Endocrine Reviews, 2022, XX, 1–31

https://doi.org/10.1210/endrev/bnac003
Advance access publication 18 January 2022
Review

A Clinical Update on Gestational Diabetes Mellitus

Arianne Sweeting,1,2, Jencia Wong,1,2 Helen R. Murphy,3,4,5 and Glynis P. Ross,1,2,
1
Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia

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2
Faculty of Medicine and Health, University of Sydney, Sydney, Australia
3
Diabetes in Pregnancy Team, Cambridge University Hospitals, Cambridge, UK
4
Norwich Medical School, Bob Champion Research and Education Building, University of East Anglia, Norwich, UK
5
Division of Women’s Health, Kings College London, London, UK
Correspondence: Arianne Sweeting, MBBS Hons, BSc, GradDip HL, FRACP, PhD, Department of Endocrinology, Royal Prince Alfred Hospital, Sydney,
Australia; Faculty of Medicine and Health, Level 2 Charles Perkins Centre D17, University of Sydney, Sydney, NSW 2006, Australia. Email: arianne.sweeting@
sydney.edu.au.

Abstract
Gestational diabetes mellitus (GDM) traditionally refers to abnormal glucose tolerance with onset or first recognition during pregnancy. GDM has
long been associated with obstetric and neonatal complications primarily relating to higher infant birthweight and is increasingly recognized as a
risk factor for future maternal and offspring cardiometabolic disease. The prevalence of GDM continues to rise internationally due to epidemiological
factors including the increase in background rates of obesity in women of reproductive age and rising maternal age and the implementation of
the revised International Association of the Diabetes and Pregnancy Study Groups’ criteria and diagnostic procedures for GDM. The current lack of
international consensus for the diagnosis of GDM reflects its complex historical evolution and pragmatic antenatal resource considerations given
GDM is now 1 of the most common complications of pregnancy. Regardless, the contemporary clinical approach to GDM should be informed not
only by its short-term complications but also by its longer term prognosis. Recent data demonstrate the effect of early in utero exposure to ma-
ternal hyperglycemia, with evidence for fetal overgrowth present prior to the traditional diagnosis of GDM from 24 weeks’ gestation, as well as the
durable adverse impact of maternal hyperglycemia on child and adolescent metabolism. The major contribution of GDM to the global epidemic of
intergenerational cardiometabolic disease highlights the importance of identifying GDM as an early risk factor for type 2 diabetes and cardiovascular
disease, broadening the prevailing clinical approach to address longer term maternal and offspring complications following a diagnosis of GDM.

Graphical Abstract

Key Words:  gestational diabetes mellitus, diagnosis, pathophysiology, genetics, outcomes, management, precision medicine, biomarkers, diabetes prevention,
COVID

Received: 7 July 2021. Editorial Decision: 4 January 2022. Corrected and Typeset: 17 February 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.
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2 Endocrine Reviews, 2022, Vol. XX, No. XX
Essential Points
1. Gestational diabetes mellitus (GDM) is 1 of the most
common medical complications of pregnancy and is
increasing in prevalence globally.
2. GDM is associated with obstetric and neonatal com-
plications primarily due to increased birthweight
and is a major risk factor for future type 2 diabetes,
obesity, and cardiovascular disease in mother and
child.
3. Detecting GDM is important because perinatal com-
plications and stillbirth risk are greatly reduced by
treatment.
4. A precision medicine approach to GDM which
recognizes severity and onset of maternal hypergly-
cemia as well as genetic and physiologic subtypes
of GDM may address the current diagnostic con-
troversy via accurate risk stratification and indi-
vidualized treatment strategies, leading to improved
clinical care models and outcomes.
5. The traditional focus on normalization of obstetric
and neonatal outcomes achieved via short-term ante-
natal maternal glucose management should now shift
to early postnatal prevention strategies to decrease the
progression from GDM to type 2 diabetes and ad-
dress longer term maternal and offspring metabolic
risk given the global epidemic of diabetes, obesity, and
cardiovascular disease.
Diabetes in pregnancy was first described in 1824 by
Bennewitz in Germany (1), with subsequent case series in the
United Kingdom and United States reporting high perinatal
mortality rates in women with diabetes in pregnancy (2-4).
In 1909, Williams reported arguably the first diagnostic cri-
teria for diabetes in pregnancy in the United States, proposing
physiological and pathophysiological thresholds for “tran-
sient glycosuria in pregnancy” (5).
In 1964, O’Sullivan and Mahan defined specific diag-
nostic criteria for gestational diabetes mellitus (GDM) in
the United States derived from the 100-g 3-hour oral glu-
cose tolerance test (OGTT) undertaken in the second and
third trimester of pregnancy in 752 women (6). GDM was
defined as ≥2 venous whole blood glucose values greater
than 2 SD above the mean glucose values for pregnancy
in their initial cohort. These glucose thresholds were pri-
marily chosen because the resulting GDM prevalence of
2% corresponded to the background population preva-
lence of diabetes, while the requirement of ≥2 elevated glu-
cose values sought to minimize the risk of preanalytical
error (7). These thresholds were validated by their identifi-
cation of subsequent diabetes up to 8 years postpartum in
an additional cohort of 1013 women. Increased perinatal
mortality was also observed in women with ≥2 glucose
values exceeding the proposed diagnostic criteria (6). In
1965, the World Health Organization (WHO) concurrently
recommended that GDM be diagnosed by either a 50- or
100-g OGTT using the 2-hour postload glucose value, but
the threshold used was the same as for diagnosing diabetes
in the nonpregnant population (8). The WHO continued
to diagnose GDM based on glucose thresholds for diabetes
in the nonpregnant population (9,10) until its endorse-
ment of the International Association of the Diabetes and
Pregnancy Study Groups (IADPSG) diagnostic criteria in
2013 (11).
Since 1973, the screening approach to GDM frequently
adopted a 2-step procedure with the 50-g 1-hour glucose
challenge test (GCT) followed by the 100-g 3-hour OGTT
if the GCT was positive. This was based on data from
O’Sullivan et  al, which showed that a 2-step diagnostic ap-
proach to GDM using the GCT as the initial screening test
and a glucose threshold of 7.9 mmol/L (143 mg/dL) was 79%
sensitive and 87% specific for diagnosing GDM on the 100-g
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3-h OGTT in a cohort of 752 women (12). The rationale for
this approach was the efficient identification of women most
at risk of GDM.
In 1979, the US National Diabetes Data Group (NDDG)
published conversions of the original O’Sullivan and Mahan
100-g 3-hour OGTT diagnostic criteria for GDM, reflecting
the transition from venous whole blood glucose to plasma
blood glucose analysis (13). These revised criteria were sub-
sequently adopted by the American Diabetes Association
(ADA) and internationally (9,14,15). In 1982, Carpenter and
Coustan recommended lowering of the NDDG diagnostic
criteria, reflecting newer preanalytical enzymatic methods
that were more specific for plasma glucose (7,16). They also
advised lowering the GCT glucose threshold to 7.5 mmol/L
(135 mg/dL) based on their study of 381 women who under-
went the 100-g 3-h OGTT after screening positive on the
GCT, whereby a GCT glucose threshold ≤ 7.5  mmol/L
(135  mg/dL) strongly correlated with a normal OGTT
(17). However, in the absence of clear evidence supporting
a specific glucose threshold for the GCT, the ADA and
the American College of Obstetricians and Gynecologists
(ACOG) continued to recommend a screen positive GCT
glucose threshold from 7.2 to 7.8 mmol/L (130-140 mg/dL)
for GDM (18,19).
The ADA did however recommend the modified Carpenter
and Coustan diagnostic glucose thresholds for GDM from
2000 (20), supported by the findings of the Toronto Tri-
Hospital Gestational Diabetes Project (21,22). These data
demonstrated a positive correlation between increasing ma-
ternal hyperglycemia even below the NDDG diagnostic
criteria for GDM and risk of obstetric and neonatal com-
plications including preeclampsia, cesarean section, and
macrosomia (neonatal birthweight > 4000 g) (21,22). In add-
ition, several large cohort studies showed that women diag-
nosed (but not treated) with GDM based on the Carpenter
and Coustan criteria were at increased risk of perinatal com-
plications including hypertensive disorders of pregnancy, in-
creased birthweight, macrosomia, neonatal hypoglycemia,
hyperbilirubinemia, and shoulder dystocia, compared to
women diagnosed and treated as GDM by NDDG diagnostic
criteria (16,23-25). From 2003 the ADA additionally endorsed
the 1-step 75-g 2-hour OGTT for the diagnosis of GDM de-
rived from the modified Carpenter and Coustan fasting, 1-
and 2-hour glucose thresholds for the 100-g 3-hour OGTT,
particularly for women at high-risk (26). This approach was
deemed more cost-effective, albeit less validated, than the
100-g 3-hour OGTT. The use of the modified Carpenter and
Coustan thresholds was associated with an almost 50% in-
crease in prevalence of GDM (16,23).
The evolution of diagnostic criteria for GDM illustrates the
historic lack of consensus for the diagnosis of GDM, with
the presence or absence of disease varying dependent on ex-
pert consensus. The underlying rationale for the diagnosis of
Endocrine Reviews, 2022, Vol. XX, No. XX
GDM also shifted over time toward identifying perinatal risk
rather than future maternal diabetes risk.
Current GDM Diagnostic Criteria
The seminal Hyperglycemia and Adverse Pregnancy
Outcomes (HAPO) study sought to provide an evidence
base to guide risk in GDM, and its results were published
in 2008 (27). This large, international, prospective, observa-
tional study evaluated the relationship between glucose levels
on the 75-g 2-hour OGTT performed at 24 to 32 weeks’
gestation (mean 27.8 weeks’ gestation) in over 25 000 preg-
nant women with the following primary perinatal outcomes:
birthweight > 90th percentile for gestational age, primary
cesarean section delivery, neonatal hypoglycemia, and cord
blood serum C-peptide > 90th centile. Secondary outcomes
were preeclampsia, preterm delivery (defined as delivery be-
fore 37 weeks’ gestation), shoulder dystocia or birth injury,
hyperbilirubinemia, and neonatal intensive care admission.
The results showed a continuous positive linear relation-
ship between maternal fasting; 1- and 2-hour plasma glucose
levels obtained on the OGTT, below those that were diag-
nostic of diabetes outside pregnancy; and risk of primary out-
comes (27). Notably, there were no specific glucose thresholds
at which obstetric and neonatal complications significantly
increased.
Based on these findings and supported by trials [the
Australian Carbohydrate Intolerance Study in Pregnant
Women (ACHOIS) and the Maternal-Fetal Medicine Units
Network (MFMU) trial] showing benefit of treatment
of more severe and “mild” degrees of maternal hyper-
glycemia, respectively (28,29), the IADPSG revised its
diagnostic criteria for GDM. Despite the lack of a clear
diagnostic glucose threshold in HAPO, the consensus of
the IADPSG was to define diagnostic thresholds for the
fasting, 1- and 2-hour glucose values for the 75-g 2-hour
OGTT based on the average glucose values at which the
odds of the primary outcomes were 1.75 times the odds of
these outcomes occurring at the mean glucose levels for the
HAPO cohort (30). The IADPSG consensus was also that
only 1 elevated glucose level for the OGTT was required
for GDM diagnosis, as each glucose threshold represented
broadly comparable level of risk. Thus, the main purpose
of the diagnostic criteria for GDM post-HAPO was to de-
fine the level of risk associated with increased perinatal
complications.
Post-HAPO, there exist several different screening and
testing approaches for the diagnosis of GDM internationally.
The IADPSG and WHO recommend universal testing of all
pregnant women between 24 to 28 weeks’ gestation with the
75-g 2-hour OGTT (11,30). These revised recommendations
were largely endorsed by several organizations including the
ADA (18), Endocrine Society (31), International Federation
of Gynecology and Obstetrics (32), Australasian Diabetes
in Pregnancy Association (33), Japan Diabetes Society (34),
Ministry of Health of China (35), and the European Board of
Gynecology and Obstetrics (36).
The National Institutes of Health did not endorse the
IADPSG recommendations, citing the expected increase in
prevalence of GDM, cost, and intervention in the context
of a lack of evidence for an associated improvement in peri-
natal outcomes (37). The National Institutes of Health and
3
ACOG continue to recommend a 2-step testing approach,
with the initial screening GCT for all women and those who
screen positive proceeding to the diagnostic 100-g 3-hour
OGTT (19,37). This approach is also endorsed by ADA (18).
However, the ACOG’s 2018 guidelines now acknowledge that
individual practices and institutions may instead choose to use
the IADPSG’s 1-step testing approach and diagnostic criteria
if appropriate for their population (19). The UK National
Institute for Health and Care Excellence (NICE) guidelines
advise a selective screening approach, whereby women with
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risk factors for GDM are recommended to undergo a diag-
nostic 75-g 2-hour OGTT at 26 to 28 weeks’ gestation, with
diagnostic (fasting or 2-hour) glucose thresholds higher than
the IADPSG diagnostic criteria for GDM (38). Several other
European bodies also currently recommend selective risk
factor-based screening, with only women fulfilling specific
high-risk criteria proceeding to a diagnostic OGTT, even if
the IADPSG diagnostic criteria for GDM are applied (39,40).
The revised IADPSG diagnostic criteria and testing approach
to GDM in comparison to other international organizations
are summarized in Table 1.
It is important to consider the increase in GDM preva-
lence associated with the IADPSG diagnostic criteria in the
context of the rising background rates of impaired glucose
tolerance, type 2 diabetes, and obesity among young adults
and women of reproductive age (46,47). For example, al-
most 18% of HAPO study participants would have met the
IADPSG diagnostic thresholds for GDM. By comparison, the
rate of prediabetes in US adults aged between 20 and 44 years
is >29% (48,49).
Studies in Indian, Israeli, and US cohorts have suggested
that the IADPSG testing approach and intervention for
GDM is cost-effective based on a combination of delaying
future type 2 diabetes and preventing perinatal complications
(50-53). For example, a US study found that the IADPSG
diagnostic criteria would be cost-effective if associated inter-
vention decreased the absolute incidence of preeclampsia by
>0.55% and cesarean delivery by >2.7% (53). In contrast,
UK health economic data show that routinely identifying
GDM is not cost-effective based on perinatal outcomes (54)
and that the universal WHO (IADPSG) testing approach is
less cost-effective than the NICE selective screening approach
(55).
Contemporary Clinical Evidence Following the
Revised IADPSG GDM Diagnostic Criteria
The lack of randomized controlled trials (RCTs) evaluating
outcomes in women diagnosed with GDM based on the
IADPSG criteria and the clinical relevance of treating the re-
sulting milder degrees of hyperglycemia remain controversial
(56). Several retrospective studies have shown that women
diagnosed with GDM by the IADPSG criteria but who were
previously classified as having normal glucose tolerance were
still at increased risk for obstetric and neonatal complications,
including gestational hypertension, preeclampsia, cesarean de-
livery, macrosomia, large-for-gestational-age (LGA), shoulder
dystocia, and neonatal intensive care admission, compared
to women with normal glucose tolerance (57-59). For ex-
ample, a 2015 retrospective study in Taiwan comparing preg-
nancy outcomes in women diagnosed and treated for GDM
using the 2-step (GCT followed by the 100-g 3-hour OGTT)
4 Endocrine Reviews, 2022, Vol. XX, No. XX
approach compared to the IADPSG 1-step approach found
that the latter was associated with a reduction in gestational
weight gain (GWG), birthweight, macrosomia, and LGA (60).
Another retrospective study in the United Kingdom reported
that women who were diagnosed with GDM based on modi-
fied IADPSG diagnostic glucose thresholds but who screened
negative for GDM on 2015 NICE diagnostic criteria had a
higher risk of LGA, cesarean delivery, and polyhydramnios
(61). Other retrospective studies have also demonstrated
higher birthweight, birthweight z-score, ponderal index, and
increased rates of LGA and cesarean delivery in untreated
women diagnosed with GDM based on the IADPSG criteria,
compared to women with normal glucose tolerance (62,63).
The recent randomized ScreenR2GDM trial compared
1-step screening (75-g 2-hour OGTT) with 2-step screening (2
GCT thresholds ≥7.2 mmol/L and ≥7.8 mmol/L used, followed
by the 100-g 3-hour OGTT) in 23 792 pregnant women in the
United States (64). Despite doubling the diagnosis of GDM
with the 1-step approach (16.5% vs 8.5%), there were no
differences in pregnancy complications including LGA [rela-
tive risk (RR) 0.95; 97.5% CI 0.87-1.05], perinatal composite
outcome (RR 1.04; 97.5% CI 0.88-1.23), gestational hyper-
tension or preeclampsia (RR 1.00; 97.5% CI 0.93-1.08), and
primary cesarean section (RR 0.98; 97.5% CI 0.93-1.02) be-
tween the different screening approaches. These findings have
not resolved the diagnostic debate for GDM, with some ar-
guing that the 1-step approach therefore demonstrates insuffi-
cient perinatal benefit for the associated increased healthcare
costs (65), while others have identified potential limitations
in study methodology (7,47,65,66). Despite randomization to
either testing strategy, the pragmatic trial design allowed clin-
icians to select a preferred strategy. Consequently, one third
of women randomized to the 1-step approach did not adhere
to the assigned screening and were tested via the 2-step ap-
proach, compared to only 8% of women randomized to the
2-step approach. Although the study attempted to adjust for
this difference using inverse probability weighting, residual
provider bias cannot be excluded (47). Given this was a popu-
lation level analysis of GDM screening, GDM (treatment)
status differed only for the 8% of women not diagnosed with
GDM based on the 2-step approach who may have otherwise
been diagnosed with GDM based on the 1-step approach.
Whether these women had potentially worse outcomes that
may have been mitigated by treatment cannot be determined
by this study. However, given the rates of pharmacotherapy
were similar between the 1- and 2-step cohorts at 43% and
46%, respectively (64), this strategy detected women with
essentially an equivalent risk of hyperglycemia warranting
pharmacotherapy (47). This observation is consistent with
other studies in UK cohorts comparing the IADPSG testing
approach to the less sensitive NICE and Canadian criteria,
whereby women demonstrated insulin resistance and re-
quired pharmacotherapy for control of hyperglycemia even
at the most sensitive thresholds of the IADPSG diagnostic cri-
teria (67).
More generally, the GCT fails to detect approximately 20%
to 25% of women with GDM, particularly those diagnosed
with GDM based on an elevated fasting glucose (68). The
frequency of GDM diagnosed by the OGTT fasting glucose
threshold in the HAPO study ranged from 24% to 26% in
Thailand and Hong Kong to >70% in the United States (69).
This highlights the variability and thus limitations of post-
glucose load screening based on ethnicity. Moreover, a recent
systematic review and meta-analysis of 25 studies (n = 4466
women) showed that even 1 abnormal value on the diagnostic
3-hour 100-g OGTT is associated with an increased risk of
perinatal complications compared to women with a normal
GCT, and this risk was similar to that of women actually
diagnosed with GDM (70).
The degree of benefit of treating women with GDM defined
by the IADPSG diagnostic criteria is yet to be determined. The
potential benefit is inferred from the treatment of maternal
hyperglycemia described in the ACHOIS and MFMU inter-
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vention trials (28,29), whereby maternal glucose levels over-
lapped with the thresholds recommended by the IADPSG. It
is worth noting that there are differences in these 2 trials with
regards to the diagnostic criteria used to define GDM and
cohort characteristics (eg, women were excluded from the
MFMU trial if they had an abnormal glucose screening test
prior to 24 weeks’ gestation or previous GDM), and thus the
generalizability of these findings in women diagnosed with
GDM based on the IADPSG criteria remains contentious.
Current Classification of Hyperglycemia in
Pregnancy and GDM
The WHO first defined GDM in 1965 as “hyperglycemia of
diabetic levels occurring during pregnancy” (8). Thus, histor-
ically, the term “GDM” encompassed the entire spectrum of
maternal hyperglycemia in pregnancy, from pregestational
diabetes to hyperglycemia first detected in pregnancy. In
1979, the NDDG defined GDM as “glucose intolerance that
has its onset or recognition during pregnancy” (13). This was
subsequently modified in 1985 at the Second International
Workshop-Conference on Gestational Diabetes as “carbohy-
drate intolerance resulting in hyperglycemia of variable se-
verity with onset or first recognition during pregnancy” and
remained the most widely used definition of GDM until re-
cently (71).
Contemporary nomenclature and diagnostic criteria now
more clearly differentiate between women with pregestational
diabetes and those with hyperglycemia first detected in preg-
nancy (30) (Fig. 1). Pregestational diabetes includes type 1
diabetes, type 2 diabetes, and other types of diabetes such
as cystic fibrosis-related diabetes, steroid/medication-induced
diabetes, and monogenic diabetes.
Hyperglycemia in pregnancy is now subclassified by the
IADPSG into 2 separate categories, namely “overt diabetes
mellitus during pregnancy” (overt diabetes) and GDM (30).
Similarly, the WHO has a binary definition of hyperglycemia
in pregnancy but has replaced the term “overt diabetes”
with “diabetes mellitus in pregnancy” (DIP) (11). The ra-
tionale for the IADPSG recommendation for early testing in
high-risk women is to diagnose DIP early in pregnancy. This
is because DIP, diagnosed based on nonpregnant diabetes
glucose thresholds, recognizes the increasing prevalence of
undiagnosed preexisting diabetes in women of childbearing
age as well as the greater risk associated with this degree
of hyperglycemia (72-74). For example, a recent study in
almost 5000 women in France found that DIP was associ-
ated with a 3.5-fold greater risk of hypertensive disorders
in pregnancy compared to women with normal glucose tol-
erance, while early‐diagnosed DIP was associated with an
increased risk of congenital malformation (7.7% vs 1.0%
for women with normal glucose tolerance), suggesting that
early hyperglycemia in pregnancy may sometimes be present
Endocrine Reviews, 2022, Vol. XX, No. XX 5

