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Gestational diabetes mellitus

Article in Nature Reviews Disease Primers · July 2019

DOI: 10.1038/s41572-019-0098-8

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NATURE REvIEWS | DiSeASe PRiMeRS | Article citation I­D:­ (2019) 5:47
PRIMER
­­Gestational diabetes mellitus
H. David McIntyre1*, Patrick Catalano2, Cuilin Zhang3, Gernot Desoye4,
Elisabeth R. Mathiesen5 and Peter Damm6
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.
Although the term ‘gestational diabetes’ was coined by societal trend for childbearing at a later age, especially
Carrington in 1957 (ref.1), it only gained wider recog- in regions in which obesity and early-​onset diabetes are
nition after the publications of John O’Sullivan in 1961 also common. For example, in the USA, the reported
(ref.2) and 1964 (ref.3). However, the phenomenon of prevalence of overt diabetes in adults 20–22 years of age
hyperglycaemia that develops during pregnancy (gen- is 4.5%, and a further 29.3% of these individuals have
erally detected in the late second trimester (13–26 com- detectable pre-​diabetes (IFG, IGT or impaired glycated
pleted weeks of gestation) or early in the third trimester haemoglobin (HbA1c))6. In the context of this epidemic
(27–40 weeks)) and resolves following delivery, was of hyperglycaemia outside pregnancy, it is highly likely
noted some time before4. that many cases diagnosed as GDM actually repre-
Complexity and controversy have shadowed the sent undiagnosed pre-​pregnancy hyperglycaemia of
diagnosis of gestational diabetes mellitus (GDM) ever varying severity.
since, partly owing to the very broad definition that was Globally, no single diagnostic protocol or set of diag­
initially promoted5, which allowed for “any degree of nostic criteria for GDM has gained universal accept-
hyperglycaemia first recognized in pregnancy”, irrespec- ance, making international comparisons difficult.
tive of the treatment required or the extent of postpar- However, the International Association of Diabetes
tum resolution of hyperglycaemia. Consequently, ‘GDM’ in Pregnancy Study Groups (IADPSG) 2010 criteria7,
encompassed a broad range of hyperglycaemia, from which were endorsed by the WHO in 2013 (ref.8), clas-
mild impaired glucose tolerance (IGT) or impaired fast- sify women who are first diagnosed during pregnancy
ing glucose (IFG) detected in late pregnancy to glucose but who would be diagnosed with diabetes if hyper-
levels characteristic of overt diabetes (or, rarely, even glycaemia were detected outside of pregnancy as
new-​onset type 1 diabetes mellitus (T1DM)) detected distinct from women who have ‘standard’ GDM.
in early pregnancy (<20 weeks of gestation). Although IADPSG described these women as having ‘overt dia-
more severe hyperglycaemia was initially uncommon, it betes’ whereas the WHO preferred the term ‘diabetes
has become much more prominent with the expanding in pregnancy’. However, both groups recognized that
worldwide epidemics of diabetes and obesity and the these women had severe hyperglycaemia that merited
­ 1
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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.
immediate treatment and might also have established
microvascular complications of diabetes that require
timely intervention9. 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
2 | Article citation ID: (2019) 5:47
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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 factors16. Women carrying a male fetus
seem to have a higher risk of developing GDM17, and
some reports18 suggest a higher risk of GDM in twin
pregnancies, although this is not a universal finding19.
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%) women20. In Australia21, 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
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 Primer

Table 1 | Glucose threshold values in the OGTT for a GDM diagnosis

Criteria or trial Sample Fasting plasma 1-hour glucose 2-hour glucose 3-hour glucose
size (n) glucose (in mmol l–1 (in mmol l–1 (in mmol l–1 (in mmol l–1
(mg dl–1)) (mg dl–1)) (mg dl–1)) (mg dl–1))
IADPSG 2010 recommended glucose thresholds
IADPSG OR 1.5 23,316 ≥5.0 (90) ≥9.3 (167) ≥7.9 (142) NA
IADPSG OR 1.75a 23,316 ≥5.1 (92) ≥10.0 (180) ≥8.5 (153) NA
IADPSG OR 2.0 23,316 ≥5.3 (95) ≥10.6 (191) ≥9.0 (162) NA
Glucose thresholds for a NA ≥7.0 (126) NA ≥11.1 (200) NA
diagnosis of overt diabetes
(IADPSG) or diabetes in
pregnancy (WHO)b
OGTT thresholds used for exclusion or inclusion in randomized trials
Crowther et al. (2005)109 1,000 ≥7.0c (126) NA ≥7.8d (140) NA
Landon et al. (2009) 110e
958 ≥5.3 (95)
c
≥10.0 (180)
d
≥8.6d (155) ≥7.8 (140)
Carpenter–Coustan NA ≥5.3 (95) ≥10.0 (180) ≥8.6 (155) ≥7.8 (140)
criteriaf (ACOG primary
recommendation)177
NDDG criteriaf (ACOG NA ≥5.8 (105) ≥10.6 (190) ≥9.2 (165) ≥8.0 (145)
alternative)
ACOG, American College of Obstetricians and Gynecologists; GDM, gestational diabetes mellitus; IADPSG, International
Association of Diabetes and Pregnancy Study Groups; NA , not applicable; NDDG, National Diabetes Data Group; OGTT, oral
glucose tolerance test. aThresholds are glucose values at which the odds of birthweight, neonate percent body fat and cord blood
C-​peptide level greater than the ninetieth percentile are 1.75 times the estimated odds of these outcomes at average glucose
values. The alternative diagnostic thresholds corresponding to OR 1.5 and 2.0 compared to the mean are also shown. At least one
elevated value is sufficient for a GDM diagnosis. bThresholds used to define overt diabetes or diabetes in pregnancy are the same
as those used outside of pregnancy. cValue for exclusion from trials. dValue for inclusion in trials. eTwo or more elevated values at 1,
2 or 3 hours after glucose ingestion were required for exclusion or inclusion in the Landon trial. fTwo or more elevated values are
required for a GDM diagnosis.

