Endocrine Reviews, 2022, 43, 763–793
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,
Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
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
1
2
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 maternal 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.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://
creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the
original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@
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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.
764
Essential Points
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 criteria for diabetes in pregnancy in the United States, proposing
physiological and pathophysiological thresholds for “transient glycosuria in pregnancy” (5).
In 1964, O’Sullivan and Mahan defined specific diagnostic criteria for gestational diabetes mellitus (GDM) in
the United States derived from the 100-g 3-hour oral glucose 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 primarily chosen because the resulting GDM prevalence of
2% corresponded to the background population prevalence of diabetes, while the requirement of ≥2 elevated glucose values sought to minimize the risk of preanalytical
error (7). These thresholds were validated by their identification 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 endorsement 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 approach 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
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 subsequently 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 underwent 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 TriHospital Gestational Diabetes Project (21,22). These data
demonstrated a positive correlation between increasing maternal hyperglycemia even below the NDDG diagnostic
criteria for GDM and risk of obstetric and neonatal complications including preeclampsia, cesarean section, and
macrosomia (neonatal birthweight > 4000 g) (21,22). In addition, several large cohort studies showed that women diagnosed (but not treated) with GDM based on the Carpenter
and Coustan criteria were at increased risk of perinatal complications including hypertensive disorders of pregnancy, increased 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 derived from the modified Carpenter and Coustan fasting, 1and 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% increase 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 expert consensus. The underlying rationale for the diagnosis of
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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 complications 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 complications and stillbirth risk are greatly reduced by
treatment.
4. A precision medicine approach to GDM which
recognizes severity and onset of maternal hyperglycemia as well as genetic and physiologic subtypes
of GDM may address the current diagnostic controversy via accurate risk stratification and individualized 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 antenatal maternal glucose management should now shift
to early postnatal prevention strategies to decrease the
progression from GDM to type 2 diabetes and address longer term maternal and offspring metabolic
risk given the global epidemic of diabetes, obesity, and
cardiovascular disease.
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GDM also shifted over time toward identifying perinatal risk
rather than future maternal diabetes risk.
Current GDM Diagnostic Criteria
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
risk factors for GDM are recommended to undergo a diagnostic 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 prevalence 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, almost 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 intervention 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 resulting 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 delivery, macrosomia, large-for-gestational-age (LGA), shoulder
dystocia, and neonatal intensive care admission, compared
to women with normal glucose tolerance (57-59). For example, a 2015 retrospective study in Taiwan comparing pregnancy outcomes in women diagnosed and treated for GDM
using the 2-step (GCT followed by the 100-g 3-hour OGTT)
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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, observational 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 pregnant 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 before 37 weeks’ gestation), shoulder dystocia or birth injury,
hyperbilirubinemia, and neonatal intensive care admission.
The results showed a continuous positive linear relationship between maternal fasting; 1- and 2-hour plasma glucose
levels obtained on the OGTT, below those that were diagnostic of diabetes outside pregnancy; and risk of primary outcomes (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 hyperglycemia, 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 define 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 perinatal outcomes (37). The National Institutes of Health and
765
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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 intervention trials (28,29), whereby maternal glucose levels overlapped 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, historically, 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 “carbohydrate intolerance resulting in hyperglycemia of variable severity with onset or first recognition during pregnancy” and
remained the most widely used definition of GDM until recently (71).
Contemporary nomenclature and diagnostic criteria now
more clearly differentiate between women with pregestational
diabetes and those with hyperglycemia first detected in pregnancy (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 rationale 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 associated with a 3.5-fold greater risk of hypertensive disorders
in pregnancy compared to women with normal glucose tolerance, 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
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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 modified 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 [relative 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 hypertension 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) between the different screening approaches. These findings have
not resolved the diagnostic debate for GDM, with some arguing that the 1-step approach therefore demonstrates insufficient 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 clinicians 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 approach, 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 population 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 required pharmacotherapy for control of hyperglycemia even
at the most sensitive thresholds of the IADPSG diagnostic criteria (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 postglucose load screening based on ethnicity. Moreover, a recent
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Table 1. Current international testing approach to gestational diabetes mellitus
Selective vs
universal
testing
Method of
screening
IADPSG (30)
WHO (11)
ADIPS (33)
FIGO (32)
JDS (34)
EBCOG (36)
Endocrine
Society (31)
China (35)
Universal
One-step: 75-g 2-h
OGTT
ADA (41)
Universal
One-step: 75-g 2-h
OGTT
Two-step: 50-g
GCT
ACOGc (19)
Universal
CDA (42)
Screen positive
threshold
(mmol/L)
Diagnostic
test
Diagnostic (plasma glucose) threshold for GDM
(mmol/L)
75-g
2-hour
OGTT
Fasting ≥ 5.1
1-h ≥ 10.0
2-h ≥ 8.5
One abnormal value needed for diagnosis
≥7.2 to 7.8a
75-g
2-hour
OGTT
100-g
3-hour
OGTT
Fasting ≥ 5.1
1-h ≥ 10.0
2-h ≥ 8.5
One abnormal value needed for diagnosis
Carpenter and Coustanb (17) or NDDG (13)
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
Two-step: 50-g
GCT
≥7.2 to 7.8*
100-g
OGTT
Carpenter and Coustanb (17) or NDDG (13)
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
Universal
Two-step: 50-g
GCT (preferred)
One-step: 75-g
2-h OGTT
(alternative)
≥7.8
50-g GCT
75-g
2-hour
OGTT
≥11.1 mmol/Le
Fasting ≥ 5.3
1-hour ≥ 10.6
2-hour ≥ 9.0
One abnormal value needed for diagnosis
NICE (38)
Selective
Risk factorsf
75-g
2-hour
OGTT
Fasting ≥ 7.0
2-hour ≥ 7.8
One abnormal value needed for diagnosis
CNGOF (39)
Selectiveg
First
trimester
fasting
glucose
75-g
OGTTh
≥5.1
Fasting ≥ 5.1
1-hour ≥ 10.0
2-hour ≥ 8.5
One abnormal value needed for diagnosis
DDG/DGGG
(43)
Universal
Two-step: 50-g
GCT
One-step:
75-g OGTT
(preferred)
50-g GCT
75-g
OGTT
≥11.1 mmol/Le
Fasting ≥ 5.1
1-hour ≥ 10.0
2-hour ≥ 8.5
One abnormal value needed for diagnosis
DIPSI (44)
Universal
One-step: 75-g
OGTT
75-g
OGTT
2-hour ≥ 7.8i
≥7.5
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).
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Organization/
country
768
Early GDM
Most international guidelines now recommend early antenatal 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 enrolled 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 became 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 excess 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 consideration. First, preanalytical glucose handling variation, particularly in the setting of a single glucose measurement, is a major
issue for GDM diagnostic accuracy (discussed in the following 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’ gestation [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’ gestation (86-88), leading to potential overdiagnosis of GDM.
In China, an early fasting glucose between 6.1 mmol/L to
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 glucose 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 established. 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 predicted 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 pregnancy (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 retrospective 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 echocardiograms (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 characteristics of women diagnosed with GDM at a median of 16 weeks’
gestation compared to those diagnosed from 24 weeks’ gestation 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 differences, 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 outcomes. A recent major RCT in the United States evaluating
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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 glucose tolerance, and 41% returned to normal glucose tolerance (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 condition of mid to late pregnancy. The ADA has not accepted
this nomenclature and defines GDM based on timing of diagnosis: 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 presented in Table 2.
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Endocrine Reviews, 2022, Vol. 43, No. 5
The Impact of Preanalytical Glucose
Processing Standards on the Diagnosis
of GDM
Although the contemporary testing approach to GDM remains contentious, it is important to recognize that the diagnosis 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
fluoride tubes, with immediate placement in an ice slurry and
centrifugation within 30 minutes (109). Citrate tubes are recommended 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 centrifugation 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
glucose based on biological variation (107).
Recent studies have shown that OGTT preanalytical glucose processing variability greatly impacts the prevalence of
GDM (67,111). Implementation of the AACC/ADA recommendations 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 practice of storing sodium fluoride tubes at room temperature and
delaying centrifugation until collection of all 3 OGTT samples (112). This increase in GDM diagnosis was entirely attributable 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 centrifugation (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 primarily 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 pregnancy (73). In 2019, the International Diabetes Federation
(IDF) estimated that 1 in 6 live births worldwide were complicated by GDM (113). More than 90% of cases of hyperglycemia in pregnancy occur in low- and middle-income countries
(114), where the prevalence and severity of maternal and neonatal complications associated with GDM (47,113) contrast
with the near-normal pregnancy outcomes of modern management of GDM in developed countries (115).
The prevalence of GDM varies widely, depending on the
population, the specific screening and the diagnostic criteria
Figure 1. Flowchart summarizing the contemporary nomenclature for hyperglycemia in pregnancy.
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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 outcome (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 different glycemic targets are required reflecting physiological
differences in early maternal glucose or whether additional
risk factors contributing to a more insulin resistant phenotype such as maternal adiposity might also have a role remain 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).
769
Endocrine Reviews, 2022, Vol. 43, No. 5
770
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
recurrence rates of up to 84% (128). The risk of recurrence
varies greatly depending on ethnicity (128). Ethnicities at increased 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
Americans (4.4%) (131). Women who have had GDM are at
increased risk for subsequent type 2 diabetes, while family history 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 continuous 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 associated 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
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
Overt diabetes during pregnancy
Fasting glucose ≥ 7.0 mmol/L
Random glucose ≥ 11.1 mmol/La
HbA1c ≥ 6.5%
WHO/FIGO/ADIPS (11,32,33)
GDM
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
Diabetes mellitus in pregnancy
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
ADA (41)
GDM
1-step strategy:
75-g 2-h OGTT
Fasting glucose ≥ 5.1 mmol/L
1-hour glucose ≥ 10.0 mmol/L
2-hour glucose ≥ 8.5 mmol/L
2-step strategy:
50-g 1-hour GCT ≥ 7.8 mmol/L
100 g 3-hour OGTT
Carpenter and Coustan (17) or
Fasting glucose ≥ 5.3 mmol/L
1-hour glucose ≥ 10.0 mmol/L
2-hour glucose ≥ 8.6 mmol/L
3-hour glucose ≥ 7.8 mmol/L
Type 2 diabetes mellitus
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%
NDDG (13)
Fasting glucose ≥ 5.8 mmol/L
1-h glucose ≥ 10.6 mmol/L
2-h glucose ≥ 9.2 mmol/L
3-h glucose ≥ 8.0 mmol/L
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).
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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 criteria, 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, corresponding to epidemiological factors including the background rates of type 2 diabetes and increased incidence of
obesity in women of childbearing age and rising maternal age
(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).
Endocrine Reviews, 2022, Vol. 43, No. 5
Pathophysiology of GDM
Normal pregnancy is associated with marked changes in
glycemic physiology (159,160). There is a progressive increase 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 promotes insulin resistance, contributing to facilitated lipolysis
by late pregnancy (167,168). The resultant increase in maternal free fatty acid (FFA) levels exacerbates maternal insulin
resistance by inhibiting maternal glucose uptake and stimulating 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 diffusion 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 approach 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 postprandial glucose, adaptations in normal pregnancy include
enhanced insulin secretion (160,165). Maternal glucose levels
are maintained at lower levels than in healthy nonpregnant
women (175,176), and euglycemia is maintained by a corresponding 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, primarily 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).