Table 1.  Current international testing approach to gestational diabetes mellitus

Organization/ Selective vs Method of Screen positive Diagnostic Diagnostic (plasma glucose) threshold for GDM
country universal screening threshold test (mmol/L)
testing (mmol/L)

IADPSG (30) Universal One-step: 75-g 2-h 75-g Fasting ≥ 5.1

WHO (11) OGTT 2-hour 1-h ≥ 10.0
ADIPS (33) OGTT 2-h ≥ 8.5
FIGO (32) One abnormal value needed for diagnosis
JDS (34)
EBCOG (36)

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Endocrine
Society (31)
China (35)
ADA (41) Universal One-step: 75-g 2-h ≥7.2 to 7.8a 75-g Fasting ≥ 5.1
OGTT 2-hour 1-h ≥ 10.0
Two-step: 50-g OGTT 2-h ≥ 8.5
GCT 100-g One abnormal value needed for diagnosis
3-hour Carpenter and Coustanb (17) or NDDG (13)
OGTT Fasting ≥ 5.3 Fasting ≥ 5.8
1-hour ≥ 10.0 1-hour ≥ 10.6
2-hour ≥ 8.6 2-hour ≥ 9.2
3-hour ≥ 7.8 3-hour ≥ 8.0
Two abnormal values needed for diagnosis
ACOGc (19) Universal Two-step: 50-g ≥7.2 to 7.8* 100-g Carpenter and Coustanb (17) or NDDG (13)
GCT OGTT Fasting ≥ 5.3 Fasting ≥ 5.8
1-hour ≥ 10.0 1-hour ≥ 10.6
2-hour ≥ 8.6 2-hour ≥ 9.2
3-hour ≥ 7.8 3-hour ≥ 8.0
Two abnormal values needed for diagnosisd
CDA (42) Universal Two-step: 50-g ≥7.8 50-g GCT ≥11.1 mmol/Le
GCT (preferred) 75-g Fasting ≥ 5.3
One-step: 75-g 2-hour 1-hour ≥ 10.6
2-h OGTT OGTT 2-hour ≥ 9.0
(alternative) One abnormal value needed for diagnosis
NICE (38) Selective Risk factorsf 75-g Fasting ≥ 7.0
2-hour 2-hour ≥ 7.8
OGTT One abnormal value needed for diagnosis
CNGOF (39) Selectiveg First ≥5.1
trimester Fasting ≥ 5.1
fasting 1-hour ≥ 10.0
glucose 2-hour ≥ 8.5
75-g One abnormal value needed for diagnosis
OGTTh
DDG/DGGG Universal Two-step: 50-g ≥7.5 50-g GCT ≥11.1 mmol/Le
(43) GCT 75-g Fasting ≥ 5.1
One-step: OGTT 1-hour ≥ 10.0
75-g OGTT 2-hour ≥ 8.5
(preferred) One abnormal value needed for diagnosis
DIPSI (44) Universal One-step: 75-g 75-g 2-hour ≥ 7.8i
OGTT OGTT