of GDM among the general South-​East Asian popula-
tion. The reasons underlying the ethnic differences are
likely to be multifactorial, including but not limited to
the major risk factors for GDM (differences in body adi-
posity, lifestyle (diet and physical activity) and genetic
susceptibility).
Modifiable lifestyle factors. Being overweight or obese
before pregnancy (body mass index (BMI) ≥25 kg m–2)
is the most significant GDM risk factor22. Cigarette
smoking by pregnant women and whether their parents
smoked are related to increased risk of GDM, inde-
pendent of pre-​pregnancy BMI and other risk factors23.
Physical activity both during and before pregnancy
reportedly reduces GDM risk24,25. In addition, a num-
ber of dietary factors affect GDM risk. To date, no con-
crete conclusions can be drawn about the role of specific
dietary factors during pregnancy in the development
of GDM22. However, there is suggestive evidence that
low plasma levels of vitamin D26 and vitamin C27 in early
pregnancy and increased dietary fat intake28,29 dur-
ing pregnancy increase the risk of developing GDM22.
Large observational studies on pre-​pregnancy diet iden-
tified various dietary factors that potentially increase
GDM risk, independent of body adiposity and physi-
cal acti­vity, including higher consumption of sugar-​
sweetened beverages30, potatoes31, fried foods32, haem
iron33 and animal fat34 and protein35. Furthermore, a diet
low in carbohydrates but high in animal fat and protein36,
as well as an overall ‘western’ dietary pattern (high intake
of red meat, processed meat, refined grain products,
sweets, french fries and pizza25) are associated with
increased GDM risk. Potential healthful dietary factors
include greater consumption of fibre29,37 and nuts35, a
prudent dietary pattern characterized by a high intake
of fruit, green leafy vegetables, poultry and fish25, and a
‘Mediterranean’ diet38.
Overall, findings from observational studies suggest
that approximately 45% of GDM cases might be prevent-
able by the adoption of a healthy diet before pregnancy,
maintaining a BMI <25 kg m–2, exercising for ≥30 min-
utes per day and avoiding cigarette smoking39. However,
owing to the lack of data on these risk factors both before
pregnancy and during pregnancy before the time of a
GDM diagnosis, it is unclear whether these behaviours
have a chronic effect on insulin sensitivity and pancreatic
β-​cell function or an acute effect due to continuing these
behaviours during pregnancy. If the effects of these risk
factors are chronic rather than acute, then prevention
of GDM would require starting lifestyle interventions
before pregnancy. Indeed, preventive efforts may need
to be made at the population level to prevent childhood
overweight and obesity, reduce excess adolescent weight
gain and promote an optimal lifestyle pattern in both
parents before pregnancy40.
Emerging risk factors. In addition to diet and lifestyle
factors, emerging data indicate a possible contribution
of environmental and psychosocial factors to the risk of
developing GDM. For example, higher exposure to
persistent organic pollutants and endocrine disruptors,
such as polybrominated diphenyl ethers41 and perfluoro­
octanoic acid42, has been associated with increased GDM
risk. Furthermore, depression in the first and second
trimester has been prospectively related to increased
GDM risk43.

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Europe
6.1 (1.8–31.0)

North America Western

and Caribbean Pacific
7.0 (6.5–11.9) 10.3 (4.5–20.3)

South and South-East

Central America Asia
11.2 (7.1–16.6) 15.0 (9.6–18.3)

Middle East and Sub-Saharan

North Africa Africa
15.2 (8.8–20.0) 10.8 (8.5–13.1)

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
criteria13, 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.

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 GDM44. In the only genome-​wide associ-
ation study of GDM in an Asian population, two genetic
variants, rs10830962 (near MTNR1B) and rs7754840
(in CDKAL1) were associated with GDM45. Subsequently,
rs10830962 was associated with β-​cell compensation for
insulin resistance in Hispanic women with prior GDM46.
In a study of 112 SNPs among 8,722 white women (2,636
with GDM and 6,086 without GDM) from two inde-
pendent populations47, 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 antigens48, whereas approximately 5% of
women with GDM have monogenic variants of dia­betes
mellitus, which most commonly involve mutations in
GCK (encoding glucokinase) in white populations49.
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 pancreas50.
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 levels51. 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

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South and North Sub-

Western South-East Central America and Middle East and Saharan
Pacific Asia America Caribbean North Africa Europe Africa

35

30
Prevalence of GDM (%)

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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 criteria13, 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.