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 resistance during pregnancy (183). This leads to decreased
glucose uptake, increased hepatic gluconeogenesis, and maternal hyperglycemia (167). It is hypothesized that this results 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 pathogenesis of GDM therefore parallels that of type 2 diabetes, characterized 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 secretory response is present from prepregnancy and increases in
early pregnancy, prior to and independent of changes in insulin 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 potential 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 association 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 substrate 1 (IRS1) and peroxisome proliferator-activated receptor
gamma (PPARG)] (200,201), and inflammation [tumor necrosis 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 significant only in Asian populations, while the association between
IRS1 and TCF7L2 and GDM risk varied depending on diagnostic 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
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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 increased 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 develop abnormal glucose tolerance compared to women who
remained within the 1990 Institute of Medicine (IOM) recommendations for GWG (131,141). Interpregnancy weight
gain is also a risk factor for GDM and perinatal complications 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 attenuated 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-gestationalage (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, previous 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).
771
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772
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 glucose. These loci have also previously been associated with
lipid metabolism (GCKR and PPP1R3B), glycogen metabolism (PPP1R3B), and obesity-related traits (PCSK1)
(209-214).
Two additional novel loci identified near hexokinase domain 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 determinants 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
testing
Method of testing
Diagnostic test
Criteria for diagnosing early GDM (mmol/L)
IADPSG (30)
Yes
Selective—women at risk
of overt diabetes during
pregnancya
Fasting glucoseb
≥5.1
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
of hyperglycemia in
pregnancyd
75-g 2-hour OGTT
Fasting 5.1-6.9 or
1-hour ≥ 10.0 or
2-hour 8.5-11.0
ADA (41)
Yes
Selective—women
with risk factors for
undiagnosed type 2
diabetese
One-step: 75-g 2-hour
OGTT
Two-step: 50-g GCT
100-g 3-hour OGTT
Fasting 5.1-6.9 or
1-hour ≥ 10.0 or
2-hour 8.5-11.0
≥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
with risk factors for
undiagnosed type 2
diabetes or GDMf
75-g 2-h OGTT or
50-g GCT
Confirmatory
100-g 3-hour OGTT
Fasting ≥ 7.0 or
2-hour ≥ 11.1
≥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
EBCOG (36)
Yes
Selective—women at risk
of overt diabetes during
pregnancyg
75-g 2-hour OGTT
Fasting 5.1-6.9 or
1-hour ≥ 10.0 or
2-hour 8.5-11.0
DDG/DGGG
(43)
Yes
Selective—women
with risk factors for
“manifest diabetes”h
Random glucose or
Fasting glucose or
75-g 2-hour OGTT
7.8-11.05 mmol/L followed by a second blood
glucose measurement or an OGTT
5.1-6.9
Fasting 5.1-6.9 or
1-hour ≥ 10.0 or
2-hour 8.5-11.0
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metabolism (194,203). The first, a 2-stage GWAS in Korean
women, compared 468 women with GDM and 1242 normoglycemic women using 2.19 million genotyped markers before 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.
CDKAL1 was significantly associated with decreased fasting
insulin concentration and homeostasis model assessment of
β-cell function in women with GDM, consistent with impaired 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 maternal metabolic traits in pregnancy (194). This study reported 5 variants associated with quantitative glycemic
traits in the general population (207,208) that were also
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773
Table 3. Continued
Organization
Early pregnancy
testing
Method of testing
Diagnostic test
Criteria for diagnosing early GDM (mmol/L)
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
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 diabetes characterized by defects in single genes regulating β-cell
development and function (217,218). MODY consists of several 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 glucose 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 maternal glycemic control largely depends on whether the GCKMODY 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
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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.
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).
774
centile) measured on serial ultrasounds from 26 weeks’ gestation, as this indicates that the fetus does not have the GCK
mutation (220).
Consequences of GDM
GDM is associated with excess neonatal and maternal shortand long-term morbidity, summarized in Table 6.
Neonatal Complications
Short-term Risk
In the HAPO study, higher maternal glucose levels were associated with an increased risk of LGA, shoulder dystocia or
birth injury, and neonatal hypoglycemia (27). A recent systematic 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) reported 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 increased 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 mortality 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
than women treated with insulin therapy (249). In contrast,
the HAPO study did not demonstrate excess perinatal mortality 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
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 birthweight was ≥4000 g (macrosomia) (242). The risk of neonatal 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 injury 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 pregnancies 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) compared 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 populationbased cohort study (n = 2 432 000) demonstrated an association 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 insight, 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
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The Pedersen hypothesis describes the pathophysiology contributing 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 (231239). Maternal hyperlipidemia also contributes to excess
fetal growth (233,240). Macrosomia and LGA increase the
risk of cesarean section, birth trauma, and perinatal complications including shoulder dystocia, brachial plexus injury
and fracture, and perinatal asphyxia (27,132,237,238,241243). 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 hypoglycemia, 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.
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775
Maternal Complications
Short-term Risk
Women with GDM are at an increased risk of obstetric intervention including IOL, cesarean section (27-29,264,265), and
complications associated with delivery including perineal lacerations and uterine rupture, predominantly relating to fetal
macrosomia and polyhydramnios (266).
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
activator activity (272).
Long-term Maternal Risk Following GDM
Women diagnosed with GDM based on pre-IADPSG diagnostic criteria are at increased risk of GDM in future pregnancies, 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 (untreated) IADPSG diagnostic criteria for GDM had developed 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 following 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 infarction or stroke in women with previous GDM compared to
Table 5. Genes linked to gestational diabetes mellitus
Gene
symbol
Gene name
Function
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
subunit-associated protein 1-like 1
Proinsulin to insulin conversion
GCKR
Glucokinase regulator
Inhibits glucokinase in liver and pancreatic islet cells
G6PC2
Glucose-6-phosphatase 2
Glucose metabolism
PCSK1
Proprotein convertase subtilisin/
kexin type 1
Endoprotease involved in proteolytic activation of polypeptide hormones and neuropeptides
precursors including proinsulin, proglucagon-like peptide 1, and pro-opiomelanocortin
PPP1R3B
Protein phosphatase 1, regulatory
subunit 3B
Regulates glycogen metabolism
HKDC1
Hexokinase domain containing 1
Involved in glucose homeostasis and hepatic lipid accumulation
BACE2
Beta-site amyloid polypeptide
cleaving enzyme 2
Proteolytic processing of CLTRNa in pancreatic β-cells
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.
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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, included 4832 children 10 to 14 years of age whose mothers
were participants of HAPO (227). The HAPO-FUS demonstrated 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
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 glucose 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 glucose 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 adiposity 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).
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776
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
Table 6. Maternal and neonatal complications of gestational diabetes mellitus
Complications
Maternal
Neonatal
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
Stillbirth
Neonatal death
Preterm birth
Congenital malformations
Macrosomia
Cardiomyopathy
Birth trauma:
Shoulder dystocia
Bone fracture
Brachial plexus injury
Hypoglycemia
Hyperbilirubinemia
Respiratory distress syndrome
Long term
Recurrence of GDM
Type 2 diabetes mellitus
Hypertension
Ischemic heart disease
Nonalcoholic fatty liver disease
Dyslipidemia
Chronic kidney disease
Metabolic syndrome
Hyperinsulinemia
Childhood obesity
Excess abdominal adiposity
Higher blood pressure
Possible earlier onset cardiovascular disease
Possible attention-deficit hyperactivity
disorder
Autism spectrum disorder
Sources: Scholtens et al (227) and Saravanan (228).
Abbreviation: GDM, gestational diabetes mellitus.
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Contemporary changes to the detection and management of
GDM have been associated with almost comparable neonatal
birthweight and adiposity outcomes to the background maternity population in developed countries (115).
The ACHOIS trial (n = 1000) was the first large RCT
to evaluate whether treatment of women with GDM reduced the risk of perinatal complications (28). GDM
was diagnosed based on a combination of fasting glucose < 7.8 mmol/L (140 mg/dL) and 2-hour postload glucose 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 (6399 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 reduced incidence of macrosomia (10% vs 21%; P < 0.001),
preeclampsia (12% vs 18%; P = 0.02), and improved maternal 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
(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 postprandial glucose target < 6.7 mmol/L (121 mg/dL) was associated with reduced rates of macrosomia (5.9% vs 14.3%;
P < 0.001), LGA (7.1% vs 14.5%; P < 0.001), shoulder dystocia (1.5% vs 4.0%; P = 0.02), cesarean section (26.9% vs
33.8%; P = 0.02), and preeclampsia and gestational hypertension (8.6% vs 13.6%; P = 0.01) compared to routine care.
However, the intervention did not lead to a significant difference in the primary composite outcome of stillbirth, perinatal 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 intensive care admission.
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Gestational Weight Gain
The main objective of GDM management is to attain maternal normoglycemia because evidence suggests that excessive fetal growth can be attenuated by maintaining near
normal glucose levels (286,287). The foundation of this approach is medical nutrition therapy. Given carbohydrates
are the primary determinant of maternal postprandial glucose levels, current dietary practice aims to modify carbohydrate 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 requirements, 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 recommend a carbohydrate intake of at least 175 g/day and a total
daily caloric intake of 2000 to 2500 kilocalories during pregnancy (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 carbohydrate 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 incidence 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 include 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 glucose 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 maternal BMI were not reported (304).
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 suggested 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
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 recommendations 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 suggests 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 correlates 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 titrating insulin therapy based on the 1-hour postprandial
values was associated with improved maternal glycemic control and may better attenuate the risk of neonatal complications 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 adequately 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 glucose ≤ 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
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Lifestyle Intervention
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778
Maternal insulin resistance
Maternal circulating glucose and free fatty acids
Placental transfer of glucose and free fatty acids to fetus
Fetal circulating insulin and IGF-1 levels
Lung surfactant synthesis & function
Neonatal hypoglycemia
Fetal substrate uptake
Macrosomia
Shoulder dystocia
Hypoxia
Respiratory distress syndrome
Brachial plexus injury
Stillbirth
Cardiomyopathy
Polycythemia
Hyperbilirubinemia
Figure 2. Perinatal consequences of gestational diabetes mellitus.
nutrition therapy (267). Depending on targets, approximately 50% of women with GDM are prescribed insulin
therapy to maintain normoglycemia (321,322), with a combination of evening intermediate-acting insulin if fasting
glucose levels are elevated and mealtime rapid-acting insulin
when indicated. Additional daytime intermediate-acting insulin 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 sensitivity observed at this stage of pregnancy (176,323). However,
substantial insulin dose reduction, recurrent maternal hypoglycemia, and/or slowing of fetal growth or preeclampsia may
indicate underlying pathophysiological placental insufficiency
(324), impacting the timing of delivery and intensity of obstetric 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 ethnicity (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 attributable risk for insulin therapy (321). A recent Australian
study found that maternal age > 30 years, family history of
diabetes, prepregnancy obesity, previous GDM, early diagnosis of GDM, fasting glucose ≥ 5.3 mmol/L (96 mg/dL) and
HbA1c ≥ 5.5% (37 mmol/mol) at diagnosis were all independent 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 improved cost effectiveness, compliance, and acceptability compared to insulin therapy (327). However, there are issues
regarding efficacy and safety, particularly longer term, and
thus insulin is generally preferred as first-line pharmacotherapy 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 insulin 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, reported that glyburide was associated with an increased risk of
neonatal complications including neonatal intensive care admission, respiratory distress syndrome, hypoglycemia, birth
injury, and LGA compared to insulin therapy (331). Although
transplacental transfer of glyburide to the fetus is highly variable, it can reach 50% to 70% of maternal plasma concentration (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 potential 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 neonates 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 outcomes 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,
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Iatrogenic preterm delivery
Endocrine Reviews, 2022, Vol. 43, No. 5
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 medical 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 ultrasound were 10-fold more likely to be LGA compared to neonates 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 gestational age-specific maternal mortality or morbidity (defined
as ≥1 of the following in the immediate perinatal period: obstetric embolism, obstetric shock, postpartum hemorrhage
with hysterectomy or other procedures to control bleeding,
sepsis, thromboembolism, or uterine rupture) between iatrogenic 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 deliveries, 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).