Abbreviations: ACOG, American College of Obstetricians and Gynecologists; ADA, American Diabetes Association; ADIPS, Australasian Diabetes in
Pregnancy Association; CDA, Canadian Diabetes Association; CNGOF, Organisme professionnel des médecins exerçant la gynécologie et l'obstétrique
en France; DDG, German Diabetes Association; DGGG, European Board of Gynecology and Obstetrics; DIPSI, Diabetes in Pregnancy Study Group of
India; FIGO, International Federation of Gynecology and Obstetrics; GCT, glucose challenge test; IADPSG, International Association of the Diabetes
and Pregnancy Study Groups; JDS, Japan Diabetes Society; NDDG, US National Diabetes Data Group; NICE, National Institute for Health and Care
Excellence; OGTT, oral glucose tolerance test; WHO, World Health Organization.
a
The ADA states that the choice of a specific positive GCT screening threshold is based upon the trade-off between sensitivity and specificity (41). ACOG
advises that in the absence of clear evidence that supports a specific GCT threshold value between 7.2 and 7.8 mmol/L, obstetricians and obstetric care
providers may select a single consistent GCT threshold for their practice based on factors such as community prevalence rates of GDM (19).
b
Plasma or serum glucose.
c
ACOG 2018 Clinical Practice Bulletin on GDM continues to recommend 2-step testing for GDM but states that individual practices and institutions may
choose to use the IADPSG’s 1-step testing approach and diagnostic criteria if appropriate for their population (19).
d
ACOG 2018 Clinical Practice Bulletin on GDM acknowledges that women who have even 1 abnormal value on the 100-g 3-hour OGTT have a
significantly increased risk of adverse perinatal outcomes compared to women without GDM but state that further research is needed to clarify the risk of
adverse outcomes and benefits of treatment in these women (19).
e
A glucose level ≥ 11.1 mmol/L following the initial screening GCT is classified as GDM, and there is no need for a subsequent 2-hour 75-g OGTT.
f
BMI > 30 kg/m2, previous macrosomia (≥4500 g), previous GDM, family history of diabetes, and family origin with a high prevalence of diabetes (South
Asian, Black Caribbean, Middle Eastern) (38).
g
Maternal age ≥ 35 years, body mass index ≥ 25 kg/m2, family history of diabetes, previous GDM, previous macrosomia (39).
h
If first trimester fasting glucose normal (ie, < 5.1 mmol/L).
i
Adapted from the WHO 1999 diagnostic criteria for GDM (45), using a nonfasting 75-g 2-hour OGTT (44).
6 Endocrine Reviews, 2022, Vol. XX, No. XX
at conception (75). However, DIP is not synonymous with
preexisting diabetes. In Australian, women with DIP who
performed an OGTT at 6 to 8 weeks postpartum, 21% had
diabetes, 38% had impaired fasting glucose or impaired glu-
cose tolerance, and 41% returned to normal glucose toler-
ance (76).
Regardless of the specific nomenclature used, DIP is distinct
from GDM, which is defined by lower glucose thresholds
on the OGTT and was historically considered to be a con-
dition of mid to late pregnancy. The ADA has not accepted
this nomenclature and defines GDM based on timing of diag-
nosis: women diagnosed with diabetes in the first trimester
are classified as having (preexisting) type 2 diabetes, while
GDM is defined as diabetes diagnosed in later pregnancy
and not meeting the diagnostic criteria for type 2 diabetes
(18). A  summary of the current international nomenclature
and diagnostic criteria for hyperglycemia in pregnancy is pre-
sented in Table 2.
Early GDM
Most international guidelines now recommend early ante-
natal testing for women at high risk to identify women with
DIP (11,18,30,38,39,42-44). This has resulted in increased
detection of milder degrees of hyperglycemia below the
threshold of DIP, referred to as GDM diagnosed prior to 24
weeks’ gestation or early GDM. Studies in women with GDM
have reported that between 27% and 66% of GDM can be
detected in early pregnancy depending on the population as
well as the screening and diagnostic criteria used (77-81).
Recent studies evaluating the relationship between maternal
glycemia and fetal growth trajectories confirm the early impact
of maternal glycemia on excess fetal growth and adiposity prior
to the diagnosis of standard GDM from 24 weeks’ gestation.
A US multiethnic prospective cohort study of 2458 women en-
rolled between 8 and 13 weeks’ gestation included 107 (4.4%)
women with GDM (82). GDM was associated with an increase
in estimated fetal weight from 20 weeks’ gestation, which be-
came significant at 28 weeks’ gestation. Similarly, Sovio et al
showed that excessive fetal growth occurred between 20 to
28 weeks’ gestation, prior to the diagnosis of GDM, especially
among women with higher body mass index [BMI (kg/m2)]
(83). An Indian study also showed that excess subcutaneous
abdominal adiposity was first detected at 20 weeks’ gestation,
at least 4 weeks prior to the diagnosis of GDM (84). Early ex-
cess adiposity persisted despite adjustments for maternal age,
BMI, GWG, fetal sex, and gestational age and remained higher
at 32 weeks’ gestation (84).
Currently, there is no consensus for the preferred testing
approach or diagnostic glycemic thresholds for early GDM.
The IADPSG recommends diagnosing early GDM based on a
fasting glucose of 5.1 mmol/L to 6.9 mmol/L (92-124 mg/dL)
(30), consistent with the diagnostic fasting glucose threshold
for standard GDM. The utility of a single fasting glucose
measurement for early GDM diagnosis warrants consider-
ation. First, preanalytical glucose handling variation, particu-
larly in the setting of a single glucose measurement, is a major
issue for GDM diagnostic accuracy (discussed in the fol-
lowing text). Second, an Israeli cohort study of 6129 women
who underwent a fasting glucose test at a median of 9.5
weeks’ gestation demonstrated a positive association between
first trimester fasting glucose up to 5.8 mmol/L (104.5 mg/dL)
and increased risk for subsequent diagnosis of GDM, LGA,
macrosomia, and cesarean section (85). Similar to the HAPO
study, a clear glucose threshold was lacking, with pregnancy
complications evident at fasting glucose levels <5.1 mmol/L
(92 mg/dL). Third, maternal fasting glucose decreases in the
first trimester, most pronounced between 6 to 10 weeks’ gesta-
tion [median decrease in glucose 0.11 mmol/L (1.98 mg/dL)]
(86), while studies have consistently shown that early fasting
glucose is poorly predictive of GDM at 24 to 28 weeks’ ges-
tation (86-88), leading to potential overdiagnosis of GDM.
In China, an early fasting glucose between 6.1  mmol/L to
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6.9  mmol/L (110-124  mg/dL) best corresponded to later
GDM diagnosis (88), but this requires further validation.
The WHO recommends the same diagnostic OGTT glu-
cose thresholds for GDM in early pregnancy as those derived
from HAPO by the IADPSG (11). However, the prognostic
value of these glucose levels in early pregnancy is yet to be es-
tablished. Others have proposed an hemoglobin A1c (HbA1c)
risk threshold (89), based primarily on evidence that an early
HbA1c ≥ 5.9% (41 mmol/mol) detected all cases of DIP and pre-
dicted adverse pregnancy outcomes in a New Zealand cohort
(90). However, studies in other cohorts have found that while
an elevated HbA1c in early pregnancy is highly specific, it lacks
sensitivity for identifying hyperglycemia and certain perinatal
complications (91,92), with no clear benefit of treating women
with HbA1c 5.7% to 6.4% (39-46  mmol/mol) in early preg-
nancy (93,94). A summary of the various international criteria
for testing of GDM in early pregnancy is presented in Table 3.
Despite the lack of diagnostic clarity for early GDM,
increasing evidence suggests that women with early GDM
represent a high-risk cohort (81). Early studies also reported
worse pregnancy outcomes and increased insulin resistance in
early GDM (78,95-97) but were confounded by the inclusion
of women with pregestational diabetes. The first large retro-
spective cohort study excluding women with DIP showed that
women diagnosed and treated for early GDM, especially those
diagnosed in the first trimester, were more insulin resistant
and at significantly greater risk for obstetric and neonatal
complications compared to women diagnosed and treated for
GDM from 24 weeks’ gestation (81). Other studies have since
confirmed these findings (98,99). Concerningly, an increased
risk of perinatal mortality and congenital abnormalities has
also been reported in the offspring of women with early
GDM (75,78,95,96), with some data demonstrating that 5%
of women with early GDM have abnormal fetal echocar-
diograms (97). A  recent meta-analysis of 13 cohort studies
showed greater perinatal mortality among women with early
GDM (RR 3.58; 95% CI 1.91-6.71) compared to women
with a later diagnosis of GDM despite treatment (100).
A recent study assessing the pathophysiological characteris-
tics of women diagnosed with GDM at a median of 16 weeks’
gestation compared to those diagnosed from 24 weeks’ ges-
tation using IADPSG diagnostic criteria reported that women
with early GDM had lower insulin sensitivity (defined by
insulin-mediated glucose clearance during an OGTT), even
after accounting for maternal BMI (101). Consistent with
the pathophysiology of GDM, women with both early and
standard GDM demonstrated impairment in pancreatic β-cell
function (102). These data underscore GDM phenotypic dif-
ferences, specifically based on timing of diagnosis and degree
of hyperglycemia (103).
A key issue is the current lack of high-quality evidence that
diagnosing and treating early GDM improves pregnancy out-
comes. A  recent major RCT in the United States evaluating
Endocrine Reviews, 2022, Vol. XX, No. XX
early testing for GDM in 962 women with obesity included a
subgroup analysis of women diagnosed and treated for GDM
[early n = 69 (15.0%) vs standard n = 56 (12.1%)] based on
the 2-step testing approach (104). The average gestational
age at GDM diagnosis was similar at 24.3 ± 5.2 weeks for
the early screen group compared to 27.1 ± 1.7 weeks in the
routine screen group. There was no difference in pregnancy
outcomes, although the primary composite perinatal out-
come (macrosomia, primary cesarean delivery, gestational
hypertension, preeclampsia, hyperbilirubinemia, shoulder
dystocia, and neonatal hypoglycemia) was nonsignificantly
higher in the early-screen group (56.9% vs 50.8%; P = 0.06).
Requirement for insulin therapy was almost 4-fold higher,
while gestational age at delivery was lower (36.7 vs 38.7
weeks’ gestation; P = 0.001) in women with early GDM. In
a post hoc analysis of the Lifestyle in Pregnancy study (105),
no difference in pregnancy outcomes was shown between
women randomized to either lifestyle intervention (n = 36) or
standard treatment (n = 54) in early pregnancy. Whether dif-
ferent glycemic targets are required reflecting physiological
differences in early maternal glucose or whether additional
risk factors contributing to a more insulin resistant pheno-
type such as maternal adiposity might also have a role re-
main unanswered (81). The ongoing Treatment of Booking
Gestational Diabetes Mellitus study, evaluating the impact of
immediate vs delayed care for gestational diabetes diagnosed
at booking, will seek to determine whether or not there is
benefit from treating early GDM (106).
The Impact of Preanalytical Glucose
Processing Standards on the Diagnosis
of GDM
Although the contemporary testing approach to GDM re-
mains contentious, it is important to recognize that the diag-
nosis of GDM is based on the laboratory measurement of
maternal glucose rather than a clinical diagnosis. Arguably
then, a major issue in the contemporary diagnosis of GDM
is optimizing preanalytical processing and measurement
of maternal plasma glucose to ensure diagnostic accuracy
(107,108). This includes optimization of sample handling and
minimization of any analytic error. Unfortunately, stringent
preanalytical processing standards are not currently routinely
applied. The American Association for Clinical Chemistry
(AACC) and ADA recommendations on laboratory testing
in diabetes advise collection of plasma glucose in sodium
Figure 1.  Flowchart summarizing the contemporary nomenclature for hyperglycemia in pregnancy.
7
fluoride tubes, with immediate placement in an ice slurry and
centrifugation within 30 minutes (109). Citrate tubes are re-
commended as an alternative where early centrifugation is
not possible. These standards are important because a major
source of preanalytical glucose measurement error in sodium
fluoride tubes is glycolysis by erythrocytes and leukocytes,
which at room temperature lowers glucose levels prior to cen-
trifugation at a rate of 5% to 7% per hour [~0.6  mmol/L
(10  mg/dL)] (109,110). By 1 hour, this degree of glucose
lowering is higher than the total analytical error threshold for
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glucose based on biological variation (107).
Recent studies have shown that OGTT preanalytical glu-
cose processing variability greatly impacts the prevalence of
GDM (67,111). Implementation of the AACC/ADA recom-
mendations in a UK cohort resulted in higher mean glucose
concentrations and 2.7-fold increased detection of GDM
based on IADPSG criteria compared with the standard prac-
tice of storing sodium fluoride tubes at room temperature and
delaying centrifugation until collection of all 3 OGTT sam-
ples (112). This increase in GDM diagnosis was entirely at-
tributable to control of glycolysis (107). Similarly, in a large
Australian multiethnic cohort (n = 12317), the rate of GDM
diagnosis based on IADPSG criteria increased from 11.6%
to 20.6% with early (within 10 minutes) vs delayed centri-
fugation (111). Mean glucose concentrations for the fasting,
1-hour, and 2-hour OGTT samples were 0.24 mmol/L (5.4%),
0.34 mmol/L (4.9%), and 0.16 mmol/L (2.3%) higher with
early centrifugation, with the increase in GDM diagnosis pri-
marily due to the resulting increase in fasting glucose levels
(111). Importantly, the HAPO study, upon which the IADPSG
diagnostic criteria for GDM was based, followed these AACC/
ADA preanalytical glucose processing standards (111).
Incidence and Prevalence of GDM
GDM is 1 of the most common medical complications of preg-
nancy (73). In 2019, the International Diabetes Federation
(IDF) estimated that 1 in 6 live births worldwide were com-
plicated by GDM (113). More than 90% of cases of hypergly-
cemia in pregnancy occur in low- and middle-income countries
(114), where the prevalence and severity of maternal and neo-
natal complications associated with GDM (47,113) contrast
with the near-normal pregnancy outcomes of modern manage-
ment of GDM in developed countries (115).
The prevalence of GDM varies widely, depending on the
population, the specific screening and the diagnostic criteria
8 Endocrine Reviews, 2022, Vol. XX, No. XX

utilized. A  2012 systematic review of the diagnostic criteria
used to define GDM reported a worldwide prevalence of GDM
of 2% to 24.5% for the WHO criteria, 3.6% to 38% for the
Carpenter and Coustan criteria, 1.4 to 50% for the NDDG cri-
teria, and 2% to 19% for the IADPSG criteria (116).
Regardless of the specific diagnostic criteria or population,
the prevalence of GDM continues to rise internationally, cor-
responding to epidemiological factors including the back-
ground rates of type 2 diabetes and increased incidence of
obesity in women of childbearing age and rising maternal age
recurrence rates of up to 84% (128). The risk of recurrence
varies greatly depending on ethnicity (128). Ethnicities at in-
creased risk for development of type 2 diabetes, such as South
and East Asians, Hispanic, Black and Native Americans,
Aboriginal and Torres Strait Islanders, and Middle Easterners
are also associated with an increased risk of GDM (129,130).
A US study of over 123 000 women reported the prevalence of
GDM using the 2000 ADA diagnostic criteria to be the highest
among Filipinas (10.9%) and Asians (10.2%), followed by
Hispanics (6.8%), non-Hispanic Whites (4.5%) and Black

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(117-124). Implementation of the revised IADPSG diagnostic
criteria have further increased the proportion of women being
diagnosed with GDM (69,125,126). The incidence of GDM
in the original HAPO study cohort applying the IADPSG
diagnostic criteria ranged from 9.3% to 25.5% depending
on study site (69). Recent international prevalence data also
demonstrate marked variability in the rate of GDM, ranging
from 6.6% in Japan and Nepal to 45.3% of pregnancies in
the United Arab Emirates (127).
Risk Factors for GDM
Several modifiable and nonmodifiable risk factors for GDM
have been identified (Table 4). A history of GDM in a previous
pregnancy is the strongest risk factor for GDM, with reported
Americans (4.4%) (131). Women who have had GDM are at
increased risk for subsequent type 2 diabetes, while family his-
tory of type 2 diabetes in a first-degree relative or sibling with
GDM is a major risk factor for GDM (129,132-134).
Increasing maternal age is also a risk factor for GDM
(129,133-135). The prospective First and Second Trimester
Evaluation of Risk trial (n = 36 056)  demonstrated a con-
tinuous positive relationship between increasing maternal age
and risk for adverse pregnancy outcomes, including GDM
(135). Maternal age 35 to 39 years and ≥40 years was associ-
ated with an adjusted odds ratio (OR) for GDM of 1.8 (95%
CI 1.5-2.1) and 2.4 (95% CI 1.9-3.1), respectively (135).
Other studies in high-risk cohorts have reported a lesser risk
between increasing maternal age and GDM after adjustment
for other risk factors (136).