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-
tion52. 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 conception53 (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 hyperglycaemia54 (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 GDM53. 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 pregnancy55 (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 muscle56.
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

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Box 1 | Risk factors for GDM
• Overweight or obesity (body mass index (BMI) ≥25 kg m–2)
• Advanced age
• Non-​white ancestry
• Family history of type 2 diabetes mellitus
• Previous history of gestational diabetes mellitus (GDM)
• Parity (number of pregnancies >20 weeks)
• Male fetus
• Multiple pregnancy
• Genetic factors
• Polycystic ovary syndrome
• Cigarette smoking
• Psychosocial factors (for example, depression in
pregnancy)
• Unhealthy dietary factors before pregnancy
• Physically inactive lifestyle before and during pregnancy
mechanism relating to decreased insulin-​mediated glu-
cose disposal has not been described. Inflammation,
often linked to obesity, has been identified as another
factor that disrupts the insulin signalling cascade58.
Tumour necrosis factor (TNF) activates a signalling
pathway that increases levels of sphingomyelinase and
ceramides, which interfere with insulin receptor tyro­sine
autophosphorylation, and promotes serine phospho-
rylation of IRS1, which disrupts the insulin signalling
cascade. In pregnancy, circulating TNF levels are signifi­
cantly negatively correlated with insulin sensitivity, even
after adjustment for maternal fat mass59.
Postpartum consequences of GDM. In the postpartum
period, within days of delivery of the placenta, there is a
rapid and substantial 120% increase in insulin sensitivity
and decrease in insulin response in comparison with late
gestation60. A series of studies examining women with
normal glucose tolerance and GDM in late pregnancy,
involving skeletal muscle biopsies and clamp studies at
1 year postpartum, revealed that improvement in insulin
resistance was associated with weight loss and increased
skeletal muscle expression of IRβ and IRS1. The change
in IRS1 levels was correlated with the change in insulin
sensitivity (regression coefficient 0.84, P < 0.007)59.
In women with previous GDM in whom there was
no significant improvement in insulin sensitivity, body
weight or body composition measures and circulating
and skeletal muscle TNF concentrations remained ele-
vated 1 year postpartum. Although skeletal muscle IRβ
and IRS1 levels improved, insulin-​stimulated insulin
receptor autophosphorylation and receptor tyrosine
kinase activity did not improve. Levels of skeletal mus-
cle 312Ser-​IRS1 also did not improve and correlated with
TNF expression61.
These data are consistent with a state of chronic
inflammation and insulin resistance in GDM and stress
the importance of postpartum retention of excess weight
gained during pregnancy as a significant risk factor for
the development of obesity and T2DM. Returning to pre-​
pregnancy body weight is associated with a substantial
improvement in the overall metabolic condition, which
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supports the concept that pregnancy need not have a
long-​term detrimental effect on a woman’s metabolic
health62. However, weight gain postpartum that is asso-
ciated with increased parity could increase the risk of
T2DM owing to progressive insulin resistance and fur-
ther deterioration of β-​cell function63, which may be par-
ticularly important for women who developed GDM and
have a greater lifetime risk of future metabolic problems.
Mechanisms of fetal consequences of GDM
The placenta is central in the maternal–fetal supply line,
as it integrates maternal exposures and provides oxygen,
macronutrients and micronutrients to the developing fetus.
The interactions of these factors with the fetal geno­type
(including epigenotype) determine the fetal pheno­type64.
The placenta partitions maternal fuels to cover its own
needs and at the same time to sustain fetal growth and
thereby mediates the effects of maternal metabolic dis-
turbances on the fetus. These metabolic changes encom-
pass foremost hyperglycaemia, which is both the means
for diagnosing GDM and the principal therapeutic target.
However, it is important to remember that the metabolic
derangements also include elevated fatty acid and amino
acid concentrations in the maternal circulation.
Placental nutrient transport. The placenta is richly
endowed with transporter molecules that ensure an ade-
quate supply of glucose, lipids and amino acids when
the mother is metabolically normal, although it does not
protect the fetus from oversupply in GDM65.
Transplacental glucose transfer becomes saturated
only when the glucose concentration difference between
the maternal and fetal circulation is ≥25 mmol l–1 (ref.66).
This high efficiency explains why glucose transfer is
unaltered in GDM at the level of the placenta itself67.
Therefore, the glucose concentration gradient between
the maternal and fetal circulation is the most important
determinant of the amount of maternal glucose reaching
the fetus. The gradient is determined not only by mater-
nal glycaemia but also by the glucose level in the fetus.
Fetal glycaemia is modified by fetal insulin levels, which
are usually elevated in GDM (see below). Fetal hyper-
insulinaemia facilitates glucose uptake into peripheral
tissues and steepens the concentration gradient. In these
conditions, the fetus also pulls (‘steals’) glucose from the
maternal circulation, the ‘fetal glucose steal’ phenom­
enon68, with the consequence that more maternal glucose
reaches the fetal circulation.
Placental transfer systems are much less efficient
for fatty acids than for glucose, and therefore only ~3%
of maternal fatty acids reach the fetal circulation69,70.
Efficient transfer is not needed, as the fetus can synthe-
size its own non-​essential fatty acids using glucose as a
precursor (Fig. 8). Consequently, only 20% of the fatty
acids in neonatal fat are derived from maternal sources71.
Fatty acid transfer does not seem to be altered by GDM,
except perhaps that of docosahexaenoic acid72, which is
important for the development of the brain and retina.
The fetus depends on maternal supply of this essen-
tial fatty acid. GDM reduces the placental levels of
the docosahexaenoic acid transporter NLS1 (encoded
by MFSD2A) by ~30%73. NLS1 levels correlate with
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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 fetus74, 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 functions65.
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
Mother Fetus
Pre-pregnancy risk factors
(e.g. obesity and inflammatory cytokines (such as TNF))
Excessive peripheral Insufficient insulin
insulin resistance production
Hyperglycaemia
Excessive endogenous Excessive peripheral Placental-
glucose production insulin resistance related and
hormones hyperinsulinaemia
↑ Glucose production ↓ Glucose uptake
• Short-term
consequences
(e.g. macrosomia
and neonatal
Hyperglycaemia hypoglycaemia)
• Long-term
consequences
• Short-term consequences (e.g. pre-eclampsia) (e.g. T2DM and
• Long-term consequences (e.g. T2DM) obesity)
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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red blood cells reflect some degree of fetal hypoxia.
The placenta responds to the increased fetal oxygen
demand by increasing its capillary surface75. Low oxygen,
hyperinsulinaemia and changes in the levels of several
other angiogenic factors in the fetal circulation in GDM
stimu­late placental angiogenesis76,77. 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 limited82.
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 fetus83. 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 control88. For example,
the placenta has poor antioxidative defences (such as
lower levels of the antioxidant enzyme catalase) in the
first 10–12 weeks of pregnancy89, resulting in the pla-
centa being especially sensitive to oxidative and meta-​
inflammatory stress, which often occurs in women
with hyperglycaemia, obesity and/or GDM90,91. 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 fetus92.
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)
­ 7
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100
GDM
T2DM