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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 neonatal outcome of neonatal hypoglycemia, respiratory distress 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 hypoglycemia 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 between 14.0% and 55.8% of women treated with metformin
also require insulin therapy to achieve optimal glycemic control (338,339). The Metformin in Gestational Diabetes: The
Offspring Follow-Up 2-year follow-up study found that children 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 biochemistry including fasting glucose, insulin, and lipids but
were larger overall based on measures including weight, arm
and waist circumference, waist-to-height ratio, and dualenergy 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 maternal 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 hypoglycemia, and increased GWG (344). More recently, a small RCT
(n = 104) suggested that glyburide and metformin were comparable 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, suggesting 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
779
780
Longer Term Management of Women
Following GDM
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 suggest 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 adiposity, 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 demonstrated 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 potentially mediated by excess infant adiposity, which correlates
with childhood adiposity (383). Table 8 presents practical tips
for managing women with GDM.
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
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 phenotype (170,385-388) to identify and translate subclassification
of GDM into more personalized clinical care (388). For example, 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 response 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 insulin 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 complications (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 glucose 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 subtypes, 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 resultant 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 traditional binary clinical risk factor approach to identifying
women at high risk in early pregnancy is limited by poor sensitivity and specificity, with studies showing that clinical risk
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Up to one third of women with GDM diagnosed by preIADPSG criteria will have glucose levels consistent with diabetes 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 maternal 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 subsequent GDM by 74% (359). Longer term, women should
perform regular cardiometabolic health assessment and optimization 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 develop 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 diagnosis (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 component of the contemporary GDM detection and management
paradigm (276).
Endocrine Reviews, 2022, Vol. 43, No. 5
Endocrine Reviews, 2022, Vol. 43, No. 5
781
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 because of decreased clinical capacity. Several temporary
pragmatic diagnostic strategies have been suggested as an
alternative to the OGTT, including measurement of fasting
plasma glucose, random plasma glucose, and HbA1c (417419). 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
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 important 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 approach to GDM.
Recent data indicates near normal birthweight and maternity 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 countries where perinatal risks are far greater and universal 1-step
testing may be more practical. There are limited RCT data to
Table 7. Recommended glycemic treatment targets in GDM
Fasting plasma
glucose (mmol/L)
Preprandial plasma
glucose (mmol/L)
1-hour post-prandial
plasma glucose (mmol/L)
2-h post-prandial plasma
glucose (mmol/L)
ADIPS (33)
≤5.0
≤7.4
≤6.7
ADA (41)
CDA (42)
≤5.3
≤7.8
≤6.7
NICE (38)
<5.3
<7.8
<6.4
ACHOIS (37)
MFMU (38)
3.5-5.5
<5.3
≤5.5
≤7.0
<6.7
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.
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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 research setting (154-156,399-403).
Biomarkers are defined as a biological observation that substitutes 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 application (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 (153,154,399,402,403,408416). Limitations to the clinical application of novel biomarkers and model performance include heterogeneity in the
testing approach to GDM and cohort characteristics, potential 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).
Endocrine Reviews, 2022, Vol. 43, No. 5
782
Table 8. Practical tips for managing women with GDM
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
pregnancy
All pregnant women should be encouraged to have a nutritionally dense diet and undertake regular exercise during 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.
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 pertain 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 separates 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 further by variation in glucose measurement due to preanalytical
glucose processing and reproducibility issues. Thus, current
diagnostic glucose thresholds for GDM must inevitably reflect compromise and consensus.
A precision medicine approach that recognizes GDM subtype 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 improve risk stratification, optimize clinical models of care, and
facilitate more individualized and consumer-friendly detection and treatment strategies.
The recent HAPO-FUS data confirming the long-term impact 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 measurement within a framework that includes timing of detection
and treatment trials with long-term clinical and health economic outcomes. For example, if the ongoing Treatment of
Booking Gestational Diabetes Mellitus trial demonstrates a
benefit for early GDM detection and treatment, there are implications for the prevailing diagnostic GDM glucose thresholds in later pregnancy. This is because these thresholds were
derived from the risk of perinatal complications in a heterogeneous 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 stillbirth 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 management 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 apparent 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 prevention strategies to decrease the progression from GDM to
type 2 diabetes and address longer term maternal and offspring cardiometabolic risk post-GDM via a life course management 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.
References
1. Bennewitz H. De Diabete Mellito, Gravidatatis Symptomate. MD
thesis, University of Berlin; 1824.
2. Barker DJP. Mothers Babies and Diseases in Later Life. BMJ; 1994.
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
Period
Endocrine Reviews, 2022, Vol. 43, No. 5
26. American Diabetes Association. Gestational diabetes mellitus.
Diabetes Care. 2003;26(suppl 1):S103-S105.
27. Metzger BE, Lowe LP, Dyer AR, et al; HAPO Study Cooperative
Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J
Med. 2008;358(19):1991-2002.
28. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med.
2005;352(24):2477-2486.
29. Landon MB, Spong CY, Thom E, et al. A multicenter, randomized
trial of treatment for mild gestational diabetes. N Engl J Med.
2009;361(14):1339-1348.
30. Metzger BE, Gabbe SG, Persson B, et al; International Association
of Diabetes and Pregnancy Study Groups Consensus Panel.
International Association of Diabetes and Pregnancy Study Groups
recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-682.
31. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy:
an Endocrine Society clinical practice guideline. J Clin Endocrinol
Metab. 2013;98(11):4227-4249.
32. Hod M, Kapur A, Sacks DA, et al. The International Federation of
Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: a pragmatic guide for diagnosis, management, and
care. Int J Gynaecol Obstet. 2015;131(suppl 3):S173-S211.
33. Nankervis A, McIntyre HD, Moses R, et al. ADIPS Consensus
Guidelines for the Testing and Diagnosis of Hyperglycaemia in
Pregnancy in Australia and New Zealand. Modified November 2014.
http://adips.org/downloads/2014ADIPSGDMGuidelinesV18.11.
2014_000.pdf. Accessed June 1, 2021.
34. Japan Diabetes Society. Evidence-based practice guideline for the
treatment for diabetes in Japan 2013. Last updated November 26,
2020. http://www.jds.or.jp/modules/en/index.php?content_id=44.
Accessed June 1, 2021.
35. Yang HX. Diagnostic criteria for gestational diabetes mellitus.
Chin Med J. 2012;125(7):1212-1213.
36. Benhalima K, Mathieu C, Damm P, et al. A proposal for the use of
uniform diagnostic criteria for gestational diabetes in Europe: an
opinion paper by the European Board & College of Obstetrics and
Gynaecology (EBCOG). Diabetologia. 2015;58(7):1422-1429.
37. Vandorsten JP, Dodson WC, Espeland MA, et al. NIH consensus
development conference: diagnosing gestational diabetes mellitus.
NIH Consens State Sci Statements. 2013;29(1):1-31.
38. National Institute for Health and Care Excellence. Diabetes in Pregnancy:
Management of Diabetes and its Complications from Pre-conception to
the Postnatal Period. NICE Clinical Guideline NG3. 2015.
39. Vambergue A. Expert consensus on gestational diabetes mellitus.
Diabetes Metab. 2010;36(6 Pt 2):511.
40. Associazione Medici Diabetologi and Società Italiana di
Diabetologia. Italian National Health System Guidelines for
the screening of gestational diabetes mellitus. May 28, 2014.
http://www.standarditaliani.it/skin/www.standarditaliani.it/pdf/
STANDARD_2014_May28.pdf. Accessed June 1, 2021.
41. American Diabetes Association. 14. Management of diabetes in
pregnancy: standards of medical care in diabetes-2020. Diabetes
Care. 2020;43(suppl 1):S183-SS92.
42. Canadian Diabetes Association Clinical Practice Guidelines
Expert Committee. Clinical practice guidelines for the prevention
and management of diabetes in Canada. Canadian J Diabetes.
2013;37(suppl 1):S1-S3.
43. Kleinwechter H, Schafer-Graf U, Buhrer C, et al. Gestational diabetes mellitus (GDM) diagnosis, therapy and follow-up care: practice Guideline of the German Diabetes Association (DDG) and the
German Association for Gynaecology and Obstetrics (DGGG).
Exp Clin Endocrinol Diabetes. 2014;122(7):395-405.
44. Seshiah V, Das AK, Balaji V, et al. Gestational diabetes mellitus—
guidelines. J Assoc Physicians India. 2006;54:622-628.
45. World Health Organization. Definition, Diagnosis and
Classification of Diabetes Mellitus and its Complications. Report
of WHO Consultation. 1999.
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
3. Duncan J. On puerperal diabetes. Trans Obstet Soc Lond.
1882;24:256-285.
4. Miller HC. The effect of diabetic and prediabetic pregnancies on
the fetus and newborn infant. J Pediatr. 1946;29(4):455-461.
5. Williams J. The clinical significance of glycosuria in pregnant
women. Am J Med Sci. 1909;137:1-26.
6. O’Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance
test in pregnancy. Diabetes. 1964;13:278-285.
7. Coustan DR. Gestational diabetes. In: Harris MI, Cowie CC,
Stern MP, Boyko EJ, Reiber GE, Bennett PH, eds. Diabetes in
America. National Institute of Health; 1995:703-717.
8. World Health Organization. Technical Report Series. No 310.
Diabetes Mellitus. Report of a WHO Expert Committee. 1965.
9. World Health Organization. Technical Report Series. No 646.
Second Report on Diabetes Mellitus. Report of a WHO Expert
Committee. 1980.
10. World Health Organization. Technical Report Series. No 727.
Second Report on Diabetes Mellitus. Report of a WHO Expert
Committee. 1985.
11. World Health Organisation. Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy: a World
Health Organization guideline. Diabetes Res Clin Pract.
2014;103(3):341-363.
12. O’Sullivan JB, Mahan CM, Charles D, Dandrow RV. Screening
criteria for high-risk gestational diabetic patients. Am J Obstet
Gynecol. 1973;116(7):895-900.
13. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes.
1979;28(12):1039-1057.
14. American College of Obstetricians and Gynecologists. Management
of Diabetes Mellitus During Pregnancy. Technical Bulletin No. 92.
1986.
15. American Diabetes Association. Gestational diabetes mellitus.
Diabetes Care. 1986;9(4):430-431.
16. Ferrara A, Hedderson MM, Quesenberry CP, Selby JV. Prevalence
of gestational diabetes mellitus detected by the National Diabetes
Data Group or the Carpenter and Coustan plasma glucose
thresholds. Diabetes Care. 2002;25(9):1625-1630.
17. Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol. 1982;144(7):768-773.
18. American Diabetes Association. 2. Classification and diagnosis
of diabetes: standards of medical care in diabetes-2018. Diabetes
Care. 2018;41(suppl 1):S13-S27.