Table 2.  Classification and diagnostic criteria for hyperglycemia in pregnancy

Organization Results

IADPSG/EBCOG (30,36)
 GDM
  Overt diabetes during pregnancy
WHO/FIGO/ADIPS (11,32,33)
 GDM
  Diabetes mellitus in pregnancy
ADA (41)
 GDM
  Type 2 diabetes mellitus
75-g 2-hour OGTT
  Fasting glucose 5.1-6.9 mmol/L
  1-hour glucose ≥ 10.0 mmol/L
  2-hour glucose 8.5-11.0 mmol/L
Fasting glucose ≥ 7.0 mmol/L
Random glucose ≥ 11.1 mmol/La
HbA1c ≥ 6.5%
75-g 2-hour OGTT
  Fasting glucose 5.1-6.9 mmol/L
  1-hour glucose ≥ 10.0 mmol/L
  2-hour glucose 8.5-11.0 mmol/L
Fasting glucose ≥ 7.0 mmol/L
2-hour glucose ≥ 11.1 mmol/L post 75-g OGTT
Random glucose ≥ 11.1 mmol/L in the presence of diabetes symptoms
1-step strategy: 2-step strategy: NDDG (13)
75-g 2-h OGTT 50-g 1-hour GCT ≥ 7.8 mmol/L   Fasting glucose ≥ 5.8 mmol/L
  Fasting glucose ≥ 5.1 mmol/L 100 g 3-hour OGTT   1-h glucose ≥ 10.6 mmol/L
  1-hour glucose ≥ 10.0 mmol/L   Carpenter and Coustan (17) or   2-h glucose ≥ 9.2 mmol/L
  2-hour glucose ≥ 8.5 mmol/L   Fasting glucose ≥ 5.3 mmol/L   3-h glucose ≥ 8.0 mmol/L
  1-hour glucose ≥ 10.0 mmol/L
  2-hour glucose ≥ 8.6 mmol/L
  3-hour glucose ≥ 7.8 mmol/L
Fasting glucose ≥ 7.0 mmol/L
2-hour glucose ≥ 11.1 mmol/L post 75 g 2-hour OGTT
Random glucose ≥ 11.1 mmol/L in the presence of diabetes symptoms
HbA1c ≥ 6.5%

75-g 2-hour OGTT: only 1 plasma glucose level needs to be elevated for the diagnosis of GDM. 100 g 3-hour OGTT: at least 2 plasma glucose levels need
to be elevated for the diagnosis of GDM.
Abbreviations: ADA, American Diabetes Association; ADIPS, Australasian Diabetes in Pregnancy Association; EBCOG, European Board & College of
Obstetrics and Gynaecology; FIGO, International Federation of Gynecology and Obstetrics; GCT, glucose challenge test; HbA1c, hemoglobulin A1c;
IADPSG/; International Association of the Diabetes and Pregnancy Study Groups; GDM, gestational diabetes mellitus; OGTT, oral glucose tolerance test;
WHO, World Health Organization.
a
The IADPSG recommends confirmation by fasting plasma glucose or HbA1c for the diagnosis of overt diabetes during pregnancy (30).
Endocrine Reviews, 2022, Vol. XX, No. XX
Maternal prepregnancy overweight (BMI 25-29.99 kg/m2)
or obesity (BMI ≥ 30  kg/m2) are common risk factors for
GDM (129,130,133,134,136,137). The risk of GDM is in-
creased almost 3-fold (95% CI 2.1-3.4) in women with
class  I  obesity (BMI 30-34.99  kg/m2) and 4-fold (95% CI
3.1-5.2) in women with class  II obesity (BMI 35-39.99  kg/
m2), compared to women with a BMI < 30 kg/m2 (138). High
GWG, particularly in the first trimester, is also associated with
an increased risk for GDM (131,139,140). Further, women
with obesity and high GWG are 3- to 4-fold more likely to de-
velop abnormal glucose tolerance compared to women who
remained within the 1990 Institute of Medicine (IOM) re-
commendations for GWG (131,141). Interpregnancy weight
gain is also a risk factor for GDM and perinatal complica-
tions in a subsequent pregnancy (142) and may be a potential
confounder when considering the risk of GDM recurrence.
Studies have demonstrated an association between polycystic
ovary syndrome and GDM, although this is significantly at-
tenuated after adjustment for maternal BMI (143,144). Other
risk factors for GDM include multiparity (133,134), twin
pregnancy (145,146), previous macrosomia (123), a history of
perinatal complications (134), maternal small-for-gestational-
age (SGA) or LGA (134), physical inactivity (129,147,148),
low-fiber high-glycemic load diets (149), greater dietary fat
and lower carbohydrate intake (137), and medications such as
glucocorticoids and anti-psychotic agents (150,151). Maternal
pre- and early pregnancy hypertension is also associated with
an increased risk of developing GDM (152,153).
Overall, noting the variation in performance and utility of
clinical risk factors based on local population factors, pre-
vious GDM and family history of diabetes appear to be the
strongest clinical risk factors for GDM (154-157). Ethnicity,
higher maternal age, and BMI are also strong predictors for
GDM (154-158).
Pathophysiology of GDM
Normal pregnancy is associated with marked changes in
glycemic physiology (159,160). There is a progressive in-
crease in insulin resistance, predominantly due to increased
circulating placental hormones including growth hormone,
corticotrophin-releasing hormone, human placental lactogen,
prolactin, estrogen, and progesterone (161-166). Increased
maternal adiposity particularly in early pregnancy also pro-
motes insulin resistance, contributing to facilitated lipolysis
by late pregnancy (167,168). The resultant increase in ma-
ternal free fatty acid (FFA) levels exacerbates maternal insulin
resistance by inhibiting maternal glucose uptake and stimu-
lating hepatic gluconeogenesis (168,169). By late pregnancy,
studies have reported decreases in maternal glucose sensitivity
between 40% and 80% in women with normal or increased
BMI (170-172). Increased maternal insulin resistance results
in higher maternal postprandial glucose levels and FFAs for
maternal growth (164,167,173) and increased facilitated dif-
fusion across the placenta, leading to greater availability of
glucose for fetal growth (161,174). This progressive rise in
maternal insulin resistance underpins the delayed testing ap-
proach to GDM, aiming to maximize detection of GDM when
insulin resistance is at its greatest in mid- to late gestation.
In addition to increased insulin resistance and elevated post-
prandial glucose, adaptations in normal pregnancy include
enhanced insulin secretion (160,165). Maternal glucose levels
9
are maintained at lower levels than in healthy nonpregnant
women (175,176), and euglycemia is maintained by a corres-
ponding 200% to 250% increase in insulin secretion, most
notable in early pregnancy (161,167,177). Human placental
lactogen, in addition to prolactin and growth hormone, pri-
marily regulate increased maternal β-cell insulin secretion and
proliferation during pregnancy (178-180). Rodent studies
have demonstrated a 3- to 4-fold increase in β-cell mass
during pregnancy, mediated via hypertrophy, hyperplasia,
neogenesis, and/or reduced apoptosis (181,182).
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GDM is characterized by a relative insulin secretory
deficit (177), in which maternal β-cell insulin secretion is
unable to compensate for the progressive rise in insulin re-
sistance during pregnancy (183). This leads to decreased
glucose uptake, increased hepatic gluconeogenesis, and ma-
ternal hyperglycemia (167). It is hypothesized that this re-
sults from the failure of β-cell mass expansion (182,184).
Hyperlipidemia, characterized predominantly by higher
serum triglycerides, may also cause lipotoxic β-cell injury,
further impairing insulin secretion (185,186). The pathogen-
esis of GDM therefore parallels that of type 2 diabetes, char-
acterized by both increased insulin resistance and relative
insulin deficiency arising from a reduction in β-cell function
and mass (187,188).
Serial studies of the insulin secretory response in women
who develop GDM suggest that the abnormal insulin secre-
tory response is present from prepregnancy and increases in
early pregnancy, prior to and independent of changes in in-
sulin sensitivity (170,189-191). These data suggest that many
women with GDM may have chronic or preexisting β-cell
dysfunction, potentially mediated by circulating hormones
including leptin (191).
Genetics of GDM
The genetics of GDM and glucose metabolism in pregnancy
remain poorly defined. Data on epigenetic mechanisms in
GDM are especially lacking and primarily limited to the po-
tential role of DNA methylation in mediating the intrauterine
effects of GDM on offspring outcomes (192,193).
Most genetic studies have focused on variants associated
with type 2 diabetes and have demonstrated a similar associ-
ation with GDM (194,195). A meta-analysis of 28 case-control
studies (n = 23425) (196) identified 6 genetic polymorphisms
at loci involved in insulin secretion [insulin-like growth factor
2 messenger RNA-binding protein 2 (IGF2BP2), melatonin
receptor 1B (MTNR1B) and transcription factor 7-like 2
(TCF7L2)] (197-199), insulin resistance [insulin receptor sub-
strate 1 (IRS1) and peroxisome proliferator-activated receptor
gamma (PPARG)] (200,201), and inflammation [tumor ne-
crosis factor alpha (TNF-α)] (202) in type 2 diabetes. Overall,
only MTNR1B, TCF7L2, and IRS1 were also significantly
associated with GDM, supporting the role of both impaired
insulin secretion and insulin resistance in the pathogenesis
of GDM as well as type 2 diabetes (196). Subgroup analysis
showed the risk alleles of TCF7L2 and PPARG were signifi-
cant only in Asian populations, while the association between
IRS1 and TCF7L2 and GDM risk varied depending on diag-
nostic criteria and genotype methodology (196), highlighting
the need for further large confirmatory studies.
Two genome-wide association studies (GWAS) have
evaluated the genetic associations for GDM and glucose
10 Endocrine Reviews, 2022, Vol. XX, No. XX

metabolism (194,203). The first, a 2-stage GWAS in Korean
women, compared 468 women with GDM and 1242 normo-
glycemic women using 2.19 million genotyped markers be-
fore further genotyping 11 loci in 1714 women, identifying
2 loci significantly associated with GDM (203). A  variant
in cyclin-dependent kinase 5 regulatory subunit-associated
protein 1-like 1 (CDKAL1) had the strongest association
with GDM, followed by a variant near MTNR1B expressed
in pancreatic β-cells (204). The IGF2BP2 variant did not
reach genome-wide significance with GDM in this study.
associated with glucose or C-peptide levels in pregnancy,
although strength of association varied across cohorts
(194). Specifically, loci in glucokinase regulator (GCKR),
glucose-6-phosphatase 2 (G6PC2), proprotein convertase
subtilisin/kexin type 1 (PCSK1), protein phosphatase 1,
regulatory subunit 3B (PPP1R3B), and MTNR1B were
associated with fasting glucose. In addition, GCKR and
PPP1R3B were associated with fasting C-peptide levels,
while MTNR1B was associated with 1-hour postload glu-
cose. These loci have also previously been associated with

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CDKAL1 was significantly associated with decreased fasting
insulin concentration and homeostasis model assessment of
β-cell function in women with GDM, consistent with im-
paired β-cell compensation. MTNR1B was associated with
decreased fasting insulin concentrations in women with
GDM and increased fasting glucose concentrations in both
women with and without GDM (203). Variants in CDKAL1
and MTNR1B have previously been associated with type 2
diabetes risk (205,206).
A subsequent GWAS performed in a subset of the
HAPO cohort (n = 4528) comprising European, Thai,
Afro-Caribbean, and Hispanic women evaluated ma-
ternal metabolic traits in pregnancy (194). This study re-
ported 5 variants associated with quantitative glycemic
traits in the general population (207,208) that were also
lipid metabolism (GCKR and PPP1R3B), glycogen me-
tabolism (PPP1R3B), and obesity-related traits (PCSK1)
(209-214).
Two additional novel loci identified near hexokinase do-
main containing 1 (HKDC1) associated with 2-hour postload
glucose, and β-site amyloid polypeptide cleaving enzyme 2
(BACE2) associated with fasting C-peptide, demonstrated
limited association with glycemic traits outside of compared
to in pregnancy (215). In general, however, studies evaluating
associations between genetic risk scores, glycemic traits in
pregnancy, and GDM have also confirmed that genetic de-
terminants of fasting glucose and insulin, insulin secretion,
and insulin sensitivity reported outside of pregnancy influence
GDM risk (216). A  summary of the genes associated with
GDM is provided in Table 5.

Table 3.  International criteria for testing of gestational diabetes mellitus in early pregnancy

Organization Early pregnancy Method of testing Diagnostic test Criteria for diagnosing early GDM (mmol/L)
testing

IADPSG (30) Yes Selective—women at risk Fasting glucoseb ≥5.1

of overt diabetes during
pregnancya
WHO (11) Not specifiedc 75-g 2-hour OGTT Fasting 5.1-6.9 or
1-hour ≥ 10.0 or
2-hour 8.5-11.0
ADIPS (33) Yes Selective—women at risk 75-g 2-hour OGTT Fasting 5.1-6.9 or
of hyperglycemia in 1-hour ≥ 10.0 or
pregnancyd 2-hour 8.5-11.0
ADA (41) Yes Selective—women One-step: 75-g 2-hour Fasting 5.1-6.9 or
with risk factors for OGTT 1-hour ≥ 10.0 or
undiagnosed type 2 Two-step: 50-g GCT 2-hour 8.5-11.0
diabetese 100-g 3-hour OGTT ≥7.2 to 7.8
Carpenter and Coustan (17) NDDG (13)
Fasting ≥ 5.3  ≥ 5.8
1-hour ≥ 10.0  ≥ 10.6
2-hour ≥ 8.6  ≥ 9.2
3-hour ≥ 7.8  ≥ 8.0
ACOG (19) Yes Selective—women 75-g 2-h OGTT or Fasting ≥ 7.0 or
with risk factors for 50-g GCT 2-hour ≥ 11.1
undiagnosed type 2 Confirmatory ≥7.2 to 7.8
diabetes or GDMf 100-g 3-hour OGTT Carpenter and Coustan (17) NDDG (13)
Fasting ≥ 5.3  ≥ 5.8
1-hour ≥ 10.0  ≥ 10.6
2-hour ≥ 8.6  ≥ 9.2
3-hour ≥ 7.8  ≥ 8.0
EBCOG (36) Yes Selective—women at risk 75-g 2-hour OGTT Fasting 5.1-6.9 or
of overt diabetes during 1-hour ≥ 10.0 or
pregnancyg 2-hour 8.5-11.0
DDG/DGGG Yes Selective—women Random glucose or 7.8-11.05 mmol/L followed by a second blood
(43) with risk factors for Fasting glucose or glucose measurement or an OGTT
“manifest diabetes”h 75-g 2-hour OGTT 5.1-6.9
Fasting 5.1-6.9 or
1-hour ≥ 10.0 or
2-hour 8.5-11.0
Endocrine Reviews, 2022, Vol. XX, No. XX 11

Table 3.  Continued

Organization Early pregnancy Method of testing Diagnostic test Criteria for diagnosing early GDM (mmol/L)
testing

CNGOF (39) Yes Selectivei Fasting glucose ≥5.1

NICE (38) Yes Selectivej 75-g 2-hour OGTT Fasting ≥ 5.6
2-hour ≥ 7.8
DIPSI (44) Yes Universal 75-g 2-hour OGTTk 2-hour ≥ 7.8

75-g 2-h OGTT: Only 1 abnormal glucose level needs to be elevated for the diagnosis of GDM. 100-g 3-h OGTT: 2 abnormal glucose levels need to be
elevated for the diagnosis of GDM.