Insulin resistance and β-cell
80
dysfunction (%)
60 Normal glucose
tolerance
40
20
0 factors for poor outcomes, including maternal over-
0 20 40 60
Lifespan (years and increasing weight)
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.
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 females93.
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 outcomes3.
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
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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 mortality97–102. 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
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 factors107. Subsequently, the large
multinational landmark Hyperglycemia and Adverse
Pregnancy Outcomes (HAPO) study108 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 units108.
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’Sullivan3 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-
nancies111. Thus, GDM is the best-​known risk factor
for T2DM112. 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 GDM113–115. 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
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substantial long-​term risks for both mother and child.
In some populations, risk of T1DM is also increased
after GDM114. Furthermore, women with previous GDM
have an increased risk of the metabolic syndrome and
cardiovascular, kidney, liver and retinal disease12,117–120.
Long-​term offspring consequences. Studies using ani-
mal models that are intended to simulate GDM have
documented that the offspring of GDM mothers have
increased risk of hyperglycaemia, diabetes, obesity, car-
diovascular disease and structural hypothalamic changes
during their subsequent pregnancies and that these
abnormal outcomes can be prevented by normalization
of maternal blood glucose levels during pregnancy121,122.
These adverse outcomes are similar to clinical obser-
vations in children from different populations that
included women with different types of diabetes melli-
tus, which noted an increased risk of diabetes and obesity
in children of women with diabetes mellitus123–125.
In a follow-​up study from Denmark of the offspring
(18–27 years of age) of women with GDM, 21% of the
offspring had pre-​diabetes or diabetes — an eightfold
increased risk compared with the background popu-
lation11. Furthermore, the risk of overweight and the
metabolic syndrome was higher (twofold and fourfold,
respectively)10 and insulin sensitivity and secretion were
reduced126. In a study of nearly 100,000 pregnant women,
children of women with GDM had increased fasting
glucose levels, insulin resistance, adiposity and cardio­
vascular risk profile127. The HAPO-​FUS confirmed
these findings but suggests that although maternal adi-
posity is a strong risk factor for offspring obesity, GDM
remains a significant risk factor, even after adjustment
for maternal BMI116,128,129.
Although differing results have been reported about
the effects of GDM on cognitive function in offspring,
there is no solid evidence that maternal GDM inde-
pendently causes impaired cognitive function125,130.
Some studies have found that the offspring of women
with an early diagnosis of GDM have an increased risk
of autism spectrum disorder131, whereas the offspring of
Insulin sensitivity index
women with GDM needing medical treatment have
an increased risk of attention-​deficit hyperactivity
disorder (ADHD)132.
In contrast to the well-​d ocumented benefits of
GDM treatment in reducing immediate maternal and
fetal complications and the findings in animal studies,
treatment of GDM does not seem to improve the long-​
term prognosis of offspring133,134. However, postpartum
follow-​up studies are still of relatively short duration
(4–10 years) and long-​term results are awaited.
In conclusion, GDM is part of a vicious circle — dia­
betes begets diabetes, without any proven interventions
to interrupt or mitigate this cycle (Fig. 9).
Diagnosis, screening and prevention
Prevention of GDM
A number of clinical trials of dietary and lifestyle
changes, dietary supplements and pharmacological
medications for the prevention of GDM have been con-
ducted. Despite promising findings from observational
studies, intervention studies seeking to demonstrate
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potential benefits from healthful diet and lifestyle
changes have been inconsistent135–137. Meta-​analyses
and systematic reviews138–143 have also reached divergent
conclusions. Both the timing of intervention (early to
mid or late pregnancy) and the intervention approaches
themselves (yoga, aerobic exercises, resistance training
and targeting different aspects of diet) were diverse in
these studies. These methodological issues may have
contributed to the markedly heterogeneous findings.
A meta-​analysis published in 2015 provides some evi-
dence that lifestyle modification (diet, physical activity
or both) initiated before the fifteenth gestational week
can reduce the risk of GDM141. Antenatal dietary sup-
plementation with myo-​inositol (a derivate of second-
ary messengers involved in several signalling pathways,
including the insulin pathway) for the prevention of
GDM is a comparatively new intervention. In two small
clinical trials, myo-​inositol supplementation reduced the
risk of GDM144,145, whereas in a larger trial, supplemen-
tation with an inositol combination in early pregnancy
did not prevent GDM in women with a family history of
diabetes146. However, of note, the overall quality of this
evidence has been assessed as low or very low and the
overall risk of bias is considered unclear144,147.
Probiotics
Probiotics have potentially beneficial effects on glucose
metabolism outside of pregnancy and have therefore
been suggested as an intervention to prevent GDM.
Initial enthusiasm was based mostly on positive findings
in a randomized controlled trial from Finland. In that
study, a probiotic preparation containing Lactobacillus
rhamnosus GG and Bifidobacterium animalis subsp. lactis
BB-12 reduced GDM prevalence from 35% to 13%148.
However, findings in subsequent studies have been
largely negative149–152, and systematic reviews yielded con-
tradictory and inconclusive results153–155. Taking a global
view, there is currently no firm evidence supporting the
use of probiotics for the prevention of GDM.
0.3
Control
0.2 GDM
0.1
0.0
Pregravid Early pregnancy Late pregnancy
Fig. 5 | Changes in insulin sensitivity during pregnancy
in normoglycaemic women and women with GDM.
Longitudinal changes in insulin sensitivity during a
hyperinsulinaemic–euglycaemic clamp (40 mU m–2 per
minute insulin infusion) in women with normal glucose
tolerance (control) and those who developed gestational
diabetes mellitus (GDM). Data are presented as the mean
and s.d. The x-​axis indicates longitudinal changes before and
during pregnancy. The y-​axis indicates the change in insulin
sensitivity index, which is defined as the glucose infusion
rate to maintain euglycaemia (90 mg dl–1) plus residual
endogenous glucose production during the clamp/mean
insulin concentration during insulin infusion at 40 mU m–2
per minute. Adapted with permission from REF.53, Elsevier.
 Primer
1,000
900 Normoglycaemic
800 GDM
Third trimester
Insulin secretion rate
700
Postpartum
600
500
400
300
200
100
0
0.0 0.1 0.2 0.3 0.4
Insulin sensitivity index
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.
Pharmacological interventions
Pharmacological interventions during pregnancy for
GDM prevention are rare, with most studies testing
metformin in high-​r isk populations, such as over-
weight and obese women156,157 or women with a history
of polycystic ovary syndrome158,159. Overall, data from
existing studies do not demonstrate a protective role
of metformin in the prevention of GDM. Large-​scale,
multiple-​arm inter­vention 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 Mahan3. 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…”)
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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 Coustan160 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-​s cale
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 pregnancy166. 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-​p eptide levels. The IADPSG
also recognized that undiagnosed T2DM in pregnant
women is increasingly prevalent in certain populations
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 Primer