19. American College of Obstetricians and Gynecologists. Practice
Bulletin No. 190: gestational diabetes mellitus. Obstet Gynecol.
2018;131(2):e49-e64.
20. American Diabetes Association. Gestational diabetes mellitus.
Diabetes Care. 2000;23(suppl 1):S77-S79.
21. Sermer M, Naylor CD, Farine D, et al. The Toronto tri-hospital
gestational diabetes project: a preliminary review. Diabetes Care.
1998;21(Suppl 2):B33-B42.
22. Sermer M, Naylor CD, Gare DJ, et al. Impact of increasing
carbohydrate intolerance on maternal-fetal outcomes in
3637 women without gestational diabetes: the Toronto TriHospital Gestational Diabetes Project. Am J Obstet Gynecol.
1995;173(1):146-156.
23. Berggren EK, Boggess KA, Stuebe AM, Jonsson Funk M. National
Diabetes Data Group vs Carpenter-Coustan criteria to diagnose
gestational diabetes. Am J Obstet Gynecol. 2011;205(3):253
e1-253.e7.
24. Cheng YW, Block-Kurbisch I, Caughey AB. Carpenter-Coustan
criteria compared with the National Diabetes Data Group
thresholds for gestational diabetes mellitus. Obstet Gynecol.
2009;114(2 Pt 1):326-332.
25. Chou CY, Lin CL, Yang CK, et al. Pregnancy outcomes of
Taiwanese women with gestational diabetes mellitus: a comparison
of Carpenter-Coustan and National Diabetes Data Group criteria.
J Womens Health (Larchmt). 2010;19(5):935-939.
783
784
64. Hillier TA, Pedula KL, Ogasawara KK, et al. A pragmatic,
randomized clinical trial of gestational diabetes screening. N Engl J
Med. 2021;384(10):895-904.
65. Casey B. Gestational diabetes—on broadening the diagnosis. N
Engl J Med. 2021;384(10):965-966.
66. Dunne F, Lindsay R, Loeken M. This is the decade to find the solution for gestational diabetes mellitus screening and treatments.
Diabet Med. 2021;38(8):e14602.
67. O’Malley EG, Reynolds CME, O’Kelly R, et al. The diagnosis of
gestational diabetes mellitus (GDM) using a 75 g oral glucose tolerance test: a prospective observational study. Diabetes Res Clin
Pract. 2020;163:108144.
68. van Leeuwen M, Louwerse MD, Opmeer BC, et al. Glucose challenge test for detecting gestational diabetes mellitus: a systematic
review. BJOG. 2012;119(4):393-401.
69. Sacks DA, Hadden DR, Maresh M, et al. Frequency of gestational diabetes mellitus at collaborating centers based on IADPSG
consensus panel-recommended criteria: the Hyperglycemia and
Adverse Pregnancy Outcome (HAPO) study. Diabetes Care.
2012;35(3):526-528.
70. Roeckner JT, Sanchez-Ramos L, Jijon-Knupp R, et al. Single abnormal value on 3-hour oral glucose tolerance test during pregnancy is associated with adverse maternal and neonatal outcomes:
a systematic review and metaanalysis. Am J Obstet Gynecol.
2016;215(3):287-297.
71. Freinkel N, Metzger BE, Phelps RL, et al. Gestational diabetes mellitus: heterogeneity of maternal age, weight, insulin secretion, HLA
antigens, and islet cell antibodies and the impact of maternal metabolism on pancreatic B-cell and somatic development in the offspring. Diabetes. 1985;34(suppl 2):1-7.
72. Schaefer UM, Songster G, Xiang A, et al. Congenital malformations
in offspring of women with hyperglycemia first detected during
pregnancy. Am J Obstet Gynecol. 1997;177(5):1165-1171.
73. Omori Y, Jovanovic L. Proposal for the reconsideration
of the definition of gestational diabetes. Diabetes Care.
2005;28(10):2592-2593.
74. Stacey T, Tennant P, McCowan L, et al. Gestational diabetes and
the risk of late stillbirth: a case-control study from England, UK.
BJOG. 2019;126(8):973-982.
75. Cosson E, Bentounes SA, Nachtergaele C, et al. Prognosis associated with sub-types of hyperglycaemia in pregnancy. J Clin Med.
2021;10(17):3904.
76. Wong T, Ross GP, Jalaludin BB, Flack JR. The clinical significance of overt diabetes in pregnancy. Diabet Med.
2013;30(4):468-474.
77. Bartha JL, Martinez-Del-Fresno P, Comino-Delgado R. Early diagnosis of gestational diabetes mellitus and prevention of diabetesrelated complications. Eur J Obstet Gynecol Reprod Biol.
2003;109(1):41-44.
78. Bartha JL, Martinez-Del-Fresno P, Comino-Delgado R. Gestational
diabetes mellitus diagnosed during early pregnancy. Am J Obstet
Gynecol. 2000;182(2):346-350.
79. Berkowitz GS, Roman SH, Lapinski RH, et al. Maternal characteristics, neonatal outcome, and the time of diagnosis of gestational
diabetes. Am J Obstet Gynecol. 1992;167(4 Pt 1):976-8282.
80. Meyer WJ, Carbone J, Gauthier DW, et al. Early gestational
glucose screening and gestational diabetes. J Reprod Med.
1996;41(9):675-679.
81. Sweeting AN, Ross GP, Hyett J, et al. Gestational diabetes mellitus
in early pregnancy: evidence for poor pregnancy outcomes despite
treatment. Diabetes Care. 2016;39(1):75-81.
82. Li M, Hinkle SN, Grantz KL, et al. Glycaemic status during
pregnancy and longitudinal measures of fetal growth in a multiracial US population: a prospective cohort study. Lancet Diabetes
Endocrinol. 2020;8(4):292-300.
83. Sovio U, Murphy HR, Smith GC. Accelerated fetal growth
prior to diagnosis of gestational diabetes mellitus: a prospective cohort study of nulliparous women. Diabetes Care.
2016;39(6):982-987.
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
46. Coustan DR, Lowe LP, Metzger BE, et al; on behalf of the
International Association of Diabetes in Pregnancy Study Groups.
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO)
study: paving the way for new diagnostic criteria for gestational
diabetes mellitus. Am J Obstet Gynecol. 2010;202(6):654 e1-654
e6.
47. McIntyre HD, Oats JJ, Kihara AB, et al. Update on diagnosis of
hyperglycemia in pregnancy and gestational diabetes mellitus from
FIGO’s Pregnancy & Non-Communicable Diseases Committee. Int
J Gynaecol Obstet. 2021;154(2):189-194.
48. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and
trends in diabetes among adults in the United States, 1988-2012.
JAMA. 2015;314(10):1021-1029.
49. Centers for Disease Control and Prevention. National Diabetes
Statistics Report, 2020. US Department of Health and Human
Services; 2020.
50. Lieberman N, Kalter-Leibovici O, Hod M. Global adaptation of
IADPSG recommendations: a national approach. Int J Gynaecol
Obstet. 2011;115(suppl 1):S45-S47.
51. Marseille E, Lohse N, Jiwani A, et al. The cost-effectiveness of gestational diabetes screening including prevention of type 2 diabetes:
application of a new model in India and Israel. J Matern Fetal
Neonatal Med. 2013;26(8):802-810.
52. Werner EF, Pettker CM, Zuckerwise L, et al. Screening for gestational diabetes mellitus: are the criteria proposed by the
International Association of the Diabetes and Pregnancy Study
Groups cost-effective? Diabetes Care. 2012;35(3):529-535.
53. Mission JF, Ohno MS, Cheng YW, Caughey AB. Gestational diabetes screening with the new IADPSG guidelines: a cost-effectiveness analysis. Am J Obstet Gynecol. 2012;207(4):326 e1-326 e9.
54. Farrar D, Simmonds M, Griffin S, et al. The identification and
treatment of women with hyperglycaemia in pregnancy: an analysis of individual participant data, systematic reviews, metaanalyses and an economic evaluation. Health Technol Assess.
2016;20(86):1-348.
55. Jacklin PB, Maresh MJ, Patterson CC, et al. A cost-effectiveness
comparison of the NICE 2015 and WHO 2013 diagnostic criteria
for women with gestational diabetes with and without risk factors.
BMJ Open. 2017;7(8):e016621.
56. Cundy T, Ackermann E, Ryan EA. Gestational diabetes: new
criteria may triple the prevalence but effect on outcomes is unclear.
BMJ. 2014;348:g1567.
57. O’Sullivan EP, Avalos G, O’Reilly M, et al. Atlantic Diabetes in
Pregnancy (DIP): the prevalence and outcomes of gestational
diabetes mellitus using new diagnostic criteria. Diabetologia.
2011;54(7):1670-1675.
58. Lapolla A, Dalfra MG, Ragazzi E, et al. New International
Association of the Diabetes and Pregnancy Study Groups (IADPSG)
recommendations for diagnosing gestational diabetes compared
with former criteria: a retrospective study on pregnancy outcome.
Diabet Med. 2011;28(9):1074-1077.
59. Benhalima K, Hanssens M, Devlieger R, et al. Analysis of pregnancy
outcomes using the new IADPSG recommendation compared with
the Carpenter and Coustan criteria in an area with a low prevalence of gestational diabetes. Int J Endocrinol. 2013;2013:248121.
60. Hung TH, Hsieh TT. The effects of implementing the International
Association of Diabetes and Pregnancy Study Groups criteria
for diagnosing gestational diabetes on maternal and neonatal
outcomes. PLoS One. 2015;10(3):e0122261.
61. Meek CL, Lewis HB, Patient C, et al. Diagnosis of gestational diabetes mellitus: falling through the net. Diabetologia.
2015;58(9):2003-2012.
62. Djelmis J, Pavic M, Mulliqi Kotori V, et al. Prevalence of gestational
diabetes mellitus according to IADPSG and NICE criteria. Int J
Gynaecol Obstet. 2016;135(3):250-254.
63. Ethridge JK Jr, Catalano PM, Waters TP. Perinatal outcomes associated with the diagnosis of gestational diabetes made by the international association of the diabetes and pregnancy study groups
criteria. Obstet Gynecol. 2014;124(3):571-578.
Endocrine Reviews, 2022, Vol. 43, No. 5
Endocrine Reviews, 2022, Vol. 43, No. 5
104. Harper LM, Jauk V, Longo S, et al. Early gestational diabetes
screening in obese women: a randomized controlled trial. Am J
Obstet Gynecol. 2020;222(5):495 e1-495 e8.
105. Vinter CA, Tanvig MH, Christensen MH, et al. Lifestyle intervention in Danish obese pregnant women with early gestational diabetes mellitus according to WHO 2013 criteria does not change
pregnancy outcomes: results from the LiP (Lifestyle in Pregnancy)
study. Diabetes Care. 2018;41(10):2079-2085.
106. Simmons D, Hague WM, Teede HJ, et al. Hyperglycaemia in
early pregnancy: the Treatment of Booking Gestational Diabetes
Mellitus (TOBOGM) study: a randomised controlled trial. Med J
Aust. 2018;209(9):405-406.
107. Bruns DE, Metzger BE, Sacks DB. Diagnosis of gestational diabetes mellitus will be flawed until we can measure glucose. Clin
Chem. 2020;66(2):265-267.
108. Bogdanet D, O’Shea P, Lyons C, et al. The oral glucose tolerance
test-is it time for a change?-a literature review with an emphasis
on pregnancy. J Clin Med. 2020;9(11):3451.