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Abbreviations: ADA, American Diabetes Association; ACOG, American College of Obstetricians and Gynecologists; ADIPS, Australasian Diabetes in Pregnancy
Association; CNGOF, Organisme professionnel des médecins exerçant la gynécologie et l'obstétrique en France; DDG, German Diabetes Association; DGGG,
European Board of Gynecology and Obstetrics; DIPSI, Diabetes in Pregnancy Study Group of India; EBCOG, European Board & College of Obstetrics and
Gynaecology; GCT, glucose challenge test; GDM, gestational diabetes mellitus; IADPSG, International Association of the Diabetes and Pregnancy Study Groups;
NICE, National Institute for Health and Care Excellence; OGTT, oral glucose tolerance test; WHO, World Health Organization.
a
High-risk criteria not explicitly defined.
b
IADPSG does not recommend routinely performing the 75-g 2-h OGTT prior to 24 weeks’ gestation but advises that a fasting glucose ≥ 5.1 mmol/L in
early pregnancy be classified as GDM (30).
c
GDM diagnosed at any time in pregnancy based on an abnormal 75-g 2-h OGTT (11).
d
High-risk criteria defined as previous hyperglycemia in pregnancy; previously elevated blood glucose level; maternal age ≥ 40 years; ethnicity: Asian, Indian
subcontinent, Aboriginal, Torres Strait Islander, Pacific Islander, Maori, Middle Eastern, non-White African; family history of diabetes (first-degree relative
with diabetes or sister with hyperglycemia in pregnancy); prepregnancy body mass index > 30 kg/m2; previous macrosomia (birth weight > 4500 g or > 90th
percentile); polycystic ovary syndrome; and medications: corticosteroids, antipsychotics (33).
e
High-risk criteria defined as body mass index ≥ 25 kg/m2 (≥ 23 kg/m2 in Asian Americans) plus 1 of the following: physical inactivity; previous GDM;
previous macrosomia (≥ 4000 g); previous stillbirth; hypertension; high density lipoprotein cholesterol ≤ 0.90 mmol/L; fasting triglycerides ≥ 2.82 mmol/L;
polycystic ovary syndrome; acanthosis nigricans; nonalcoholic steatohepatitis; morbid obesity and other conditions associated with insulin resistance;
hemoglobulin A1c ≥ 5.7%; impaired glucose tolerance or impaired fasting glucose; cardiovascular disease; family history of diabetes (first-degree relative);
and ethnicity: African American, American Indian, Asian American, Hispanic, Latina, or Pacific Islander ethnicity. Note that the ADA recommends testing
for GDM at 24 to 28 weeks’ gestation and have no specific definition for early GDM (41).
f
ACOG states that the best test for early GDM screening is not clear but suggest the testing approach and diagnostic criteria used to diagnose type 2
diabetes in the nonpregnant population and thus have no specific definition for early GDM (19).
g
High-risk criteria defined as previous GDM; overweight/obesity; family history of diabetes (first-degree relative with diabetes); previous macrosomia (>4000g or
>90th percentile); polycystic ovary syndrome; ethnicity: Mediterranean, South Asian, black African, North African, Caribbean, Middle Eastern, or Hispanic (36).
h
High-risk criteria defined as age ≥ 45 years; prepregnancy body mass index ≥ 30 kg/m2; physical inactivity; family history of diabetes; high-risk ethnicity
(eg. Asians, Latin Americans); previous macrosomia ≥ 4500 g; previous GDM; hypertension; prepregnancy dyslipidemia (high-density lipoprotein
cholesterol ≤ 0.90 mmol/L, fasting triglycerides ≥ 2.82 mmol/L); polycystic ovary syndrome; prediabetes in an earlier test; other clinical conditions
associated with insulin resistance (eg, acanthosis nigricans); history of coronary artery disease/peripheral artery disease/cerebral vascular disease;
medications associated with hyperglycemia (eg. glucocorticoids). Note that the DDG/DGGG recommends that a 75-g 2-h OGTT be the initial early test in
high-risk women (defined as women with ≥2 risk factors for GDM) (43).
i
High-risk criteria are defined as previous GDM, previous impaired glucose tolerance, and/or obesity (39).
j
High-risk criteria defined as body mass index> 30 kg/m2; previous macrosomia (≥4500 g); previous GDM; family history of diabetes (first-degree relative
with diabetes); minority ethnic family origin with a high prevalence of diabetes. The updated 2015 NICE guidelines state that women with previous GDM
should undergo early self-monitoring of blood glucose or a 75-g 2-hour OGTT as soon as possible after booking (first or second trimester), and a repeat
75-g 2-hour OGTT at 24 to 28 weeks’ gestation if the initial OGTT was negative (38).
k
2-hour postload glucose measured on nonfasting 75-g OGTT (44).

Table 4.  Key risk factors for gestational diabetes mellitus
Previous GDM
An ethnicity with a high prevalence of diabetes
Maternal age > 35 years
Family history of diabetes (first-degree relative with diabetes)
Obesity (BMI > 30 kg/m2)
Previous macrosomia (birthweight > 4500 g)
Polycystic ovary syndrome
Iatrogenic: glucocorticoids and antipsychotic medication
Abbreviations: BMI, body mass index; GDM, gestational diabetes mellitus.
Maturity-onset Diabetes of the Young
Maturity-onset diabetes of the young (MODY) is the most
common form of monogenic diabetes; inherited forms of dia-
betes characterized by defects in single genes regulating β-cell
development and function (217,218). MODY consists of sev-
eral autosomal dominant forms of diabetes accounting for up
to 2% of all diabetes diagnoses (219). A diagnosis of MODY
requires confirmatory molecular genetic testing, and thus
MODY is frequently misdiagnosed as preexisting diabetes or
GDM, accounting for up to 5% of GDM “cases” (220-223).
A  UK study reported that HNF-1α (MODY3) (52%) and
glucokinase (GCK)-MODY subtype (MODY2) (32%) were
most frequent in probands confirmed with MODY, followed
by HNF-4α (MODY1) and HNF-1β (MODY5) (224).
Women with GCK-MODY often first present following
antenatal screening for GDM, with an estimated prevalence
of 1% of all GDM “cases” actually GCK-MODY (220,222).
GCK-MODY is caused by mutations in the glucokinase gene,
leading to a greater set point for glucose stimulated insulin
release (219). Clinically, GCK-MODY is defined by mild,
stable fasting hyperglycemia [fasting glucose 98-150  mg/
dL (5.4-8.3  mmol/L)] and low rates of microvascular and
macrovascular complications (220). It should be suspected
following a positive OGTT in pregnancy if the fasting glu-
cose is ≥5.5 mmol/L, the glucose increment from the fasting
to 2-hour (75-g) OGTT is small (<4.6 mmol/L), and there is
a positive family history of mild hyperglycemia or diabetes.
In addition, a combination of fasting glucose ≥ 100  mg/dL
(5.6 mmol/L) and BMI < 25 kg/m2 has been shown to have a
sensitivity of 68% and a specificity of 99% for differentiating
GCK-MODY from GDM (220). Importantly, management
differs from that of GDM because the need for intensive ma-
ternal glycemic control largely depends on whether the GCK-
MODY mutation is also present in the fetus (220,225,226).
Maternal insulin therapy is therefore only recommended in
the presence of increased fetal abdominal growth (>75th
12
centile) measured on serial ultrasounds from 26 weeks’ ges-
tation, as this indicates that the fetus does not have the GCK
mutation (220).
Consequences of GDM
GDM is associated with excess neonatal and maternal short-
and long-term morbidity, summarized in Table 6.
Neonatal Complications
The Pedersen hypothesis describes the pathophysiology con-
tributing to perinatal complications in GDM (229). Maternal
hyperglycemia results in fetal hyperglycemia via facilitated
diffusion of glucose by the glucose transporter 1 (GLUT1)
(230). Fetal hyperglycemia results in fetal hyperinsulinemia,
promoting fetal anabolism, excessive fetal adiposity, and
accelerated growth, leading to LGA and macrosomia (231-
239). Maternal hyperlipidemia also contributes to excess
fetal growth (233,240). Macrosomia and LGA increase the
risk of cesarean section, birth trauma, and perinatal compli-
cations including shoulder dystocia, brachial plexus injury
and fracture, and perinatal asphyxia (27,132,237,238,241-
243). Increased risk of perinatal asphyxia is associated with
fetal death in utero, polycythemia, and hyperbilirubinemia
(27,244-246). Fetal hyperinsulinemia can also increase the
risk of metabolic abnormalities including neonatal hypogly-
cemia, hyperbilirubinemia, and respiratory distress syndrome
postpartum (27,244). The risk appears to be greater among
offspring of women with more severe hyperglycemia (247).
Figure 2 summarizes the perinatal consequences of GDM.
Short-term Risk
In the HAPO study, higher maternal glucose levels were as-
sociated with an increased risk of LGA, shoulder dystocia or
birth injury, and neonatal hypoglycemia (27). A  recent sys-
tematic review (n = 207 172) confirmed similar positive linear
associations for maternal glycemia based on maternal glucose
thresholds for the GCT, 75-g 2-hour OGTT, or 100-g 3-hour
OGTT and risk of cesarean section, induction of labor (IOL),
LGA, macrosomia, and shoulder dystocia (248). GDM has
also been associated with an increased risk of preterm birth,
birth trauma, neonatal respiratory distress syndrome, and
hypertrophic cardiomyopathy (27,244,249). An increased
risk of congenital malformations in the offspring has been
reported, although whether this persists after adjustment for
maternal age, BMI, ethnicity, and other contributing factors
is unknown (250). A  French cohort study (n = 796 346) re-
ported a 30% higher risk of cardiac malformations in the
offspring of women with GDM compared to women with
normal glucose tolerance, after excluding women with likely
undiagnosed pregestational diabetes (249). However, this in-
creased risk only reached statistical significance in women
treated with insulin therapy. Maternal BMI, which was not
evaluated in these studies, may account for these findings
(251,252). Similarly, a reported increase in perinatal mor-
tality after 35 weeks’ gestation in the offspring of women
with GDM may also be confounded by obesity (253-256). An
increased risk of perinatal mortality after 37 weeks’ gestation
was demonstrated in French women with GDM on dietary
intervention, possibly because these women delivered later
Endocrine Reviews, 2022, Vol. XX, No. XX
than women treated with insulin therapy (249). In contrast,
the HAPO study did not demonstrate excess perinatal mor-
tality in their untreated cohort (27).
Modern management of GDM and associated maternal
risk factors is associated with near-normal birthweight in
developed countries (115,257). This is important because
birthweight is the major risk factor for shoulder dystocia,
brachial plexus injury, neonatal hypoglycemia, and neonatal
respiratory distress syndrome in the offspring of women
with and without GDM (242). A retrospective cohort study
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of 36 241 pregnancies in the United States reported that the
risk of shoulder dystocia among infants of women without
GDM compared to women with GDM was 0.9% vs 1.6%
if birthweight was <4000  g and 6.0% vs 10.5% if birth-
weight was ≥4000  g (macrosomia) (242). The risk of neo-
natal hypoglycemia in infants with birthweight < 4000 g was
1.2% vs 2.6% and 2.4% vs 5.3% for birthweight ≥ 4000 g,
in women without GDM compared to women with GDM,
respectively. Similar findings were seen for brachial plexus in-
jury and neonatal respiratory distress syndrome. Thus, GDM
confers increased risk of perinatal complications independent
of birthweight.
The risk of stillbirth is also greater in women with GDM.
A large US retrospective analysis examined stillbirth rates at
various stages of gestation in over 4 million women, including
193 028 women with GDM. The overall risk of stillbirth from
36 to 42 weeks’ gestation was higher in women with GDM
compared to women without GDM (17.1 vs 12.7 per 10 000
deliveries; RR 1.34; 95% CI 1.2-1.5) (253). This increased
risk of stillbirth was also observed at each gestational week:
3.3 to 8.6 per 10 000 ongoing pregnancies in women with
GDM compared to 2.1 to 6.4 per 10 000 ongoing pregnan-
cies in women without GDM from 36 to 41 weeks’ gestation
(253). For women with GDM, the relative risk of stillbirth
was highest in week 37 (RR 1.84, 95% CI 1.5-2.3). Notably,
the risk of stillbirth is highest in women with undiagnosed
GDM. In a UK prospective case-control study (n = 1024),
women with undiagnosed GDM based on a fasting glucose
level ≥ 5.6mmol/L (≥100 mg/dL) had a 4-fold greater risk of
late stillbirth (defined as occurring ≥28 weeks’ gestation) com-
pared to women with fasting glucose < 5.6mmol/L (<100 mg/
dL) (74). In contrast, women at risk of GDM based on NICE
risk factors who were diagnosed with GDM on the OGTT
had a similar risk of stillbirth to women who were not at risk
of GDM. This suggests that diagnosing and managing GDM
reduces the risk of stillbirth to near-normal levels (74).
Long-term Risk in the Offspring
Recent epidemiological studies suggest an increased risk of
later adverse cardiometabolic sequelae in the offspring of
women with GDM (227,258). A  large Danish population-
based cohort study (n = 2 432 000) demonstrated an asso-
ciation between maternal diabetes and an increased rate of
early onset cardiovascular disease (CVD; ≤40  years of age)
among offspring (259). GDM specifically was associated with
a 19% increased risk of early onset CVD (95% CI 1.07-1.32).
A  longitudinal UK study provides potential mechanistic in-
sight, finding that GDM was associated with alterations in
fetal cardiac function and structure, with reduced systolic and
diastolic ventricular function persisting in infancy (260). This
is consistent with the association between in utero exposure to
Endocrine Reviews, 2022, Vol. XX, No. XX 13

maternal hyperglycemia and fetal programming first reported
in the Native American Pima population, characterized by a
high prevalence of obesity, type 2 diabetes, and GDM (261).
The recent HAPO Follow Up Study (HAPO-FUS), which
was not confounded by treatment of maternal glycemia, in-
cluded 4832 children 10 to 14  years of age whose mothers
were participants of HAPO (227). The HAPO-FUS demon-
strated a durable impact of maternal glycemia with long-term
offspring glucose metabolism, including at glucose levels
lower than those diagnostic for GDM (227). A  generally
As demonstrated in HAPO and other studies, women with
GDM also have an increased risk of gestational hypertension
and preeclampsia (267-269). Consistent with the association
between diabetes and microvascular disease, abnormalities
in glucose metabolism affect trophoblast invasion, leading
to impaired placentation and greater risk for preeclampsia
(270). The mechanism likely relates to insulin resistance and
inflammatory pathway activation (271,272), with in vitro
studies showing that elevated glucose concentrations inhibit
trophoblast invasiveness by preventing uterine plasminogen