Normal glucose tolerance Normoglycaemic GDM

(non-pregnant) pregnancy

Insulin Glucose Glucose Glucose

GLUT4
Insulin P P P
receptor P P
P P P
P P
P P P
pSer pTyr pSer pTyr pSer pTyr
IRS1 IRS1 IRS1
Insulin Insulin Insulin
PI3K action PI3K action PI3K action

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 muscle55. In late pregnancy, skeletal muscle IRS1
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 tolerance56.

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 bodies8,172
but were disputed by others162,173,174. The IADPSG crite-
ria are largely followed in Australia169 and Japan170 and
are officially endorsed in Europe175 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 guidelines177 and 2018
Canadian guidelines178 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 testing179. 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 diagnosis177 to the acceptance by
IADPSG that only a single elevated value on the OGTT
is sufficient to make a GDM diagnosis7.
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
OGTT180, whereas another systematic review concluded
that the one-​step method is associated with improved
pregnancy outcomes181. 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 result182,
whereas 75% of women in a study from western Canada
received appropriate follow-​up testing within 2 weeks183.
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 publication3. 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

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Primer
Maternal Placental Fetal
Amino
acids
+ mended diet is similar to a general diabetes diet, includes
Glucose
Glucose ↑ Insulin
Macrophage + (IOM) recommends a diet with ≥175 g of carbohydrates
Lipogenesis
Liver
Lipoproteins + and the minimum carbohydrate intake recommended
EL
FFA FFA
FFA
pool
White adipose
Syncytiotrophoblast Endothelium
tissue
Fig. 8 | Pathophysiology of fetal phenotype in GDM. Maternal glucose is the main
macronutrient that sustains fetal growth. In women with gestational diabetes mellitus
(GDM), prolonged fetal exposure to hyperglycaemia and/or some amino acids (for
example, leucine and arginine) induces hyperinsulinaemia. Free fatty acids (FFAs) derived
from maternal lipoproteins are released by endothelial lipase (EL)-mediated lipolysis on
the surface of the placenta. Only a small proportion of these FFAs cross the placenta,
where they contribute to the fetal FFA pool, which comprises predominantly FFAs
resulting from hepatic de novo lipogenesis, using the excess glucose (due to maternal
overnutrition) as a precursor. Fetal insulin stimulates triglyceride synthesis and, thus,
fat storage in white adipocytes in the fetus in a sex-​dependent manner93. Solid lines
represent macronutrient flow; dotted lines represent regulating effects of fetal insulin.
study in Denmark found a >40% GDM diagnostic rate
in a low-​risk population using the IADPSG and WHO
criteria, without a clear relationship of GDM diagnosis to
adverse pregnancy outcomes185. The 2015 guidelines from
FIGO172 recommend a more flexible approach that allows
for differing diagnostic processes and glucose thresholds
in specific geographic regions and ethnic groups.
Management
The primary goal of GDM treatment is the prevention
of fetal overgrowth and pregnancy complications. This
aim is usually achieved by dietary modification, and
promotion of physical activity to minimize postprandial
glucose elevations and pharmacotherapy is required only
in a minority of women.
Lifestyle intervention
Glucose is the main nutrient that promotes fetal growth
(although other nutrients, such as lipids and amino
acids, also influence growth). Increased maternal gly-
caemia is directly associated with fetal overgrowth and
many of the pregnancy complications in GDM (the
Pedersen hypothesis). Therefore, control of maternal
hyperglycaemia logically remains the primary goal of
GDM treatment. In two large, randomized controlled
studies, lifestyle advice (supplemented with insulin
administration if necessary) reduced the prevalence of
fetal overgrowth (LGA; infant mass >90th percentile) by
~50% to within the normal expected population range
and reduced the risk of shoulder dystocia109,110. Lifestyle
modification is the cornerstone of treatment and should
12 | Article citation ID: (2019) 5:47
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be initiated shortly after diagnosis186,187. The diet should
contain sufficient macronutrients and micronutrients,
limit postprandial glucose excursions and prevent
excessive maternal gestational weight gain. The recom-
mainly low-​glycaemic-index carbohydrates and often
apportions daily caloric intake into three main meals and
2–4 snacks. To ensure sufficient fetal growth and cere-
bral development and function, the Institute of Medicine
daily188,189. Maternal ketonaemia and/or ketonuria in
pregnant women with diabetes has been associated with
lower mental and/or motor function in the offspring190,
by IOM ensures sufficient carbohydrates to avoid star-
vation ketonaemia. A low-​glycaemic-index diet has been
shown in randomized trials to be associated with less
frequent insulin use and lower birthweight than control
diets188. The average total caloric intake was 1,600 kcal
daily in the pregnant women in these trials, which
probably reflects some degree of caloric restriction188.
Caloric restriction up to 30% of the required intake has
been suggested as safe in obese pregnant women187, but
evidence is lacking in those who are not obese.
Lifestyle intervention also includes recommendations
for daily physical activity, such as walking, cycling and
swimming191. Diet and physical activity are sufficient to
control the glycaemic status in ~70–85% of women with
GDM187,191. In addition to more appropriate fetal growth,
this lifestyle intervention is also associated with reduced
occurrence of postnatal depression among mothers109,
and a systematic review demonstrated that exercise
interventions reduce postpartum weight retention in
pregnant women192.
Patient involvement and treatment goals
Women with GDM are encouraged to self-​monitor their
preprandial and postprandial blood glucose levels before
and 1–2 hours after main meals193. Glucose targets vary
between various international guidelines. At present, the
American Diabetes Association (ADA) recommends fast-
ing glucose values <95 mg dl–1 (5.3 mmol l–1) and either
1-hour postprandial glucose <140 mg dl–1 (7.8 mmol l–1)
or 2-hour postprandial glucose <120 mg dl–1 (6.7 mmol l–1)
and, if measured, HbA1c levels <6%191. Initially, prepran-
dial and postprandial glucose measurements with the
three main meals are recommended daily. If the gly­caemic
goals are easily obtained within 2 weeks of initiating life-