109. Sacks DB, Arnold M, Bakris GL, et al. Position statement executive summary: guidelines and recommendations for laboratory
analysis in the diagnosis and management of diabetes mellitus.
Diabetes Care. 2011;34(6):1419-1423.
110. Chan AY, Swaminathan R, Cockram CS. Effectiveness of sodium fluoride as a preservative of glucose in blood. Clin Chem.
1989;35(2):315-317.
111. Potter JM, Hickman PE, Oakman C, et al. Strict preanalytical
oral glucose tolerance test blood sample handling is essential for diagnosing gestational diabetes mellitus. Diabetes Care.
2020;43(7):1438-1441.
112. Daly N, Flynn I, Carroll C, et al. Impact of implementing
preanalytical laboratory standards on the diagnosis of gestational
diabetes mellitus: a prospective observational study. Clin Chem.
2016;62(2):387-391.
113. International Diabetes Federation. IDF Diabetes Atlas. 9th ed.
2019.
114. Guariguata L, Linnenkamp U, Beagley J, et al. Global estimates of
the prevalence of hyperglycaemia in pregnancy. Diabetes Res Clin
Pract. 2014;103(2):176-185.
115. Prentice PM, Olga L, Petry CJ, et al. Reduced size at birth and
persisting reductions in adiposity in recent, compared with earlier,
cohorts of infants born to mothers with gestational diabetes mellitus. Diabetologia. 2019;62(11):1977-1987.
116. Hartling L, Dryden DM. Screening and diagnosing gestational diabetes mellitus. Evid Rep Technol Assess (Full Rep).
2012;210:1-327.
117. Bottalico JN. Recurrent gestational diabetes: risk factors, diagnosis, management, and implications. Semin Perinatol.
2007;31(3):176-184.
118. Anna V, van der Ploeg H, P, Cheung NW, et al. Sociodemographic
correlates of the increasing trend in prevalence of gestational diabetes mellitus in a large population of women between 1995 and
2005. Diabetes Care. 2008;31(12):2288-2293.
119. Chu SY, Callaghan WM, Kim SY, et al. Maternal obesity and risk of gestational diabetes mellitus. Diabetes Care.
2007;30(8):2070-2076.
120. Torloni MR, Betran AP, Horta BL, et al. Prepregnancy BMI and
the risk of gestational diabetes: a systematic review of the literature with meta-analysis. Obes Rev. 2009;10(2):194-203.
121. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity,
diabetes, and obesity-related health risk factors, 2001. JAMA.
2003;289(1):76-79.
122. Mulla WR, Henry TQ, Homko CJ. Gestational diabetes
screening after HAPO: has anything changed? Curr Diab Rep.
2010;10(3):224-228.
123. Petry CJ. Gestational diabetes: risk factors and recent advances in
its genetics and treatment. Br J Nutr. 2010;104(6):775-787.
124. Hunt KJ, Schuller KL. The increasing prevalence of diabetes in
pregnancy. Obstet Gynecol Clin North Am. 2007;34(2):173-199,
vii.
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
84. Venkataraman H, Ram U, Craik S, et al. Increased fetal adiposity
prior to diagnosis of gestational diabetes in South Asians: more evidence for the “thin-fat” baby. Diabetologia. 2017;60(3):399-405.
85. Riskin-Mashiah S, Damti A, Younes G, et al. Normal fasting
plasma glucose levels during pregnancy: a hospital-based study. J
Perinat Med. 2011;39(2):209-211.
86. Mills JL, Jovanovic L, Knopp R, et al. Physiological reduction
in fasting plasma glucose concentration in the first trimester
of normal pregnancy: the diabetes in early pregnancy study.
Metabolism. 1998;47(9):1140-1144.
87. Corrado F, D’Anna R, Cannata ML, et al. Correspondence between first-trimester fasting glycaemia, and oral glucose tolerance test in gestational diabetes diagnosis. Diabetes Metab.
2012;38(5):458-61.
88. Zhu WW, Yang HX, Wei YM, et al. Evaluation of the value
of fasting plasma glucose in the first prenatal visit to diagnose gestational diabetes mellitus in china. Diabetes Care.
2013;36(3):586-590.
89. McIntyre HD, Sacks DA, Barbour LA, et al. Issues with the diagnosis and classification of hyperglycemia in early pregnancy.
Diabetes Care. 2016;39(1):53-54.
90. Hughes RC, Moore MP, Gullam JE, et al. An early pregnancy
HbA1c ≤5.9% (41 mmol/mol) is optimal for detecting diabetes
and identifies women at increased risk of adverse pregnancy
outcomes. Diabetes Care. 2014;37(11):2953-2959.
91. Sweeting AN, Ross GP, Hyett J, et al. Baseline HbA1c to identify
high-risk gestational diabetes: utility in early vs standard gestational diabetes. J Clin Endocrinol Metab. 2017;102(1):150-156.
92. Immanuel J, Simmons D, Desoye G, et al. Performance of early
pregnancy HbA1c for predicting gestational diabetes mellitus and
adverse pregnancy outcomes in obese European women. Diabetes
Res Clin Pract. 2020;168:108378.
93. Osmundson SS, Norton ME, El-Sayed YY, et al. Early screening
and treatment of women with prediabetes: a randomized
controlled trial. Am J Perinatol. 2016;33(2):172-179.
94. Roeder HA, Moore TR, Wolfson T, Ramos GA. Treating hyperglycemia in the first trimester: a randomized controlled trial. Am
J Obstet Gynecol MFM. 2017;1(1):33-41.
95. Hawkins JS, Lo JY, Casey BM, et al. Diet-treated gestational diabetes mellitus: comparison of early vs routine diagnosis. Am J
Obstet Gynecol. 2008;198(3):287 e1-287 e6.
96. Most OL, Kim JH, Arslan AA, et al. Maternal and neonatal
outcomes in early glucose tolerance testing in an obstetric population in New York city. J Perinat Med. 2009;37(2):114-117.
97. Gupta S, Dolin C, Jadhav A, et al. Obstetrical outcomes in patients
with early onset gestational diabetes. J Matern Fetal Neonatal
Med. 2016;29(1):27-31.
98. Harreiter J, Simmons D, Desoye G, et al. IADPSG and WHO
2013 gestational diabetes mellitus criteria identify obese women
with marked insulin resistance in early pregnancy. Diabetes Care.
2016;39(7):e90-e92.
99. Egan AM, Vellinga A, Harreiter J, et al. Epidemiology of gestational diabetes mellitus according to IADPSG/WHO 2013
criteria among obese pregnant women in Europe. Diabetologia.
2017;60(10):1913-1921.
100. Immanuel J, Simmons D. Screening and treatment for early-onset
gestational diabetes mellitus: a systematic review and metaanalysis. Curr Diab Rep. 2017;17(11):115.
101. Bozkurt L, Gobl CS, Pfligl L, et al. Pathophysiological characteristics and effects of obesity in women with early and late manifestation of gestational diabetes diagnosed by the International
Association of Diabetes and Pregnancy Study Groups criteria. J
Clin Endocrinol Metab. 2015;100(3):1113-1120.
102. Bozkurt L, Gobl CS, Hormayer AT, et al. The impact of
preconceptional obesity on trajectories of maternal lipids during
gestation. Sci Rep. 2016;6:29971.
103. Sweeting AN, Ross GP, Hyett J, et al. Gestational diabetes in
the first trimester: is early testing justified? Lancet Diabetes
Endocrinol. 2017;5(8):571-573.
785
786
147. Chasan-Taber L, Schmidt MD, Pekow P, et al. Physical activity
and gestational diabetes mellitus among Hispanic women. J
Womens Health (Larchmt). 2008;17(6):999-1008.
148. Mottola MF. The role of exercise in the prevention and
treatment of gestational diabetes mellitus. Curr Diab Rep.
2008;8(4):299-304.
149. Zhang C, Liu S, Solomon CG, et al. Dietary fiber intake, dietary glycemic load, and the risk for gestational diabetes mellitus.
Diabetes Care. 2006;29(10):2223-2230.
150. Kucukgoncu S, Guloksuz S, Celik K, et al. Antipsychotic exposure
in pregnancy and the risk of gestational diabetes: a systematic review and meta-analysis. Schizophr Bull. 2020;46(2):311-318.
151. Galbally M, Frayne J, Watson SJ, et al. The association between
gestational diabetes mellitus, antipsychotics and severe mental
illness in pregnancy: a multicentre study. Aust N Z J Obstet
Gynaecol. 2020;60(1):63-69.
152. Hedderson MM, Ferrara A. High blood pressure before and during
early pregnancy is associated with an increased risk of gestational
diabetes mellitus. Diabetes Care. 2008;31(12):2362-2367.
153. Lao TT, Ho LF. First-trimester blood pressure and gestational
diabetes in high-risk Chinese women. J Soc Gynecol Investig.
2003;10(2):94-98.
154. Sweeting AN, Appelblom H, Ross GP, et al. First trimester prediction of gestational diabetes mellitus: a clinical model based
on maternal demographic parameters. Diabetes Res Clin Pract.
2017;127:44-50.
155. Syngelaki A, Visser GH, Krithinakis K, et al. First trimester
screening for gestational diabetes mellitus by maternal factors and
markers of inflammation. Metabolism. 2016;65(3):131-137.
156. Nanda S, Savvidou M, Syngelaki A, et al. Prediction of gestational
diabetes mellitus by maternal factors and biomarkers at 11 to 13
weeks. Prenat Diagn. 2011;31(2):135-141.
157. van Leeuwen M, Opmeer BC, Zweers EJ, et al. Estimating the
risk of gestational diabetes mellitus: a clinical prediction model
based on patient characteristics and medical history. BJOG.
2010;117(1):69-75.
158. Naylor CD, Sermer M, Chen E, et al; Toronto Trihospital Gestational
Diabetes Project Investigators. Selective screening for gestational
diabetes mellitus. N Engl J Med. 1997;337(22):1591-1596.
159. Catalano PM. Trying to understand gestational diabetes. Diabet
Med. 2014;31(3):273-281.
160. Catalano PM. Carbohydrate metabolism and gestational diabetes.
Clin Obstet Gynecol. 1994;37(1):25-38.
161. Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin
Obstet Gynecol. 2007;50(4):938-948.
162. Costrini NV, Kalkhoff RK. Relative effects of pregnancy, estradiol, and progesterone on plasma insulin and pancreatic islet insulin secretion. J Clin Invest. 1971;50(5):992-999.
163. Kalkhoff RK, Kissebah AH, Kim HJ. Carbohydrate and lipid metabolism during normal pregnancy: relationship to gestational
hormone action. Semin Perinatol. 1978;2(4):291-307.
164. Leturque A, Hauguel S, Sutter Dub MT, et al. Effects of placental
lactogen and progesterone on insulin stimulated glucose metabolism in rat muscles in vitro. Diabete Metab. 1989;15(4):176-181.
165. Ryan EA, Enns L. Role of gestational hormones in the induction of
insulin resistance. J Clin Endocrinol Metab. 1988;67(2):341-347.
166. Alvarez JJ, Montelongo A, Iglesias A, Lasuncion MA, Herrera E.
Longitudinal study on lipoprotein profile, high density lipoprotein
subclass, and postheparin lipases during gestation in women. J
Lipid Res. 1996;37(2):299-308.