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linear relationship between maternal antenatal glucose and
offspring glucose levels and related outcomes was observed.
Increasing maternal glucose categories were associated with
a higher risk of impaired fasting glucose and impaired glu-
cose tolerance and higher timed glucose measures and HbA1c
levels and were inversely associated with insulin sensitivity
and disposition index by 14  years of age, independent of
maternal and childhood BMI and family history of diabetes
(227). A  positive association was observed between GDM
defined by any criteria and glucose levels and impaired glu-
cose tolerance in the offspring at ages 10 to 14  years and
an inverse association with offspring insulin sensitivity (262).
Higher frequencies of childhood obesity and measures of adi-
posity across increasing categories of maternal OGTT glucose
levels were also noted (262). Recent evidence for increased
glucose-linked hypothalamic activation in offspring aged 7 to
11 years previously exposed to maternal obesity and GDM in
utero, which predicted higher subsequent BMI, represents 1
possible mechanism for this increased childhood obesity risk
(263).
Maternal Complications
Short-term Risk
Women with GDM are at an increased risk of obstetric inter-
vention including IOL, cesarean section (27-29,264,265), and
complications associated with delivery including perineal la-
cerations and uterine rupture, predominantly relating to fetal
macrosomia and polyhydramnios (266).
activator activity (272).
Long-term Maternal Risk Following GDM
Women diagnosed with GDM based on pre-IADPSG diag-
nostic criteria are at increased risk of GDM in future preg-
nancies, with reported recurrence rates of 30% to 84%
(128). A  diagnosis of GDM is also associated with up to a
20-fold greater lifetime risk of type 2 diabetes (273,274).
A  recent large meta-analysis and systematic review (20
studies, n = 1 332 373 including 67 956 women with GDM)
showed that women with a history of GDM have a 10-fold
increased risk of developing type 2 diabetes, mostly within
the first 5 years post-GDM (273). HAPO-FUS demonstrated
that over 50% of women whose OGTT thresholds met (un-
treated) IADPSG diagnostic criteria for GDM had devel-
oped impaired glucose tolerance after 14 years of follow-up
(275). These data highlight the importance of a management
approach to GDM that focuses on early prevention of type
2 diabetes. For example, the updated NICE guidelines now
recommend diabetes prevention for all women with previous
GDM (276,277).
Previous GDM is also associated with cardiovascular
risk factors such as obesity, hypertension, and dyslipidemia
(274,278-280). The lifetime risk of cardiovascular disease fol-
lowing GDM is almost 3-fold higher in women who develop
type 2 diabetes and 1.5 fold higher even in women without
type 2 diabetes (280). Studies also report a 26% greater risk
of hypertension and a 43% greater risk of myocardial infarc-
tion or stroke in women with previous GDM compared to

Table 5.  Genes linked to gestational diabetes mellitus

Gene Gene name Function

symbol

MTNR1B Melatonin receptor 1B Receptor mediating the action of melatonin, including its inhibitory effect on insulin
secretion
TCF7L2 Transcription factor 7-like 2 Blood glucose homeostasis
IRS1 Insulin receptor substrate 1 Receptor mediating the control of various cellular processes by insulin
CDKAL1 Cyclin-dependent kinase 5 regulatory Proinsulin to insulin conversion
subunit-associated protein 1-like 1
GCKR Glucokinase regulator Inhibits glucokinase in liver and pancreatic islet cells
G6PC2 Glucose-6-phosphatase 2 Glucose metabolism
PCSK1 Proprotein convertase subtilisin/ Endoprotease involved in proteolytic activation of polypeptide hormones and neuropeptides
kexin type 1 precursors including proinsulin, proglucagon-like peptide 1, and pro-opiomelanocortin
PPP1R3B Protein phosphatase 1, regulatory Regulates glycogen metabolism
subunit 3B
HKDC1 Hexokinase domain containing 1 Involved in glucose homeostasis and hepatic lipid accumulation
BACE2 Beta-site amyloid polypeptide Proteolytic processing of CLTRNa in pancreatic β-cells
cleaving enzyme 2