style interventions, women may reduce the frequency
of preprandial and postprandial glucose measure­ments
to twice weekly as long as the values are within target.
Continuous glucose monitoring has become available at
a reasonable price and may replace finger-​prick tests in
selected cases. In our opinion, an average blood glucose
level of 5–7 mmol l–1 can be recommended, although
precise targets vary widely between and even within
countries and regions. In the future, more detailed recom­
mendations for time in target and time below target for
women with GDM may be developed.
In addition to hyperglycaemia, excessive gestational
weight gain is also associated with fetal overgrowth in
both healthy and GDM pregnancies189,194, which has
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led to recommendations for weekly gestational weight-​ safe to postpone initiation of pharmacological treat-
gain goals that are dependent on maternal BMI before ment. Conversely, excessive fetal growth may lead to
pregnancy. For obese, overweight and healthy-​weight intensification of treatment with lower glycaemia goals195.
women, the IOM189 recommends a maximum weekly
weight gain of 220 g, 280 g and 420 g, respectively. There Insulin. Traditionally, insulin has been the primary med-
is some evidence that even lower targets for obese women ical treatment if the glycaemic treatment goals are not
may be safe and are associated with more appropriate achieved with lifestyle intervention within 1–2 weeks.
fetal growth194. Many clinicians will therefore accept a Insulin is effective and safe for the fetus, as it does not cross
diet aimed at weight stability, and some clinicians even the placenta. Human insulin and several insulin analogues
recommend some weight loss in obese women after (for example, insulin aspart, insulin lispro and insulin
diagnosis of GDM. To follow the recommendations for detemir) have been formally tested and are considered safe
weekly weight gain, the weight of the mother should be to use in pregnancy191. Insulin glargine is also often used
monitored carefully at frequent intervals after diagnosis and, although there are no randomized trials supporting
of GDM. Both caregivers and patients should be aware of the use of insulin glargine, a synthesis of published cohort
both the blood glucose targets and the weight-​gain goals. studies has not raised specific concerns about its use in
pregnancy196,197. The main issue with insulin therapy is
Medical treatment of GDM the burden for the women, which can include discomfort,
When glycaemia remains elevated after ≥1–2 weeks fear of needles, the cost of treatment and the risk of hypo-
of lifestyle interventions, daily glucose testing should glycaemia. Episodes of mild hypoglycaemia occur often,
be continued and pharmacological treatment should be whereas episodes of severe hypoglycaemia (that require
initiated. Ultrasonography-​based assessment of fetal help from a third party) are rare.
growth may also assist in guiding the intensity of glu- During medical treatment, the goals for glucose con-
cose control that is needed in an individual woman. trol and weight gain are the same as those for lifestyle
If the baby is growing appropriately, in particular if fetal interventions alone. The insulin treatment can be a
abdominal circumference is <75th percentile, it may be 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-​
Table 2 | Outcomes from the HAPO study and the HAPO-​FUS
acting and long-​acting insulin are also effective198. Insulin
Outcome GDMa Non-​GDM Statistical detemir has been associated with less hyperglycaemia
(%) (%) significance and hypoglycaemia than slow-​acting human neutral
Perinatal outcomesb protamine Hagedorn (NPH) insulin199. However, when
Pre-​eclampsia 9.1 4.5 P < 0.001 choosing the type of insulin, the cost of the insulin must
also be considered. An initial dose of 0.3 international
Preterm delivery (<37 weeks) 9.4 6.4 P < 0.001
units (IU) per kg (body weight) per 24 hours can be used
Primary caesarean delivery 24.4 16.8 P < 0.001 when initiating the insulin treatment, and a final insulin
Shoulder dystocia or birth injury 1.8 1.3 P < 0.01 dose close to 1 IU per kg (body weight) is often needed198.
Birthweight greater than ninetieth percentile 16.2 8.3 P < 0.001 Insulin treatment is time consuming for caregivers
and requires training and education of the pregnant
Neonate percentage body fat greater than 16.6 8.5 P < 0.001 women, and patient contact is frequently needed to
ninetieth percentile
adjust the insulin dose. Consequently, oral glucose-​
Cord blood C-​peptide level greater than 17.5 6.7 P < 0.001 lowering medications, such as two well-​established oral
ninetieth percentile
agents, metformin and the sulfonylurea glibenclamide,
Clinical neonatal hypoglycaemia 2.7 1.9 P < 0.001 have been studied in women with GDM. Other glucose-​
Admission to newborn intensive care 9.1 7.8 P < 0.01 lowering agents are generally not advocated for use in
Long-​term outcomes c pregnancy owing to documented complications, such as
neonatal hypoglycaemia, fear of unexpected fetal com-
Maternal diabetes 10.7 1.6 P < 0.001 plications and possible metabolic or epigenetic changes
Maternal pre-​diabetes 41.5 18.4 P < 0.001 in the developing fetus.
Offspring overweight or obesity 39.5 28.6 P < 0.001
Metformin. Metformin acts mainly by suppressing
Offspring obesity 19.1 9.9 P < 0.001
hepatic glucose production, leading to a reduction in
Offspring percentage body fat greater than 21.7 13.9 P < 0.001 fasting plasma glucose levels and HbA1c. Metformin is
eighty-​fifth percentile the first-​line treatment in non-​pregnant patients with
Offspring impaired fasting glucose (ADA 9.2 7.4 Not significant T2DM200. Although it is inexpensive and easy to use,
threshold of ≥5.6 mmol l–1) metformin commonly causes gastrointestinal symptoms,
Offspring impaired glucose tolerance 10.6 5.0 P < 0.001 may cause low vitamin B12 and, rarely, may increase the
Offspring diabetes 0.3 0.2 Not significant risk of lactic acidosis. Perhaps more importantly, met-
ADA, American Diabetes Association; GDM, gestational diabetes mellitus; HAPO, Hyperglycemia
formin crosses the placenta and thus can potentially
and Adverse Pregnancy Outcomes; HAPO-​FUS, HAPO Follow-​Up Study. aWomen classified affect the developing fetus. In randomized clinical trials,
post hoc as having GDM by International Association of Diabetes and Pregnancy Study Groups metformin seems to be comparable to insulin in glycae-
(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 study108. cOutcomes are from mic control and immediate neonatal outcomes201,202.
the HAPO-​FUS116. At least one-​third of women with GDM who are treated

