRS |^ Article citation ID: (2019) 5:47 13
with metformin also need additional treatment with insulin^203. Because metformin crosses the placenta, the long-term effects of treatment in utero on the child must be considered 204. The adiposity and blood pressure in 2-year-old offspring of mothers with GDM were compar- able for metformin and insulin treatment205,206, although children exposed to metformin in utero had, on average, more subcutaneous fat at the upper arm. The 9-year-old offspring of women treated with metformin were taller than those whose mothers were treated with insulin 207. In another randomized trial, offspring were heavier at 1 year of age and both taller and heavier at 18 months of age if they had been exposed to metformin in utero 208.
Sulfonylureas. Sulfonylureas augment insulin secretion, and the resulting hyperinsulinaemia leads to a decline in fasting plasma glucose levels and HbA1c. In a randomized clinical trial, glibenclamide (also known as glyburide in the USA) was as effective as insulin in achieving gly- caemic control, and rates of LGA and overall perinatal outcomes were similar 209. However, contrary to initial findings with early, less-sensitive assays, glibenclamide crosses the placenta210,211, and the fetal:maternal concen- tration ratio is highly variable^210 and may have an effect on the developing fetus. Follow-up studies of children who have been exposed to glibenclamide antenatally are not available. In a meta-analysis comparing the efficacy and safety of insulin, metformin and glibenclamide 203 , glibencla- mide was associated with higher birthweight and higher rates of macrosomia and neonatal hypoglycaemia than insulin. Compared with metformin, glibenclamide was associated with higher birthweight and higher rates of macrosomia. Insulin and/or metformin treatment is therefore considered superior to glibenclamide treat- ment. Glibenclamide has been widely used in women with GDM in the USA, and a US health-care insurance
registry study found higher rates of LGA, neonatal hypo- glycaemia, birth injury and neonatal admission to the intensive care unit with glibenclamide than with insu- lin 212. Together, these findings argue against the use of glibenclamide as first-line pharmacotherapy in women with GDM. The major international guidelines for treatment of women with GDM, including those from the ADA 191 , the Endocrine Society^168 , FIGO^172 and the British NICE guidelines^179 , all recommend lifestyle interventions and insulin as the cornerstones of GDM treatment but differ regarding the possible use of metformin or glibencla- mide in pregnancy. In summary, insulin remains the gold standard for pharmacotherapy of GDM, but met- formin or glibenclamide may be chosen in individual cases depending on convenience and cost (box 2).
Pharmacotherapy immediately after delivery. Pharma- cotherapy for treatment of GDM can be stopped imme- diately after delivery, although glucose monitoring for a few days to exclude marked ongoing hyperglycaemia is recommended. Healthy eating, which during breast- feeding should include a carbohydrate intake of at least 210 g daily, is recommended. If hyperglycaemia consistent with overt diabetes persists postpartum (fasting glucose >7.0 mmol l –1^ and/or postprandial glucose >11.0 mmol l –1^ ), lifestyle interventions can be initiated and pharmacotherapy can possibly be reiniti- ated with insulin, metformin or glibenclamide, which are considered safe during lactation (box 2).
Long-term maternal complications Epidemiological studies indicate that maintaining physical activity, adopting healthful dietary patterns^213 , avoiding weight gain after pregnancy and frequent, pro- longed and more intensive breastfeeding reduce the risk of progression to overt diabetes 214–216^. Consistent with this, lifestyle interventions and medical treatment both decrease progression to diabetes by ~50% in women with previous GDM in randomized controlled trials with up to 10 years follow-up 217–219^. Therefore, there is great potential for preventing or delaying the onset of T2DM and cardiovascular disease in these women. Guidelines recommend breastfeeding, a lifelong healthy life- style (including weight loss if necessary), an OGTT 2–6 months after delivery and thereafter assessment of glucose tolerance every 1–3 years 191 using either fast- ing glucose levels, OGTT or HbA1c levels. In addition, women with prior GDM should be screened for cardio- vascular risk factors. Although these guidelines and recommendations have been available for years, they are not generally implemented and followed in everyday clinical practice, for various reasons114,220.
Quality of life For most women, a GDM diagnosis will cause a consid- erable change in their perception of pregnancy. A med- ical diagnosis of GDM will change their pregnancy from ‘normal’ to ‘abnormal’ and could potentially be associ- ated with anxiety for maternal and fetal health 221,^. However, as formal studies are rare, little is known about this topic.
Metabolic ageing
Adult metabolic syndrome, T2DM and obesity
Fetal–neonatal metabolic programming of obesity
Pregnancy
- Increased insulin resistance (obesity or GDM)
- Metabolic inflammation
- Childhood obesity
- Pre-metabolic syndrome?
Fig. 9 |^ Application of the DOHAD hypothesis to GDM. Schematic representation of the cycle of intrauterine exposure of offspring to maternal metabolic disturbances, resulting in subsequent fetal metabolic programming, childhood obesity and metabolic disturbances and later leading to overt adult disease that contributes to increased exposure in the next generation. DOHAD, Developmental Origins of Health and Disease; GDM, gestational diabetes mellitus; T2DM, type 2 diabetes mellitus.
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Insulin therapy remains the most widely accepted pharmacological intervention for treating GDM. Glibenclamide (glyburide), after decades of wide- spread use in the USA, is increasingly associated with LGA infants and neonatal hypoglycaemia^237. Metformin, despite encouraging immediate pregnancy out- comes, is associated with greater childhood size and adiposity 207,238,239^ , raising questions regarding its wide- spread use. Although oral agents are easier to admin- ister and are preferred by women with GDM, these recent experiences highlight the need for caution and long-term follow-up before major changes in guidelines are made. The complex interplay between obesity per se, metabolic inflammation and hyperglycaemia (partly driven by obesity), as contributing causes of excess fetal growth, other adverse pregnancy outcomes and later effects in offspring, remains incompletely under- stood and deserves further attention 57. Publications from the HAPO- FUS 116,128,129^ of long- term follow- up
results suggest that maternal glycaemia more strongly influences offspring glucose metabolic status than pre- viously thought, whereas the reverse seems to be true for offspring adiposity. These findings raise the possi- bility that targeted interventions based on an improved understanding of the underlying pathophysiology of GDM might eventually be able to improve short-term and long-term outcomes in offspring. In conclusion, although much is known about GDM, evidence gaps and evidence–practice gaps persist at all points in translating molecular understanding of GDM to efficacious therapies. A coordinated, well- implemented focus on the health of a mother with GDM and the health and development of her baby across the life cycle offers the promise of substantial health gains^240 but requires enhanced knowledge at the basic, clinical and implementation science levels and a commitment to action on the part of policy-makers and clinicians.
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RElatED links WHO: http://www.who.int/about/regions/en
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