167. Barbour LA, McCurdy CE, Hernandez TL, Kirwan JP,
Catalano PM, Friedman JE. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes
Care. 2007;30(suppl 2):S112-S119.
168. Bomba-Opon D, Wielgos M, Szymanska M, et al. Effects of free
fatty acids on the course of gestational diabetes mellitus. Neuro
Endocrinol Lett. 2006;27(1-2):277-280.
169. Boden G, Chen X, Ruiz J, et al. Mechanisms of fatty
acid-induced inhibition of glucose uptake. J Clin Invest.
1994;93(6):2438-2446.
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
125. Agarwal MM, Dhatt GS, Shah SM. Gestational diabetes mellitus: simplifying the international association of diabetes and
pregnancy diagnostic algorithm using fasting plasma glucose.
Diabetes Care. 2010;33(9):2018-2020.
126. Moses RG, Morris GJ, Petocz P, et al. The impact of potential new
diagnostic criteria on the prevalence of gestational diabetes mellitus in Australia. Med J Aust. 2011;194(7):338-340.
127. Brown FM, Wyckoff J. Application of one-step IADPSG versus
two-step diagnostic criteria for gestational diabetes in the real
world: impact on health services, clinical care, and outcomes.
Curr Diab Rep. 2017;17(10):85.
128. Kim C, Berger DK, Chamany S. Recurrence of gestational diabetes mellitus: a systematic review. Diabetes Care.
2007;30(5):1314-1319.
129. Solomon CG, Willett WC, Carey VJ, et al. A prospective study of
pregravid determinants of gestational diabetes mellitus. JAMA.
1997;278(13):1078-1083.
130. Chamberlain C, McNamara B, Williams ED, et al. Diabetes in
pregnancy among indigenous women in Australia, Canada,
New Zealand and the United States. Diabetes Metab Res Rev.
2013;29(4):241-256.
131. Hedderson MM, Gunderson EP, Ferrara A. Gestational weight
gain and risk of gestational diabetes mellitus. Obstet Gynecol.
2010;115(3):597-604.
132. Kjos SL, Buchanan TA. Gestational diabetes mellitus. N Engl J
Med. 1999;341(23):1749-1756.
133. Di Cianni G, Volpe L, Lencioni C, et al. Prevalence and risk factors
for gestational diabetes assessed by universal screening. Diabetes
Res Clin Pract. 2003;62(2):131-137.
134. Cypryk K, Szymczak W, Czupryniak L, et al. Gestational diabetes mellitus—an analysis of risk factors. Endokrynol Pol.
2008;59(5):393-397.
135. Cleary-Goldman J, Malone FD, Vidaver J, et al. Impact of maternal age on obstetric outcome. Obstet Gynecol. 2005;105(5 Pt
1):983-990.
136. Yang H, Wei Y, Gao X, et al. Risk factors for gestational diabetes
mellitus in Chinese women: a prospective study of 16,286 pregnant women in China. Diabet Med. 2009;26(11):1099-1104.
137. Morisset AS, St-Yves A, Veillette J, et al. Prevention of gestational
diabetes mellitus: a review of studies on weight management.
Diabetes Metab Res Rev. 2010;26(1):17-25.
138. Weiss JL, Malone FD, Emig D, et al. Obesity, obstetric
complications and cesarean delivery rate—a population-based
screening study. Am J Obstet Gynecol. 2004;190(4):1091-1097.
139. Gibson KS, Waters TP, Catalano PM. Maternal weight gain
in women who develop gestational diabetes mellitus. Obstet
Gynecol. 2012;119(3):560-565.
140. Morisset AS, Tchernof A, Dube MC, et al. Weight gain measures
in women with gestational diabetes mellitus. J Womens Health
(Larchmt). 2011;20(3):375-380.
141. Tovar A, Must A, Bermudez OI, et al. The impact of gestational weight gain and diet on abnormal glucose tolerance
during pregnancy in Hispanic women. Matern Child Health J.
2009;13(4):520-530.
142. Teulings N, Masconi KL, Ozanne SE, et al. Effect of interpregnancy
weight change on perinatal outcomes: systematic review and
meta-analysis. BMC Pregnancy Childbirth. 2019;19(1):386.
143. Lo JC, Feigenbaum SL, Escobar GJ, et al. Increased prevalence of
gestational diabetes mellitus among women with diagnosed polycystic ovary syndrome: a population-based study. Diabetes Care.
2006;29(8):1915-1917.
144. Mikola M, Hiilesmaa V, Halttunen M, et al. Obstetric outcome
in women with polycystic ovarian syndrome. Hum Reprod.
2001;16(2):226-229.
145. Dinham GK, Henry A, Lowe SA, et al. Twin pregnancies complicated by gestational diabetes mellitus: a single centre cohort study.
Diabet Med. 2016;33(12):1659-1667.
146. Rauh-Hain JA, Rana S, Tamez H, et al. Risk for developing gestational diabetes in women with twin pregnancies. J Matern Fetal
Neonatal Med. 2009;22(4):293-299.
Endocrine Reviews, 2022, Vol. 43, No. 5
Endocrine Reviews, 2022, Vol. 43, No. 5
192. Dluski DF, Wolińska E, Skrzypczak M. Epigenetic changes in gestational diabetes mellitus. Int J Mol Sci. 2021;22(14):7649.
193. Elliott HR, Sharp GC, Relton CL, et al. Epigenetics and gestational diabetes: a review of epigenetic epidemiology studies and
their use to explore epigenetic mediation and improve prediction.
Diabetologia. 2019;62(12):2171-2178.
194. Hayes MG, Urbanek M, Hivert MF, et al. Identification of
HKDC1 and BACE2 as genes influencing glycemic traits during
pregnancy through genome-wide association studies. Diabetes.
2013;62(9):3282-3291.
195. Liu S, Liu Y, Liao S. Heterogeneous impact of type 2 diabetes mellitus-related genetic variants on gestational glycemic
traits: review and future research needs. Mol Genet Genomics.
2019;294(4):811-847.
196. Wu L, Cui L, Tam WH, et al. Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis.
Sci Rep. 2016;6:30539.
197. Chon SJ, Kim SY, Cho NR, et al. Association of variants in
PPARgamma(2), IGF2BP2, and KCNQ1 with a susceptibility to
gestational diabetes mellitus in a Korean population. Yonsei Med
J. 2013;54(2):352-357.
198. Kim JY, Cheong HS, Park BL, et al. Melatonin receptor 1 B
polymorphisms associated with the risk of gestational diabetes
mellitus. BMC Med Genet. 2011;12:82.
199. Klein K, Haslinger P, Bancher-Todesca D, et al. Transcription
factor 7-like 2 gene polymorphisms and gestational diabetes mellitus. J Matern Fetal Neonatal Med. 2012;25(9):1783-1786.
200. Alharbi KK, Khan IA, Abotalib Z, et al. Insulin receptor
substrate-1 (IRS-1) Gly927Arg: correlation with gestational diabetes mellitus in Saudi women. Biomed Res Int.
2014;2014:146495.
201. Tok EC, Ertunc D, Bilgin O, et al. PPAR-gamma2 Pro12Ala polymorphism is associated with weight gain in women with gestational diabetes mellitus. Eur J Obstet Gynecol Reprod Biol.
2006;129(1):25-30.
202. Montazeri S, Nalliah S, Radhakrishnan AK. Is there a genetic variation association in the IL-10 and TNF alpha promoter gene with
gestational diabetes mellitus? Hereditas. 2010;147(2):94-102.
203. Kwak SH, Kim SH, Cho YM, et al. A genome-wide association
study of gestational diabetes mellitus in Korean women. Diabetes.
2012;61(2):531-541.
204. Lyssenko V, Nagorny CL, Erdos MR, et al. Common variant in
MTNR1B associated with increased risk of type 2 diabetes and
impaired early insulin secretion. Nat Genet. 2009;41(1):82-88.
205. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000
shared controls. Nature. 2007;447(7145):661-678.
206. Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C, et al.
A variant near MTNR1B is associated with increased fasting
plasma glucose levels and type 2 diabetes risk. Nat Genet.
2009;41(1):89-94.
207. Saxena R, Elbers CC, Guo Y, et al. Large-scale gene-centric metaanalysis across 39 studies identifies type 2 diabetes loci. Am J
Hum Genet. 2012;90(3):410-425.
208. Manning AK, Hivert MF, Scott RA, et al. A genome-wide approach accounting for body mass index identifies genetic variants
influencing fasting glycemic traits and insulin resistance. Nat
Genet. 2012;44(6):659-669.
209. Sparso T, Andersen G, Nielsen T, et al. The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol,
reduced fasting and OGTT-related insulinaemia, and reduced risk
of type 2 diabetes. Diabetologia. 2008;51(1):70-75.
210. Vaxillaire M, Cavalcanti-Proenca C, Dechaume A, et al. The
common P446L polymorphism in GCKR inversely modulates
fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population.
Diabetes. 2008;57(8):2253-2257.
211. Agius L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J. 2008;414(1):1-18.
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
170. Catalano PM, Huston L, Amini SB, et al. Longitudinal changes
in glucose metabolism during pregnancy in obese women with
normal glucose tolerance and gestational diabetes mellitus. Am J
Obstet Gynecol. 1999;180(4):903-916.
171. Buchanan TA, Metzger BE, Freinkel N, et al. Insulin sensitivity
and B-cell responsiveness to glucose during late pregnancy in
lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am J Obstet Gynecol.
1990;162(4):1008-1014.
172. Sivan E, Chen X, Homko CJ, et al. Longitudinal study of carbohydrate metabolism in healthy obese pregnant women. Diabetes
Care. 1997;20(9):1470-1475.
173. Caro JF, Dohm LG, Pories WJ, et al. Cellular alterations in
liver, skeletal muscle, and adipose tissue responsible for insulin
resistance in obesity and type II diabetes. Diabetes Metab Rev.
1989;5(8):665-689.
174. Freinkel N, Metzger BE, Nitzan M, et al. Faciltated anabolism in late
pregnancy: some novel maternal compensations for accelerated starvation. In: Malaise WJ, Pirart J, Vallence-Own J, eds. International
Congress Series 312. Excerpta Medica; 1974:474-488.
175. Yogev Y, Ben-Haroush A, Chen R, et al. Diurnal glycemic profile
in obese and normal weight nondiabetic pregnant women. Am J
Obstet Gynecol. 2004;191(3):949-953.
176. Hernandez TL, Friedman JE, Van Pelt RE, et al. Patterns of glycemia in normal pregnancy: should the current therapeutic targets
be challenged? Diabetes Care. 2011;34(7):1660-1668.
177. Kuhl C. Etiology and pathogenesis of gestational diabetes.
Diabetes Care. 1998;21(suppl 2):B19-B26.
178. Parsons JA, Brelje TC, Sorenson RL. Adaptation of islets of
Langerhans to pregnancy: increased islet cell proliferation and
insulin secretion correlates with the onset of placental lactogen
secretion. Endocrinology. 1992;130(3):1459-1466.
179. Sorenson RL, Brelje TC. Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of
lactogenic hormones. Horm Metab Res. 1997;29(6):301-307.
180. Nielsen JH, Galsgaard ED, Moldrup A, et al. Regulation of
beta-cell mass by hormones and growth factors. Diabetes.
2001;50(suppl 1):S25-S29.
181. Parsons JA, Bartke A, Sorenson RL. Number and size of islets
of Langerhans in pregnant, human growth hormone-expressing
transgenic, and pituitary dwarf mice: effect of lactogenic
hormones. Endocrinology. 1995;136(5):2013-2021.