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Primer
Pregnancy
• Increased insulin
resistance
(obesity or GDM)
• Metabolic
Metabolic inflammation
ageing
Adult metabolic syndrome, Fetal–neonatal metabolic
T2DM and obesity programming of obesity
• 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.
with metformin also need additional treatment with
insulin203. Because metformin crosses the placenta, the
long-​term effects of treatment in utero on the child must
be considered204. 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 insulin207.
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 utero208.
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 similar209. However, contrary to initial
findings with early, less-​sensitive assays, glibenclamide
crosses the placenta210,211, and the fetal:maternal concen-
tration ratio is highly variable210 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 glibenclamide203, 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
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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-
lin212. 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 ADA191,
the Endocrine Society168, FIGO172 and the British NICE
guidelines179, 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 patterns213,
avoiding weight gain after pregnancy and frequent, pro-
longed and more intensive breastfeeding reduce the risk
of progression to overt diabetes214–216. 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-​up217–219. 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 years191 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 health221,222.
However, as formal studies are rare, little is known about
this topic.
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A systematic review reported that QOL is more fre-
quently reduced in women with GDM than in pregnant
women without GDM223. However, it is not clear whether
this is caused by GDM itself or is due to confounding
factors, such as obesity, gestational weight gain, socio-​
economic status or pre-​existing depression. Interestingly,
in the landmark ACHOIS randomized controlled trial of
treatment versus no treatment of GDM, treated women
with GDM had a higher QOL score at 3 months post-
partum than those who were not treated109. This result
most likely reflects the beneficial effect of the generally
increased care that women receive during pregnancy
after a GDM diagnosis.
Depression has been reported more often in women
with GDM, both before and after pregnancy, than in
pregnant women without GDM, indicating that GDM
is not the cause of depression43,224,225. Thus, a knowledge
gap still exists about the effect of GDM on QOL, and
further studies are needed.
Outlook
Currently accepted features of GDM
The evidence discussed above clearly supports the
existence of the phenomenon of gestational diabetes
— hyperglycaemia arising during pregnancy owing to
pathophysiological changes in gestation. Furthermore,
although there is no clear or natural set of diagnostic
cut-​off levels for hyperglycaemia, current treatment
protocols, including diet, exercise and insulin, reduce
immediate pregnancy complications, in particular exces-
sive fetal growth and its consequences and maternal
hypertensive disorders of pregnancy.
Conversely, the factors that influence the risk of
developing GDM have changed, particularly advancing
maternal age at the time of childbearing and increasing
Box 2 | Key points in the treatment of GDM
Lifestyle intervention with diet and physical activity is the cornerstone of treatment,
and only a minority of women with gestational diabetes mellitus (GDM) need
pharmacotherapy.
Diet
• Ensure sufficient intake of micronutrients and macronutrients, including >175 g of
carbohydrates daily
• Minimize glycaemic excursions by intake of low-​glycaemic-index carbohydrates
divided over several meals and snacks daily
• Provide appropriate level of gestational weight gain
Physical activity
• Light exercise, such as walking, swimming and cycling
• Regimen appropriate for pregnancy
Pharmacotherapy
If the glycaemic goals are not attained within 1–2 weeks of initiating dietary changes
and physical activity
• Insulin is the gold-​standard treatment for hyperglycaemia
• Metformin may be chosen in selected cases, dependent on convenience and cost
Treatment after delivery
• Continue lifestyle interventions
• Encourage breastfeeding
• Pharmacotherapy can be stopped immediately after delivery
• Regular screening for the development of diabetes mellitus is recommended
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Primer
population obesity. Therefore, many cases currently clas-
sified as GDM probably represent pre-existing undiag­
nosed pre-diabetes, which is not specifically related
to pregnancy226.
GDM is also clearly associated with increased risk
of later maternal diabetes and cardiovascular disease.
Preventive strategies have been clearly elucidated227,228 and
proved to be efficacious, but long-​term implementation
on a broad population scale remains elusive.
Unfortunately, current treatment protocols have not
been proved to effectively reduce the risks of later obesity
and impaired glucose metabolism in offspring133,134.
Areas for future GDM research
Despite many years of attempting to achieve interna-
tional consensus on GDM diagnostic criteria, uniform
recommendations remain elusive and the ‘pragmatic’
approach of FIGO172, which allows for regional vari­
ations so long as the overarching principles of uniform
testing and treatment are adhered to, may represent the
best available compromise solution.
A key area of uncertainty is the definition of healthy
or desirable glucose levels and by inference ‘GDM equiv-
alent’ glucose levels in early pregnancy (<20 weeks of
gestation), and both epidemiological studies and clinical
trials in this area are eagerly awaited229,230. Furthermore,
additional biomarkers that predict pregnancy compli-
cations are highly desirable, as are non-​fasting alterna-
tives to the complex and burdensome OGTT. Plasma
glycated CD59 is the most promising current candidate,
but further research is required before it can be widely
adopted231. In addition, differences in fetal sex-​related
GDM pregnancy outcomes232 and later outcomes134 are
increasingly reported, and their underlying mechanisms
are a fertile area for future investigation87,233. Attempts to
understand the molecular mechanisms underlying sex
differences in GDM will inevitably require more studies
of placental factors (such as exosomes and hormones)
and their effects on maternal insulin resistance and β-​cell
function. It is also unclear whether and how the fetal
pancreatic β-​cell response to maternally derived insulin
secretagogues, such as arginine and other amino acids, is
changed in GDM. Transplacental transfer of these amino
acids has not been studied in GDM, although they have
been shown to stimulate insulin release, at least in the
first half of pregnancy, and they are also indirectly
involved in regulating the vascular tone of the feto-​
placental circulation234. GDM-​associated changes in vas-
cular tone may result in umbilical blood flow differences
between GDM and non-​GDM pregnancies235.
To date, attempts at prevention of GDM through
lifestyle interventions, probiotics, inositol supplemen-
tation and medications have not shown consistent bene­
fits236, and none could be recommended for routine
use. The focus of preventive efforts probably needs to
shift to the preconception period or very early in gesta­
tion to achieve the hoped-​for reductions in both GDM
prevalence and consequent pregnancy complications.
Population-​based efforts to reduce the prevalence of obe-
sity and hyperglycaemia across the life course, especially
in girls and young women, may ultimately be required to
reverse the tide of these dual global epidemics.
­ 15
Primer