Genes were identified and selected from the genome-wide association studies (194,203). The name and function of each gene was determined from
GeneCards (https://www.genecards.org).
a
Collectrin, amino acid transport regulator is a stimulator of β-cell replication.
14
women without GDM (281,282). The significance of GDM
as a risk factor for type 2 diabetes and cardiovascular disease
has been recently recognized by international organizations
including the American Heart Association (283).
Management of GDM
Benefits of Intervention on Perinatal Outcomes
Contemporary changes to the detection and management of
GDM have been associated with almost comparable neonatal
birthweight and adiposity outcomes to the background ma-
ternity population in developed countries (115).
The ACHOIS trial (n = 1000) was the first large RCT
to evaluate whether treatment of women with GDM re-
duced the risk of perinatal complications (28). GDM
was diagnosed based on a combination of fasting glu-
cose < 7.8  mmol/L (140  mg/dL) and 2-hour postload glu-
cose 7.8 to 11.0  mmol/L (140-199  mg/dL), respectively,
using the 75-g 2-hour OGTT between 24 and 34 weeks’
gestation, following screening with either positive clinical
risk factors or the GCT (28). ACHOIS demonstrated that a
combination of dietary advice, self-monitoring of maternal
glucose levels (SMBG), and insulin therapy, if required, to
achieve SMBG targets [fasting glucose 3.5-5.5 mmol/L (63-
99  mg/dL), preprandial glucose ≤ 5.5  mmol/L (99  mg/dL),
and 2-hour postprandial glucose ≤ 7.0  mmol/L (126  mg/
dL)], reduced the rate of serious perinatal complications
(a composite of death, shoulder dystocia, nerve palsy, and
fracture) compared to routine care (1% vs 4%; P = 0.01).
In addition, such interventions were associated with a re-
duced incidence of macrosomia (10% vs 21%; P < 0.001),
preeclampsia (12% vs 18%; P = 0.02), and improved ma-
ternal health-related quality of life (28).
In 2009, the MFMU trial (n = 958) reported that treatment
of “mild” GDM was also associated with improved outcomes
Table 6.  Maternal and neonatal complications of gestational diabetes mellitus
Complications Maternal
Short term Preeclampsia
Gestational hypertension
Hydramnios
Urinary tract/vaginal infections
Instrumental delivery
Cesarean delivery
Traumatic labor/perineal tears
Postpartum hemorrhage
Difficulty initiating and/or maintaining breastfeeding
Long term Recurrence of GDM
Type 2 diabetes mellitus
Hypertension
Ischemic heart disease
Nonalcoholic fatty liver disease
Dyslipidemia
Chronic kidney disease
Sources: Scholtens et al (227) and Saravanan (228).
Abbreviation: GDM, gestational diabetes mellitus.
Endocrine Reviews, 2022, Vol. XX, No. XX
(29). Following a positive GCT between 24 and 30 + 6 weeks’
gestation, “mild” GDM was defined on a positive 100-g
3-hour OGTT by a fasting glucose < 5.3 mmol/L (95 mg/dL),
and at least 2 postload glucose thresholds that exceeded the
2000 ADA diagnostic thresholds [1-, 2-, or 3-hour thresholds
10.0  mmol/L (180  mg/dL), 8.6  mmol/L (155  mg/dL), and
7.8 mmol/L (140 mg/dL), respectively]. Women with previous
GDM were excluded from the study. Dietary intervention,
SMBG, and insulin therapy, if required, to achieve a fasting
glucose target < 5.3  mmol/L (95  mg/dL) and 2-hour post-
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prandial glucose target < 6.7 mmol/L (121 mg/dL) was asso-
ciated with reduced rates of macrosomia (5.9% vs 14.3%;
P < 0.001), LGA (7.1% vs 14.5%; P < 0.001), shoulder dys-
tocia (1.5% vs 4.0%; P = 0.02), cesarean section (26.9% vs
33.8%; P = 0.02), and preeclampsia and gestational hyper-
tension (8.6% vs 13.6%; P = 0.01) compared to routine care.
However, the intervention did not lead to a significant dif-
ference in the primary composite outcome of stillbirth, peri-
natal death, and neonatal complications (hyperbilirubinemia,
hypoglycemia, hyperinsulinemia, and birth trauma) (29).
Treatment targets in the MFMU trial were lower than that
of the ACHOIS trial, and whether this may account for the
reduction in cesarean section not shown in the ACHOIS trial
is unclear. These key findings, supported by other studies
(22,284), were highlighted by the IADPSG to support the
lowering of the GDM diagnostic criteria and treating mild
hyperglycemia (30).
A recent Cochrane review (8 RCTs; n = 1418) reported that
GDM treatment, including dietary intervention and insulin
therapy, reduced a composite outcome of perinatal morbidity
(death, shoulder dystocia, bone fracture, and nerve palsy) by
68% compared to routine antenatal care (285). Treatment
was also associated with reductions in macrosomia, LGA,
and preeclampsia but an increase in IOL and neonatal inten-
sive care admission.
Neonatal
Stillbirth
Neonatal death
Preterm birth
Congenital malformations
Macrosomia
Cardiomyopathy
Birth trauma:
  Shoulder dystocia
  Bone fracture
  Brachial plexus injury
Hypoglycemia
Hyperbilirubinemia
Respiratory distress syndrome
Metabolic syndrome
Hyperinsulinemia
Childhood obesity
Excess abdominal adiposity
Higher blood pressure
Possible earlier onset cardiovascular disease
Possible attention-deficit hyperactivity
disorder
Autism spectrum disorder
Endocrine Reviews, 2022, Vol. XX, No. XX
Lifestyle Intervention
The main objective of GDM management is to attain ma-
ternal normoglycemia because evidence suggests that ex-
cessive fetal growth can be attenuated by maintaining near
normal glucose levels (286,287). The foundation of this ap-
proach is medical nutrition therapy. Given carbohydrates
are the primary determinant of maternal postprandial glu-
cose levels, current dietary practice aims to modify carbohy-
drate quality (glycemic index) and distribution (32,288,289).
The original nutritional approach for GDM decreased total
carbohydrate intake to 33% to 40% of total energy intake
(EI) and was associated with reduced postprandial glycemia
and fetal overgrowth (290). More recent evidence suggests
that higher carbohydrate intake and quality (lower glycemic
index) between 60% and 70% EI can also limit maternal
hyperglycemia (291-293). Nevertheless, there remain limited
data to support a specific dietary intervention for GDM (294).
A  recent meta-analysis (18 RCTs; n = 1151) showed that
enhancing nutritional quality (modified dietary intervention,
defined as a dietary intervention different from the usual one
used in the control group) after GDM diagnosis, irrespective
of the specific dietary approach, improved maternal fasting
and postprandial glycemia, and reduced pharmacotherapy re-
quirements, birthweight, and macrosomia (295).
Guidelines therefore currently recommend a range of
carbohydrate intake between 33% and 55% EI (32,288,289).
Studies have reported improved pregnancy outcomes in GDM
with both lower carbohydrate (42%E) and high‐carbohydrate
(55%E) diets (296), reflected in the most recent Academy of
Nutrition and Dietetics guidelines, which state that beneficial
effects on pregnancy outcomes in GDM are seen with a range
of carbohydrate intakes (288). The IOM guidelines recom-
mend a carbohydrate intake of at least 175 g/day and a total
daily caloric intake of 2000 to 2500 kilocalories during preg-
nancy (289). The ACOG recommends a lower carbohydrate
diet (33-40%E) (297). However, the ADA has raised concerns
over the corresponding higher maternal fat intake, fetal lipid
exposure, and overgrowth resulting from lowering carbohy-
drate intake (298) and withdrew specific dietary guidelines
for GDM in 2005 (299).
Given maternal glucose primarily supports fetal growth
and brain development (300), theoretically if the maternal
diet is too low in carbohydrate, the maternal-fetal glucose
gradient may be compromised. Restriction of total maternal
EI is associated with reduced fetal growth (301). A  recent
systematic review similarly showed that lower carbohydrate
intake correlated with lower birthweight and greater inci-
dence of SGA (302), with a lower carbohydrate threshold of
47% EI associated with appropriate fetal growth (302,303).
Importantly, the lower carbohydrate threshold independent
of energy restriction in GDM is yet to be established.
Related safety concerns with lower carbohydrate diets in-
clude the potential risk of higher fetal exposure to maternal
ketones (304) and micronutrient deficiency (305,306). In
vitro studies have shown that ketones suppress trophoblast
uptake of glucose, jeopardizing glucose transfer across the
placenta (307). Clinically, a prospective US cohort study
of women with preexisting diabetes, GDM, or normal glu-
cose tolerance demonstrated an inverse correlation between
higher maternal third trimester beta-hydroxybutyrate and
FFAs and lower offspring intellectual development scores at
2 to 5 years of age, although total carbohydrate, EI, and ma-
ternal BMI were not reported (304).
15
Gestational Weight Gain
The IOM has published recommendations for weight gain
during pregnancy based on prepregnancy BMI (289), but
no specific recommendations for weight gain in GDM exist
(286). In women with overweight or obesity, studies have sug-
gested that weight reduction or gain ≤ 5 kg increased the risk
of SGA (308). A recent systematic review based on data from
almost 740 000 women demonstrated that GWG of 5 kg to
9 kg in women with class I obesity (BMI 30-34.99 kg/m2), 1
to <5 kg for class II obesity (35-39.99 kg/m2), and no GWG
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for women with class III obesity (BMI ≥ 40kg/m2), minimized
the combined risk of LGA, SGA, and cesarean section (309).
A meta-analysis (n = 88 599)  evaluating the relationship
between GWG and pregnancy outcomes in GDM specifically
showed that GWG greater than the IOM recommendations was
associated with an increased risk of pharmacotherapy, as well as
of hypertensive disorders of pregnancy, cesarean section, LGA,
and macrosomia (310). GWG below the IOM recommenda-
tions was protective for LGA (RR 0.71; 95% CI 0.56-0.90) and
macrosomia (RR 0.57; 95% CI 0.40-0.83) and did not increase
the risk of SGA (RR 1.40; 95% CI 0.86-2.27) (289). This sug-
gests that GWG targets in GDM may need to be lower than
the current recommendations for normal pregnancy. However,
from a practical perspective, only 30% of women gained less
than the recommended IOM GWG targets (310).
Maternal Glucose Targets
Fasting and postprandial glucose testing with either the 1- or
2-hour postprandial glucose value is recommended in women
with GDM. The 1-hour postprandial glucose approximates to
the peak glucose excursion in pregnancy in women without
diabetes and those with type 1 diabetes (175). Studies have
shown that the 1-hour postprandial peak glucose level cor-
relates with amniotic fluid insulin levels, reflecting fetal
hyperinsulism (311) and with fetal abdominal circumference
in women with type 1 diabetes (286). An RCT that compared
pre- to postprandial maternal SMBG values showed that ti-
trating insulin therapy based on the 1-hour postprandial
values was associated with improved maternal glycemic con-
trol and may better attenuate the risk of neonatal complica-
tions attributed to fetal hyperinsulinemia (312).
Treatment targets based on maternal SMBG levels vary
internationally (Table 7). There is some suggestion that
lower glucose targets may improve pregnancy outcomes in
GDM (176,313,314), but this is yet to be evaluated in ad-
equately powered RCTs. Conversely, lower glycemic targets
may be associated with an increased risk of SGA (315-317)
and maternal and fetal hypoglycemia (318,319). A  small
study evaluating stringent glycemic targets in 180 women
with GDM failed to demonstrate additional benefits, with
no differences in the rates of cesarean section, birthweight,
macrosomia, or SGA in the offspring of women randomized
to intensive [preprandial glucose ≤ 5.0  mmol/L (90  mg/dL)
and 1-hour postprandial glucose ≤ 6.7 mmol/L (121 mg/dL)]
compared to standard treatment targets [preprandial glu-
cose ≤ 5.8  mmol/L (104.5  mg/dL) and 1-hour postprandial
glucose ≤ 7.8 mmol/L (140 mg/dL)] (320).
Insulin Therapy
Insulin has traditionally been the preferred treatment for
GDM if maternal glucose levels remain elevated on medical
16
Maternal insulin resistance
Placental transfer of glucose and free fatty acids to fetus
Lung surfactant synthesis & function
Iatrogenic preterm delivery
Respiratory distress syndrome
Figure 2.  Perinatal consequences of gestational diabetes mellitus.
nutrition therapy (267). Depending on targets, approxi-
mately 50% of women with GDM are prescribed insulin
therapy to maintain normoglycemia (321,322), with a com-
bination of evening intermediate-acting insulin if fasting
glucose levels are elevated and mealtime rapid-acting insulin
when indicated. Additional daytime intermediate-acting in-
sulin may also be needed to control prelunch or predinner
hyperglycemia.
Decreasing insulin doses in the third trimester may simply
reflect the physiological increase in maternal insulin sensi-
tivity observed at this stage of pregnancy (176,323). However,
substantial insulin dose reduction, recurrent maternal hypo-
glycemia, and/or slowing of fetal growth or preeclampsia may
indicate underlying pathophysiological placental insufficiency
(324), impacting the timing of delivery and intensity of ob-
stetric monitoring.
Risk factors for insulin therapy include earlier diagnosis of
GDM (81), the pattern and degree of elevation of the 75-g
2-hour OGTT diagnostic glucose thresholds (325), and eth-
nicity (325). Other risk factors including gestational age
and HbA1c level at the time of GDM diagnosis, BMI, and
family history of diabetes account for only 9% of the at-
tributable risk for insulin therapy (321). A recent Australian
study found that maternal age > 30  years, family history of
diabetes, prepregnancy obesity, previous GDM, early diag-
nosis of GDM, fasting glucose ≥ 5.3 mmol/L (96 mg/dL) and
HbA1c ≥ 5.5% (37  mmol/mol) at diagnosis were all inde-
pendent predictors for insulin therapy (326). Insulin usage
could also be estimated according to the number of predictors
present, with up to 93% of women with 6 to 7 predictors
using insulin therapy compared with less than 15% of women
with 0 to 1 predictors (326).
Oral Pharmacotherapy
Oral pharmacotherapy options include glyburide and
metformin. Oral pharmacotherapy is associated with im-
proved cost effectiveness, compliance, and acceptability com-
pared to insulin therapy (327). However, there are issues
regarding efficacy and safety, particularly longer term, and
Endocrine Reviews, 2022, Vol. XX, No. XX
Maternal circulating glucose and free fatty acids
Fetal circulating insulin and IGF-1 levels
Fetal substrate uptake Neonatal hypoglycemia
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Macrosomia
Shoulder dystocia Hypoxia Cardiomyopathy
Brachial plexus injury
Stillbirth Polycythemia
Hyperbilirubinemia
thus insulin is generally preferred as first-line pharmaco-
therapy following lifestyle intervention.
Glyburide is commonly prescribed as first-line therapy for
GDM in the United States (328). An early study evaluating
the efficacy of glyburide vs insulin therapy in 404 women
with GDM reported no differences in maternal glucose levels
or neonatal outcomes between the treatment groups (329).
However, subsequent studies show that approximately 20%
of women treated with glyburide required additional in-
sulin therapy to achieve adequate maternal glycemia (330).
Moreover, a large retrospective US study of almost 111 000
women with GDM, in which 4982 women were treated with
glyburide and 4191 women were treated with insulin, re-
ported that glyburide was associated with an increased risk of
neonatal complications including neonatal intensive care ad-
mission, respiratory distress syndrome, hypoglycemia, birth
injury, and LGA compared to insulin therapy (331). Although
transplacental transfer of glyburide to the fetus is highly vari-
able, it can reach 50% to 70% of maternal plasma concen-
tration (332), potentially causing direct stimulation of fetal
insulin production (333).
The use of metformin in pregnancy continues to rise (334).
However, its use remains controversial, due to the poten-
tial concerns regarding long-term metabolic programming
effects of placental transfer of metformin to the fetus, with
some studies suggesting similar plasma concentrations of
metformin in the maternal and fetal circulation (335). A recent
systematic review and meta-analysis of 28 studies (n = 3976)
evaluating growth in offspring of women with GDM exposed
to metformin compared to insulin therapy found that neo-
nates exposed to metformin had lower birthweights (mean
difference −107.7 g; 95% CI −182.3 to −32.7), decreased risk
of LGA (OR 0.78; 95% CI 0.62-0.99), and macrosomia (OR
0.59; 95% CI 0.46-0.77) and lower ponderal indices than
neonates whose mothers were treated with insulin (336). No
difference in the risk of SGA was found, in contrast to out-
comes in women with type 2 diabetes, with the Metformin
in Women with Type 2 Diabetes RCT observing more than
double the rate of SGA (95% CI 1.16-3.71) in the metformin
treated cohort, in association with lower insulin doses, HbA1c,
Endocrine Reviews, 2022, Vol. XX, No. XX
and GWG (337). Offspring of women with GDM exposed to
metformin also demonstrate accelerated postnatal growth at
18 to 24 months of age (2 studies; n = 411; mean difference
in weight 440 g; 95% CI 50-830), resulting in higher BMI at
5 to 9 years of age (3 studies; n = 520; BMI mean difference
0.78 kg/m2, 95% CI 0.23-1.33) (336).
The Metformin in Gestational Diabetes trial randomized
751 women to receive either metformin or insulin therapy,
finding no significant difference in the composite neo-
natal outcome of neonatal hypoglycemia, respiratory dis-
tress syndrome, hyperbilirubinemia, low Apgar scores, birth
trauma, and preterm birth (322). There was a trend toward
increased preterm birth and decreased maternal GWG in
women treated with metformin, while severe neonatal hypo-
glycemia was highest in those treated with insulin. Almost
50% of women treated with metformin required the addition
of insulin therapy (322). Other studies have reported that be-
tween 14.0% and 55.8% of women treated with metformin
also require insulin therapy to achieve optimal glycemic con-
trol (338,339). The Metformin in Gestational Diabetes: The
Offspring Follow-Up 2-year follow-up study found that chil-
dren exposed to metformin had increased subcutaneous fat
localized to the arm compared with children whose mothers
were treated with insulin alone (340). By 7 and 9  years of
age the children exposed to metformin had similar offspring
total and abdominal body fat percentage and metabolic bio-
chemistry including fasting glucose, insulin, and lipids but
were larger overall based on measures including weight, arm
and waist circumference, waist-to-height ratio, and dual-
energy X-ray absorptiometry fat mass and lean mass (341).
These findings are consistent with a recent follow-up study of
metformin therapy in pregnant women with polycystic ovary
syndrome, which showed that children exposed to metformin
in utero had higher BMI and rates of overweight and obesity
at 4 years of age (342).
A recent Cochrane review (8 RCTs; n = 1487) evaluating
the use of metformin, glyburide, and acarbose in women
with GDM found that the benefits and potential harms of
these therapies in comparison to each other are unclear
(343). Other meta-analyses comparing glyburide, metformin,
and insulin have shown that metformin was associated with
lower GWG, gestational hypertension, and postprandial ma-
ternal glucose levels compared to either glyburide or insulin
(344,345), but metformin was associated with an increased
risk of preterm birth compared to insulin (345). Compared
to metformin, glyburide was associated with a higher risk of
increased birthweight, LGA, macrosomia, neonatal hypogly-
cemia, and increased GWG (344). More recently, a small RCT
(n = 104) suggested that glyburide and metformin were com-
parable in terms of maternal glycemia and perinatal outcomes
(346). Treatment success after second-line (oral) therapy was
higher in the (first-line) metformin vs glyburide cohort (87%
vs 50%; P = 0.03), suggesting that metformin may be the
preferred first-line therapy. Overall, most women required
either a combination of metformin and glyburide to achieve
glycemic control and/or replacement of first-line oral therapy
due to hypoglycemia and gastrointestinal side effects, sug-
gesting neither agent alone is likely to be successful in most
women with GDM. Combined oral pharmacotherapy had
an efficacy rate of 89%, with only 11% of women required
third-line therapy with insulin (346). However, the effects of
dual oral therapy crossing the placenta on long-term potential
17
fetal programming via their effects on cellular metabolism,
hepatic gluconeogenesis, and insulin sensitivity (metformin)
(347) and fetal hyperinsulinemia (glyburide) is unknown
(348).
Obstetric Management
A recent Cochrane review consisting of only 3 small RCTs
(n = 524) reported insufficient (very low certainty) evidence
to evaluate the use of fetal biometry in guiding the med-
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ical management of GDM (349). Nevertheless, serial fetal
growth ultrasounds, particularly assessing fetal abdominal
circumference, are potentially useful in guiding the intensity
of maternal glucose targets and insulin therapy (350-352).
Studies have demonstrated that neonates with an estimated
fetal weight ≥ 75th percentile on early third trimester ultra-
sound were 10-fold more likely to be LGA compared to neo-
nates with an estimated fetal weight < 75th percentile (353).
Measured fetal abdominal circumference < 90th percentile on
2 ultrasounds at 3- to 4-week intervals has also been shown
to provide high reliability in excluding the risk of LGA (351).
Moreover, a recent retrospective study (n = 275) found that
estimated fetal weight or abdominal circumference up to the
30th percentile on third trimester ultrasound was associated
with a greater risk of adverse neonatal outcomes, comparable
to that observed with abdominal circumference or estimated
fetal weight > 95th percentile in women with hyperglycemia
in pregnancy (including GDM) (354). These findings suggest
the potential utility of fetal biometry at thresholds other than
defining SGA or LGA in identifying higher risk pregnancies
in GDM.
The optimal timing of delivery in GDM is complex, guided
by maternal glycemic control in addition to maternal and fetal
factors, and has not been definitively established. Current
guidelines recommend delivery by 40 + 6 weeks’ gestation
in low-risk women with GDM managed with diet  alone
and from 39 + 0 to 39 + 6 weeks’ gestation for women with
GDM well controlled with therapy (38,277,355). A  recent
Canadian population-based cohort study examining the
week-specific risks of severe pregnancy complications in
women with diabetes included 138 917 women with GDM
and 2 553 243 women without diabetes over a 10-year
period (356). There was no significant difference in gesta-
tional age-specific maternal mortality or morbidity (defined
as ≥1 of the following in the immediate perinatal period: ob-
stetric embolism, obstetric shock, postpartum hemorrhage
with hysterectomy or other procedures to control bleeding,
sepsis, thromboembolism, or uterine rupture) between iat-
rogenic delivery and expectant management in women with
GDM. However, iatrogenic delivery was associated with an
increased risk of neonatal mortality and morbidity (birth or
fetal asphyxia, grade 3 or 4 intraventricular hemorrhage,
neonatal convulsions, other disturbances of cerebral status
of newborn, respiratory distress syndrome, birth injury,
shoulder dystocia, stillbirth or neonatal death) at 36 to 37
weeks’ gestation (76.7 and 27.8 excess cases per 1000 de-
liveries, respectively) but a lower risk of neonatal morbidity
and mortality at 38 to 40 weeks’ gestation (7.9, 27.3, and
15.9 fewer cases per 1000 deliveries, respectively) compared
with expectant management, suggesting that delivery at 38,
39, or 40 weeks’ gestation may provide the best neonatal
outcomes in women with GDM (356).
18
Longer Term Management of Women
Following GDM
Up to one third of women with GDM diagnosed by pre-
IADPSG criteria will have glucose levels consistent with dia-
betes or prediabetes on postpartum testing at 6 to 12 weeks
(357). Thus, a repeat OGTT or fasting glucose as early as
6 to 12 weeks’ postpartum is recommended to confirm ma-
ternal glucose status (41,277). Only around 25% of women
are tested at this time point with compliance with postpartum
testing ranging between 23% and 58% (357,358). In women
with GDM with overweight or obesity, a reduction in
interpregnancy BMI of ≥2.0  kg/m2 reduces the risk of sub-
sequent GDM by 74% (359). Longer term, women should
perform regular cardiometabolic health assessment and op-
timization of lifestyle measures to reduce their greater risk
of type 2 diabetes and cardiovascular disease (282,360,361).
Up to 74% of women with obesity and previous GDM de-
velop type 2 diabetes compared with <25% of women who
achieve a normal BMI postpartum following GDM (362). It
is unclear how relevant these studies in older women are for
current clinical care given recent data that 50% of women
develop type 2 diabetes within 5 to 10 years post-GDM diag-
nosis (273). The Diabetes Prevention Program demonstrated
that lifestyle intervention and metformin therapy improved
insulin sensitivity and preserved β-cell function in women
with a history of previous GDM (363). Early type 2 diabetes
prevention following GDM is therefore an essential compo-
nent of the contemporary GDM detection and management
paradigm (276).
Treatment of GDM and Long-term Offspring
Outcomes
Importantly, despite a reduction in the risk of macrosomia
at birth, the ACHOIS and MFMU follow-up studies did not
demonstrate a beneficial impact on childhood obesity and
glucose tolerance at 5 to 10 years of age in the offspring of
women who received treatment for maternal hyperglycemia
(364,365). Other prospective cohort studies similarly sug-
gest that the offspring of women with treated GDM still
have a greater risk of obesity, type 2 diabetes, the metabolic
syndrome, and cardiovascular disease from early childhood
and adolescence (258,366-380). For example, a 2017 Danish
National Birth Cohort study (n = 561) reported increased adi-
posity, an adverse cardiometabolic profile, and earlier onset
puberty among adolescent females of women with GDM
(381). A  prospective offspring cohort study of women with
GDM who achieved good antenatal glycemic control dem-
onstrated that offspring adiposity (adipose tissue quantity
measured using magnetic resonance imaging) was similar
in the GDM and normal glucose tolerance groups within 2
weeks postpartum but was 16.0% greater (95% CI 6.0-27.1;
P = 0.002) by 2 months of age (382). The mechanism for this
greater adiposity and rapid weight gain in early infancy is
uncertain given both groups were predominantly breastfed.
Consistent with the ACHOIS and MFMU follow-up studies
(364,365), these data suggest that the current approach to
glycemic control in GDM may not mitigate its impact on
longer term infant health. Further, this pathway may be po-
tentially mediated by excess infant adiposity, which correlates
with childhood adiposity (383). Table 8 presents practical tips
for managing women with GDM.
Endocrine Reviews, 2022, Vol. XX, No. XX
Precision Medicine in GDM: Physiological
Heterogeneity, Subtype Classification, Risk
Prediction, and Biomarker Utility
Precision medicine seeks to improve diagnostics, prognostics,
prediction, and therapeutics in diabetes, including GDM, by
evaluating and translating various biological axes including
metabolomics, genomics, lipidomics, proteomics, technology,
clinical risk factors and biomarkers, and mathematical and
computer modeling into clinical practice (384). The Precision
Medicine in Diabetes Initiative was launched in 2018 by the
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ADA, in partnership with the European Association for the
Study of Diabetes, with their first consensus report published
in 2020 (384).
In GDM, precision medicine represents the increasing
understanding of heterogeneity within its genotype and pheno-
type (170,385-388) to identify and translate subclassification
of GDM into more personalized clinical care (388). For ex-
ample, physiologic subtypes of GDM based on the underlying
mechanisms leading to maternal hyperglycemia have been
recently characterized (386). Among 809 women from the
Genetics of Glucose Regulation in Gestation and Growth
pregnancy cohort, heterogeneity in the contribution of insulin
resistance and deficiency to GDM were characterized based
on validated indices of insulin sensitivity and secretory re-
sponse measured during the 75-g OGTT performed between
24 and 30 weeks’ gestation (388). Compared to women
with normal glucose tolerance, women with insulin resistant
GDM (51% of GDM) had higher BMI and fasting glucose,
hypertriglyceridemia, and hyperinsulinemia, larger infants,
and almost double the risk of GDM-associated pregnancy
complications. In contrast, women with predominantly in-
sulin secretion defects had comparable BMI, fasting glucose,
infant birthweight, and risk of adverse outcomes to those
with normal glucose tolerance (388).
Other studies have also suggested that greater insulin
resistance in GDM carries a higher risk of perinatal com-
plications (389). A recent multicenter prospective study of
1813 women evaluating subtypes of GDM based on insulin
resistance (389) found that women with GDM and high
insulin resistance [n = 189 (82.9%)] had a higher BMI,
systolic blood pressure, fasting glucose, and lipid levels in
early pregnancy compared to women with normal glucose
tolerance or those diagnoses with insulin-sensitive GDM.
Insulin-sensitive women with GDM [n = 39 (17.1%)] had
a significantly lower BMI than women with normal glu-
cose tolerance but similar blood pressure, early pregnancy
fasting glucose and lipid levels, and pregnancy outcomes.
Despite no differences in insulin treatment and early
postpartum glucose intolerance among the GDM sub-
types, women with GDM and high insulin resistance had
a greater than 2-fold risk of preterm birth and an almost
5-fold increased risk of neonatal hypoglycemia compared
with women with normal glucose tolerance. This suggests
the high insulin resistance GDM subtype has a greater risk
of pregnancy complications potentially arising from the re-
sultant fetal hyperinsulinemia (389).
The contemporary precision medicine approach to GDM
also includes the increasing exploration of early pregnancy
risk prediction and risk management models (390). The trad-
itional binary clinical risk factor approach to identifying
women at high risk in early pregnancy is limited by poor sen-
sitivity and specificity, with studies showing that clinical risk
Endocrine Reviews, 2022, Vol. XX, No. XX
factor-based screening fails to identify 10% to over 30% of
women with GDM (391-396). The Pregnancy Outcome for
Women with Pre-gestational Diabetes Along the Irish Atlantic
Seaboard study found that the prevalence of women with
GDM who had no risk factors was low, ranging from 2.7%
to 5.4% (397). However, despite the absence of risk factors,
these women with GDM had more pregnancy complications
than those with normal glucose tolerance (397). Other studies
have also reported that women without risk factors diagnosed
with GDM have comparable pregnancy outcomes to women
with GDM identified as high risk (393). Thus, clinical risk
factors alone are not predictive of GDM risk for all women.
Although some improvement in the predictive accuracy for
GDM is seen in clinical risk scoring approaches (158,398),
greater improvement via multivariate risk prediction and
mathematical or computer models combining clinical risk
factors and biomarkers have been reported in the GDM re-
search setting (154-156,399-403).
Biomarkers are defined as a biological observation that sub-
stitutes and ideally predicts the clinically relevant endpoint
(ie, GDM) (404). Biomarker discovery and application in the
early detection of GDM has become a major research area.
However, few biomarkers are specific enough for clinical ap-
plication (405). Most novel biomarkers with potential utility
for the prediction of GDM are involved in pathophysiological
pathways related to insulin resistance, dyslipidemia, and type
2 diabetes (402,406) but are frequently mediated by maternal
obesity (240,407). Early pregnancy risk prediction models
for GDM combining clinical risk factors and biomarkers
have included various measures of maternal glucose, lipids,
adipokines, inflammatory markers, and pragmatic aneuploidy
and preeclampsia screening markers, with model performance
(area under the curve) up to 0.91 (153,154,399,402,403,408-
416). Limitations to the clinical application of novel bio-
markers and model performance include heterogeneity in the
testing approach to GDM and cohort characteristics, poten-
tial overestimation of model performance due to overfitting
of the data to the index study population, the lack of external
clinical validation studies, and limited regulatory guidance
for validating biomarker assays (405).
The COVID-19 Pandemic and GDM
The COVID-19 pandemic has led to dynamic changes in
the testing approach and model of care for women with
GDM to minimize the risk of virus transmission and be-
cause of decreased clinical capacity. Several temporary
pragmatic diagnostic strategies have been suggested as an
Table 7.  Recommended glycemic treatment targets in GDM
Fasting plasma Preprandial plasma
glucose (mmol/L) glucose (mmol/L)
ADIPS (33) ≤5.0
ADA (41) ≤5.3
CDA (42)
NICE (38) <5.3
ACHOIS (37) 3.5-5.5 ≤5.5
MFMU (38) <5.3
Abbreviations: ACHOIS, Australian Carbohydrate Intolerance Study in Pregnant Women Study; ADA, American Diabetes Association; ADIPS, Australasian
Diabetes in Pregnancy Society; CDA, Canadian Diabetes Association; NICE, UK National Institute for Health and Care Excellence; MFMU, National
Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
19
alternative to the OGTT, including measurement of fasting
plasma glucose, random plasma glucose, and HbA1c (417-
419). A secondary analysis of 5974 women from the HAPO
study (420), reported that the UK, Canadian, and Australian
COVID-19–modified diagnostic approaches reduced the
frequency of GDM by 81%, 82%, and 25%, respectively.
Short-term pregnancy complications in the subgroup of
women now with undiagnosed GDM (“missed GDM”)
were comparable to women diagnosed with GDM based
on the Canadian-modified diagnostic criteria, slightly lower
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for the UK-modified criteria, but significantly lower for the
Australasian Diabetes in Pregnancy Association–modified
criteria. While all approaches recommend universal testing,
the Australian approach adopts a lower fasting glucose
threshold of 4.7 mmol/L to identify women who require an
OGTT and does not include HbA1c measurement (420).
A retrospective UK study of over 18 000 women sought to
define evidence-based recommendations for pragmatic GDM
testing during the COVID-19 pandemic (421), reporting
that ~5% of women would be identified as GDM based on
a random glucose threshold ≥ 8.5  mmol/L (153  mg/dL) at
12 weeks’ gestation and fasting glucose ≥ 5.2 to 5.4 mmol/L
(94-97 mg/dL) or HbA1c ≥ 5.7% (39 mmol/mol) measured
at 28 weeks’ gestation. Each test predicted some, but not all,
obstetric and perinatal complications, lacking the sensitivity
of the OGTT for the diagnosis of GDM but overall may
provide adequate risk stratification where the OGTT is not
feasible (421).
Conclusion
GDM is one of the most common complications of pregnancy
and is increasing in global prevalence. Diagnosing GDM is im-
portant because perinatal complications and stillbirth risk are
reduced by treatment. Despite the benefit of identifying and
treating GDM, much of the current (short-term) diagnostic
and management approach to GDM remains contentious.
These differences confound interpretation and application
of trial data, preventing a single standard international ap-
proach to GDM.
Recent data indicates near normal birthweight and ma-
ternity population outcomes in women with GDM based
on modern IADPSG criteria in developed countries,
demonstrating that even treatment of “milder” maternal
hyperglycemia improves pregnancy outcomes. However,
most cases of GDM occur in low- and middle-income coun-
tries where perinatal risks are far greater and universal 1-step
testing may be more practical. There are limited RCT data to
1-hour post-prandial 2-h post-prandial plasma
plasma glucose (mmol/L) glucose (mmol/L)
≤7.4 ≤6.7
≤7.8 ≤6.7
<7.8 <6.4
≤7.0
<6.7
20 Endocrine Reviews, 2022, Vol. XX, No. XX