182. Rieck S, White P, Schug J, et al. The transcriptional response of the islet to pregnancy in mice. Mol Endocrinol.
2009;23(10):1702-1712.
183. Buchanan TA, Kitzmiller JL. Metabolic interactions of diabetes
and pregnancy. Annu Rev Med. 1994;45:245-260.
184. Rieck S, Kaestner KH. Expansion of beta-cell mass in response to
pregnancy. Trends Endocrinol Metab. 2010;21(3):151-158.
185. Koukkou E, Watts GF, Lowy C. Serum lipid, lipoprotein and
apolipoprotein changes in gestational diabetes mellitus: a cross-sectional and prospective study. J Clin Pathol. 1996;49(8):634-637.
186. Nolan CJ. Controversies in gestational diabetes. Best Pract Res
Clin Obstet Gynaecol. 2011;25(1):37-49.
187. Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell
dedifferentiation as a mechanism of diabetic beta cell failure. Cell.
2012;150(6):1223-1234.
188. Halban PA, Polonsky KS, Bowden DW, et al. beta-cell failure in
type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care. 2014;37(6):1751-1758.
189. Catalano PM, Tyzbir ED, Wolfe RR, et al. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am J Physiol. 1993;264(1 Pt 1):E60-E67.
190. Homko C, Sivan E, Chen X, et al. Insulin secretion during and
after pregnancy in patients with gestational diabetes mellitus. J
Clin Endocrinol Metab. 2001;86(2):568-573.
191. Powe CE, Huston Presley LP, Locascio JJ, et al. Augmented insulin secretory response in early pregnancy. Diabetologia.
2019;62(8):1445-1452.
787
788
235. Spellacy WN, Miller S, Winegar A, et al. Macrosomia—maternal characteristics and infant complications. Obstet Gynecol.
1985;66(2):158-161.
236. Jang HC, Cho NH, Min YK, et al. Increased macrosomia and
perinatal morbidity independent of maternal obesity and advanced age in Korean women with GDM. Diabetes Care.
1997;20(10):1582-1588.
237. Langer O, Yogev Y, Most O, et al. Gestational diabetes:
the consequences of not treating. Am J Obstet Gynecol.
2005;192(4):989-997.
238. Weiss PA, Haeusler M, Tamussino K, et al. Can glucose tolerance test
predict fetal hyperinsulinism? BJOG. 2000;107(12):1480-1485.
239. Boulet SL, Alexander GR, Salihu HM, et al. Macrosomic births in
the united states: determinants, outcomes, and proposed grades of
risk. Am J Obstet Gynecol. 2003;188(5):1372-1378.
240. Ryckman KK, Spracklen CN, Smith CJ, et al. Maternal lipid levels
during pregnancy and gestational diabetes: a systematic review
and meta-analysis. BJOG. 2015;122(5):643-651.
241. Jovanovic L, Pettitt DJ. Gestational diabetes mellitus. JAMA.
2001;286(20):2516-2518.
242. Esakoff TF, Cheng YW, Sparks TN, et al. The association between
birthweight 4000 g or greater and perinatal outcomes in patients
with and without gestational diabetes mellitus. Am J Obstet
Gynecol. 2009;200(6):672 e1-672 e4.
243. Henriksen T. The macrosomic fetus: a challenge in current obstetrics. Acta Obstet Gynecol Scand. 2008;87(2):134-145.
244. Reece EA, Leguizamon G, Wiznitzer A. Gestational diabetes: the
need for a common ground. Lancet. 2009;373(9677):1789-1797.
245. Cetin H, Yalaz M, Akisu M, et al. Polycythaemia in infants of
diabetic mothers: beta-hydroxybutyrate stimulates erythropoietic
activity. J Int Med Res. 2011;39(3):815-821.
246. Farrar D, Fairley L, Santorelli G, et al. Association between
hyperglycaemia and adverse perinatal outcomes in south Asian and
white British women: analysis of data from the Born in Bradford
cohort. Lancet Diabetes Endocrinol. 2015;3(10):795-804.
247. Balsells M, Corcoy R, Adelantado JM, et al. Gestational diabetes
mellitus: metabolic control during labour. Diabetes Nutr Metab.
2000;13(5):257-262.
248. Farrar D, Simmonds M, Bryant M, et al. Hyperglycaemia and
risk of adverse perinatal outcomes: systematic review and metaanalysis. BMJ. 2016;354:i4694.
249. Billionnet C, Mitanchez D, Weill A, et al. Gestational diabetes
and adverse perinatal outcomes from 716,152 births in France in
2012. Diabetologia. 2017;60(4):636-644.
250. Allen VM, Armson BA. SOGC Clinical Practice Guideline: teratogenicity associated with pre-existing and gestational diabetes. J
Obstet Gynaecol Can. 2007;29(11):927-934.
251. Owens LA, O’Sullivan EP, Kirwan B, et al. ATLANTIC DIP:
the impact of obesity on pregnancy outcome in glucose-tolerant
women. Diabetes Care. 2010;33(3):577-579.
252. Dennedy MC, Avalos G, O’Reilly MW, et al. ATLANTIC-DIP: raised
maternal body mass index (BMI) adversely affects maternal and
fetal outcomes in glucose-tolerant women according to International
Association of Diabetes and Pregnancy Study Groups (IADPSG)
criteria. J Clin Endocrinol Metab. 2012;97(4):E608-E612.
253. Rosenstein MG, Cheng YW, Snowden JM, et al. The risk of stillbirth
and infant death stratified by gestational age in women with gestational diabetes. Am J Obstet Gynecol. 2012;206(4):309 e1-309 e7.
254. Mitanchez D. Foetal and neonatal complications in gestational diabetes: perinatal mortality, congenital malformations, macrosomia,
shoulder dystocia, birth injuries, neonatal complications. Diabetes
Metab. 2010;36(6 Pt 2):617-627.
255. Cundy T, Gamble G, Townend K, et al. Perinatal mortality in type
2 diabetes mellitus. Diabet Med. 2000;17(1):33-39.
256. Hutcheon JA, Kuret V, Joseph KS, et al. Immortal time bias in the
study of stillbirth risk factors: the example of gestational diabetes.
Epidemiology. 2013;24(6):787-790.
257. Poston L, Bell R, Croker H, et al. Effect of a behavioural intervention in obese pregnant women (the UPBEAT study): a multicentre,
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
212. Chasman DI, Pare G, Mora S, et al. Forty-three loci associated
with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis. PLoS Genet. 2009;5(11):e1000730.
213. Seidah NG. The proprotein convertases, 20 years later. Methods
Mol Biol. 2011;768:23-57.
214. Benzinou M, Creemers JW, Choquet H, et al. Common
nonsynonymous variants in PCSK1 confer risk of obesity. Nat
Genet. 2008;40(8):943-945.
215. Hayes A, Chevalier A, D’Souza M, et al. Early childhood obesity: association with healthcare expenditure in Australia. Obesity
(Silver Spring). 2016;24(8):1752-8.
216. Powe CE, Nodzenski M, Talbot O, et al. Genetic determinants
of glycemic traits and the risk of gestational diabetes mellitus.
Diabetes. 2018;67(12):2703-2709.
217. Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N
Engl J Med. 2001;345(13):971-980.
218. Hattersley AT, Patel KA. Precision diabetes: learning from monogenic diabetes. Diabetologia. 2017;60(5):769-777.
219. Dickens LT, Naylor RN. Clinical management of women
with monogenic diabetes during pregnancy. Curr Diab Rep.
2018;18(3):12.
220. Chakera AJ, Steele AM, Gloyn AL, et al. Recognition and management of individuals with hyperglycemia because of a heterozygous
glucokinase mutation. Diabetes Care. 2015;38(7):1383-1392.
221. Urbanova J, Brunerova L, Nunes M, et al. Identification of MODY
among patients screened for gestational diabetes: a clinician’s
guide. Arch Gynecol Obstet. 2020;302(2):305-314.
222. Wang Z, Ping F, Zhang Q, et al. Preliminary screening of mutations
in the glucokinase gene of Chinese patients with gestational diabetes. J Diabetes Investig. 2018;9(1):199-203.
223. Gjesing AP, Rui G, Lauenborg J, et al. High prevalence of diabetespredisposing variants in MODY genes among Danish women
with gestational diabetes mellitus. J Endocr Soc. 2017;1(6):
681-690.
224. Shields BM, Hicks S, Shepherd MH, et al. Maturity-onset diabetes of the young (MODY): how many cases are we missing?
Diabetologia. 2010;53(12):2504-2508.
225. Spyer G, Hattersley AT, Sykes JE, et al. Influence of maternal and
fetal glucokinase mutations in gestational diabetes. Am J Obstet
Gynecol. 2001;185(1):240-241.
226. Hattersley AT, Beards F, Ballantyne E, et al. Mutations in the
glucokinase gene of the fetus result in reduced birth weight. Nat
Genet. 1998;19(3):268-270.
227. Scholtens DM, Kuang A, Lowe LP, et al. Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal
glycemia and childhood glucose metabolism. Diabetes Care.
2019;42(3):381-392.
228. Saravanan P; Diabetes in Pregnancy Working Group. Gestational
diabetes: opportunities for improving maternal and child health.
Lancet Diabetes Endocrinol. 2020;8(9):793-800.
229. Pedersen J. Hyperglycaemia-hyperinsulinism theory and birthweight. In: The Pregnant Diabetic and Her Newborn: Problems
and Management. Williams and Wilkins; 1977:211-220.
230. Illsley NP. Glucose transporters in the human placenta. Placenta.
2000;21(1):14-22.
231. Pedersen J. Weight and length at birth of infants of diabetic
mothers. Acta Endocrinol (Copenh). 1954;16(4):330-342.
232. Whitelaw A. Subcutaneous fat in newborn infants of diabetic
mothers: an indication of quality of diabetic control. Lancet.
1977;1(8001):15-18.
233. Vrijkotte TG, Krukziener N, Hutten BA, et al. Maternal lipid
profile during early pregnancy and pregnancy complications
and outcomes: the ABCD study. J Clin Endocrinol Metab.
2012;97(11):3917-3925.
234. Yang X, Hsu-Hage B, Zhang H, et al. Women with impaired glucose tolerance during pregnancy have significantly poor pregnancy outcomes. Diabetes Care. 2002;25(9):
1619-1624.
Endocrine Reviews, 2022, Vol. 43, No. 5
Endocrine Reviews, 2022, Vol. 43, No. 5
258.
259.
260.
261.
262.
264.
265.
266.
267.
268.
269.
270.
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
289.
290.
291.
292.
293.
294.
295.
preconception to the postnatal period. NICE Guidelines NG3.
2015. Last updated December 16, 2020. https://www.nice.org.uk/
guidance/ng3
Carr DB, Utzschneider KM, Hull RL, et al. Gestational diabetes mellitus increases the risk of cardiovascular disease in
women with a family history of type 2 diabetes. Diabetes Care.
2006;29(9):2078-2083.
Gunderson EP, Chiang V, Pletcher MJ, et al. History of gestational
diabetes mellitus and future risk of atherosclerosis in mid-life: the
Coronary Artery Risk Development in Young Adults study. J Am
Heart Assoc. 2014;3(2):e000490.
Retnakaran R. Glucose tolerance status in pregnancy: a window
to the future risk of diabetes and cardiovascular disease in young
women. Curr Diabetes Rev. 2009;5(4):239-244.