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 hypoglycaemia237. Metformin,
despite encouraging immediate pregnancy out-
comes, is associated with greater childhood size and
adiposity207,238,239, 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 attention57. Publications
from the HAPO-​FUS116,128,129 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 gains240
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.
Published online xx xx xxxx

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Acknowledgements
C.Z. is supported by the intramural research program of the
Eunice Kennedy Shriver National Institute of Child Health and
Human Development, NIH.
Author contributions
Introduction (H.D.M.); Epidemiology (C.Z.); Mechanisms/
pathophysiology (P.C. and G.D.); Diagnosis, screening
and prevention (H.D.M., C.Z. and E.R.M.); Management
(P.C. and E.R.M.); Quality of life (P.D.); Outlook (H.D.M., P.C.,
C.Z., G.D. and P.D.); Overview of the Primer (H.D.M.).
Competing interests
P.D. is participating in multi-​centre and multinational clinical
studies on the use of insulin in pregnant women with pre-​
existing diabetes in collaboration with Novo Nordisk; no per-
sonal honorarium is involved. E.R.M. is participating in
multinational clinical studies on the use of insulin in pregnant
women with pre-​existing diabetes in collaboration with Novo
Nordisk. E.R.M. has given talks for Novo Nordisk, AstraZeneca,
Lilly and Sanofi Aventis and has received a salary for these tasks.
H.D.M., C.Z., P.C. and G.D. declare no competing interests.
Peer review information
Nature Reviews Disease Primers thanks D. Coustan,
T. Buchanan and L. Sobrevia for their contribution to the
peer review of this work.
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