Table 8.  Practical tips for managing women with GDM

Period Tips

Preconception All women should be encouraged to plan for pregnancy.

Optimize modifiable risk factors prior to pregnancy (eg. BMI, diet, physical activity).
Glucose assessment in high-risk women to detect undiagnosed preexisting glucose intolerance or diabetes.
During All pregnant women should be encouraged to have a nutritionally dense diet and undertake regular exercise during pregnancy
pregnancy unless there are obstetric contraindications.
All pregnant women should be given personalized gestational weight gain targets and have their weight monitored at clinical
reviews.
High-risk women who have not undergone prepregnancy glucose assessment should be tested early for diabetes in pregnancy.

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Test all pregnant women without known diabetes/early GDM for GDM at 24 to 28 weeks’ gestation according to
recommended screening and diagnostic criteria.
GDM management ideally involves a multidisciplinary team with regular diabetes and obstetric assessment and includes patient
education, lifestyle modification and support.
Women should monitor their blood glucose levels. Pharmacotherapy, usually insulin, should be commenced if glucose levels are
elevated despite lifestyle optimization. Metformin can be considered unless there are concerns with inadequate fetal growth.
Timing of delivery is an individualized decision based on maternal and fetal well-being in addition to maternal glycemic control.
Postpartum Early postpartum OGTT to assess glucose status.
Regular long-term follow-up focused on diabetes and vascular risk factor modification and assessment to reduce subsequent
risk of GDM, diabetes, and cardiovascular disease.
Family lifestyle support, which includes optimizing diet, physical activity, and weight in the offspring.

Abbreviations: GDM, gestational diabetes mellitus; OGTT, oral glucose tolerate test.

guide diagnosis and management in this setting, and further
evidence is urgently needed. In developed countries including
the United Kingdom, the main issue arguably does not per-
tain to women diagnosed with GDM but rather high-risk
women who remain unscreened (associated with factors such
as lower socioeconomic status and higher BMI) who are at
highest risk of stillbirth (74).
The background to the various GDM diagnostic criteria is
informative in demonstrating that no approach clearly sep-
arates risk groups. It is also now evident that a continuum
of risk for GDM exists based on both the timing and degree
of maternal hyperglycemia. This underscores the difficulty of
defining absolute glucose thresholds at a single timepoint in
pregnancy for the diagnosis of GDM and is confounded fur-
ther by variation in glucose measurement due to preanalytical
glucose processing and reproducibility issues. Thus, current
diagnostic glucose thresholds for GDM must inevitably re-
flect compromise and consensus.
A precision medicine approach that recognizes GDM sub-
type and heterogeneity, enhanced by further research into the
genetics of GDM and validation of novel biomarkers and new
technologies such as continuous glucose monitoring may im-
prove risk stratification, optimize clinical models of care, and
facilitate more individualized and consumer-friendly detec-
tion and treatment strategies.
The recent HAPO-FUS data confirming the long-term im-
pact of maternal hyperglycemia on maternal and offspring
metabolic health (227,262) highlight an important paradigm
shift. The approach to GDM should reflect an evidence base
that evaluates diagnostic glucose thresholds and measure-
ment within a framework that includes timing of detection
and treatment trials with long-term clinical and health eco-
nomic outcomes. For example, if the ongoing Treatment of
Booking Gestational Diabetes Mellitus trial demonstrates a
benefit for early GDM detection and treatment, there are im-
plications for the prevailing diagnostic GDM glucose thresh-
olds in later pregnancy. This is because these thresholds were
derived from the risk of perinatal complications in a heteroge-
neous GDM cohort, which included women who would fulfill
early GDM criteria.
Other important areas for research include the evaluation
of dietary interventions establishing the optimal carbohydrate
threshold in GDM, further clarity on the potential long-term
impact of intrauterine metformin on the offspring, as well as
the efficacy of preconception and early pregnancy preventive
strategies targeting risk factors other than glycemia, such as
maternal obesity and GWG. Improved obstetric assessment
of placental function, especially in late pregnancy, to inform
timing of delivery and identify women at highest risk of still-
birth in GDM is also needed.
The complications of GDM may indeed be greater based
on the severity of maternal glycemia and associated vascular
risk factors. Nevertheless, the traditional focus on diagnostic
criteria and short-term antenatal maternal glucose manage-
ment fails to address the importance of identifying “milder”
(IADPSG-defined) GDM as a risk factor for future maternal
and offspring diabetes and CVD risk. It should also be ap-
parent that the increasing prevalence of GDM largely reflects
the worsening metabolic health burden including prediabetes
and obesity in women of childbearing age. The clinical focus
for GDM must therefore urgently shift to early postnatal pre-
vention strategies to decrease the progression from GDM to
type 2 diabetes and address longer term maternal and off-
spring cardiometabolic risk post-GDM via a life course man-
agement approach.
Financial Support
A.S.  was supported by an NHMRC Fellowship Grant
(GNT1148952).
Disclosure Summary
A.S., J.W., H.M., and G.P.R. have nothing to declare.
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