Tobias DK, Hu FB, Forman JP, et al. Increased risk of hypertension after gestational diabetes mellitus: findings from a large prospective cohort study. Diabetes Care. 2011;34(7):1582-1584.
Tobias DK, Stuart JJ, Li S, et al. Association of history of gestational diabetes with long-term cardiovascular disease risk in
a large prospective cohort of US Women. JAMA Intern Med.
2017;177(12):1735-1742.
Brown HL, Warner JJ, Gianos E, et al. Promoting risk identification and reduction of cardiovascular disease in women through
collaboration with obstetricians and gynecologists: a presidential
advisory from the American Heart Association and the American
College of Obstetricians and Gynecologists. Circulation.
2018;137(24):e843-ee52.
Knudsen LS, Christensen IJ, Lottenburger T, et al. Pre-analytical
and biological variability in circulating interleukin 6 in healthy
subjects and patients with rheumatoid arthritis. Biomarkers.
2008;13(1):59-78.
Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes.
Cochrane Database Syst Rev. 2009;3:CD003395.
Jovanovic-Peterson L, Peterson CM, Reed GF, et al. Maternal
postprandial glucose levels and infant birth weight: the Diabetes
in Early Pregnancy Study. The National Institute of Child Health
and Human Development—Diabetes in Early Pregnancy Study.
Am J Obstet Gynecol. 1991;164(1 Pt 1):103-111.
Bain E, Crane M, Tieu J, et al. Diet and exercise interventions for
preventing gestational diabetes mellitus. Cochrane Database Syst
Rev. 0443;2015;4:CD01.
Duarte-Gardea MO, Gonzales-Pacheco DM, Reader DM, et al.
Academy of nutrition and dietetics gestational diabetes evidence-based nutrition practice guideline. J Acad Nutr Diet.
2018;118(9):1719-1742.
Rasmussen KM, Yaktine AL, eds.; Institute of Medicine and
National Research Council Committee to Reexamine IOM
Pregnancy Weight Guidelines. Weight Gain During Pregnancy:
Reexamining the Guidelines. National Academies Press; 2009.
Jovanovic-Peterson L, Peterson CM. Dietary manipulation as a
primary treatment strategy for pregnancies complicated by diabetes. J Am Coll Nutr. 1990;9(4):320-325.
Hernandez TL, Van Pelt RE, Anderson MA, et al. A higher-complex
carbohydrate diet in gestational diabetes mellitus achieves glucose
targets and lowers postprandial lipids: a randomized crossover
study. Diabetes Care. 2014;37(5):1254-1262.
Hernandez TL, Van Pelt RE, Anderson MA, et al. Women with
gestational diabetes mellitus randomized to a higher-complex carbohydrate/low-fat diet manifest lower adipose tissue insulin resistance, inflammation, glucose, and free fatty acids: a pilot study.
Diabetes Care. 2016;39(1):39-42.
Asemi Z, Tabassi Z, Samimi M, et al. Favourable effects of the
Dietary Approaches to Stop Hypertension diet on glucose tolerance and lipid profiles in gestational diabetes: a randomised clinical trial. Br J Nutr. 2013;109(11):2024-2030.
Han S, Middleton P, Shepherd E, et al. Different types of dietary
advice for women with gestational diabetes mellitus. Cochrane
Database Syst Rev. 2017;2:CD009275.
Yamamoto JM, Kellett JE, Balsells M, et al. Gestational diabetes mellitus and diet: a systematic review and meta-analysis of
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
263.
randomised controlled trial. Lancet Diabetes Endocrinol.
2015;3(10):767-777.
Tam WH, Ma RCW, Ozaki R, et al. In utero exposure to maternal hyperglycemia increases childhood cardiometabolic risk in
Offspring. Diabetes Care. 2017;40(5):679-686.
Yu Y, Arah OA, Liew Z, et al. Maternal diabetes during pregnancy and early onset of cardiovascular disease in offspring:
population based cohort study with 40 years of follow-up. BMJ.
2019;367:l6398.
Hod M. The fetal heart in gestational diabetes: long-term effects.
BJOG. 2021;128(2):280.
Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure
to diabetes conveys risks for type 2 diabetes and obesity: a study
of discordant sibships. Diabetes. 2000;49(12):2208-2211.
Lowe WL Jr., Lowe LP, Kuang A, et al. Maternal glucose levels
during pregnancy and childhood adiposity in the Hyperglycemia
and Adverse Pregnancy Outcome Follow-up Study. Diabetologia.
2019;62(4):598-610.
Page KA, Luo S, Wang X, et al. Children exposed to maternal
obesity or gestational diabetes mellitus during early fetal development have hypothalamic alterations that predict future weight
gain. Diabetes Care. 2019;42(8):1473-1480.
Anderberg E, Kallen K, Berntorp K. The impact of gestational diabetes mellitus on pregnancy outcome comparing different cutoff criteria for abnormal glucose tolerance. Acta Obstet Gynecol
Scand. 2010;89(12):1532-1537.
Ju H, Rumbold AR, Willson KJ, et al. Borderline gestational
diabetes mellitus and pregnancy outcomes. BMC Pregnancy
Childbirth. 2008;8:31.
Jastrow N, Roberge S, Gauthier RJ, et al. Effect of birth weight on
adverse obstetric outcomes in vaginal birth after cesarean delivery.
Obstet Gynecol. 2010;115(2 Pt 1):338-343.
Metzger BE, Coustan DR. Summary and recommendations of
the Fourth International Workshop-Conference on Gestational
Diabetes Mellitus. The Organizing Committee. Diabetes Care.
1998;21(suppl 2):B161-B167.
Hiden U, Lassance L, Tabrizi NG, et al. Fetal insulin and IGF-II
contribute to gestational diabetes mellitus (GDM)-associated
up-regulation of membrane-type matrix metalloproteinase 1
(MT1-MMP) in the human feto-placental endothelium. J Clin
Endocrinol Metab. 2012;97(10):3613-3621.
Dunne FP, Avalos G, Durkan M, et al. ATLANTIC DIP: pregnancy outcomes for women with type 1 and type 2 diabetes. Ir
Med J. 2012;105(5 suppl):6-9.
Roberts JM, Redman CW. Pre-eclampsia: more than pregnancyinduced hypertension. Lancet. 1993;341(8858):1447-1451.
Desoye G, Hauguel-de Mouzon S. The human placenta in gestational diabetes mellitus. The Insulin and Cytokine Network.
Diabetes Care. 2007;30(suppl 2):S120-S126.
Belkacemi L, Lash GE, Macdonald-Goodfellow SK, et al.
Inhibition of human trophoblast invasiveness by high glucose concentrations. J Clin Endocrinol Metab. 2005;90(8):
4846-4851.
Vounzoulaki E, Khunti K, Abner SC, et al. Progression to type 2
diabetes in women with a known history of gestational diabetes:
systematic review and meta-analysis. BMJ. 2020;369:m1361.
Daly B, Toulis KA, Thomas N, et al. Increased risk of ischemic
heart disease, hypertension, and type 2 diabetes in women with
previous gestational diabetes mellitus, a target group in general
practice for preventive interventions: a population-based cohort
study.. PLoS Med. 2018;15(1):e1002488.
Lowe WL Jr, Scholtens DM, Kuang A, et al. Hyperglycemia and
adverse pregnancy outcome follow-up study (HAPO FUS): maternal gestational diabetes mellitus and childhood glucose metabolism. Diabetes Care. 2019;42(3):372-380.
Murphy HR. 2020 NICE guideline update: good news for pregnant women with type 1 diabetes and past or current gestational
diabetes. Diabet Med. 2021;38(6):e14576.
National Institute for Health and Care Excellence. Diabetes in
pregnancy: management of diabetes and its complications from
789
Endocrine Reviews, 2022, Vol. 43, No. 5
790
296.
297.
298.
299.
301.
302.
303.
304.
305.
306.
307.
308.
309.
310.
311.
312.
313.
314.
315.
316.
317. Langer O, Rodriguez DA, Xenakis EM, et al. Intensified versus
conventional management of gestational diabetes. Am J Obstet
Gynecol. 1994;170(4):1036-1046.
318. Pregnancy outcomes in the diabetes control and complications
trial. Am J Obstet Gynecol. 1996;174(4):1343-1353.
319. Martis R, Brown J, Alsweiler J, et al. Different intensities of
glycaemic control for women with gestational diabetes mellitus.
Cochrane Database Syst Rev. 2016;4:CD011624.
320. Snyder JMI, Melzter S, Nadeau J. Gestational diabetes and glycemic control: a randomized clinical trial. Am J Obstet Gynecol.
1998;178(1 Pt 2):S55.
321. Pertot T, Molyneaux L, Tan K, et al. Can common clinical
parameters be used to identify patients who will need insulin treatment in gestational diabetes mellitus? Diabetes Care.
2011;34(10):2214-2216.
322. Rowan JA, Hague WM, Gao W, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med.
2008;358(19):2003-2015.
323. Murphy HR, Rayman G, Duffield K, et al. Changes in the glycemic profiles of women with type 1 and type 2 diabetes during
pregnancy. Diabetes Care. 2007;30(11):2785-2791.
324. Padmanabhan S, McLean M, Cheung NW. Falling insulin requirements are associated with adverse obstetric
outcomes in women with preexisting diabetes. Diabetes Care.
2014;37(10):2685-2692.
325. Wong VW. Gestational diabetes mellitus in five ethnic groups:
a comparison of their clinical characteristics. Diabet Med.
2012;29(3):366-371.
326. Barnes RA, Wong T, Ross GP, et al. A novel validated model
for the prediction of insulin therapy initiation and adverse perinatal outcomes in women with gestational diabetes mellitus.
Diabetologia. 2016;59(11):2331-2338.
327. Ryu RJ, Hays KE, Hebert MF. Gestational diabetes mellitus
management with oral hypoglycemic agents. Semin Perinatol.
2014;38(8):508-515.
328. Camelo Castillo W, Boggess K, Sturmer T, et al. Trends in
glyburide compared with insulin use for gestational diabetes
treatment in the United States, 2000-2011. Obstet Gynecol.
2014;123(6):1177-1184.
329. Langer O, Conway DL, Berkus MD, et al. A comparison of
glyburide and insulin in women with gestational diabetes mellitus.
N Engl J Med. 2000;343(16):1134-1138.
330. Kremer CJ, Duff P. Glyburide for the treatment of gestational diabetes. Am J Obstet Gynecol. 2004;190(5):1438-1439.
331. Camelo Castillo W, Boggess K, Sturmer T, et al. Association
of adverse pregnancy outcomes with glyburide vs insulin in
women with gestational diabetes. JAMA Pediatr. 2015;169(5):
452-458.
332. Schwartz RA, Rosenn B, Aleksa K, et al. Glyburide transport across
the human placenta. Obstet Gynecol. 2015;125(3):583-588.
333. Cheng YW, Chung JH, Block-Kurbisch I, et al. Treatment of gestational diabetes mellitus: glyburide compared to subcutaneous
insulin therapy and associated perinatal outcomes. J Matern Fetal
Neonatal Med. 2012;25(4):379-384.
334. Lindsay RS, Loeken MR. Metformin use in pregnancy: promises
and uncertainties. Diabetologia. 2017;60(9):1612-1619.
335. Charles B, Norris R, Xiao X, et al. Population pharmacokinetics
of metformin in late pregnancy. Ther Drug Monit. 2006;28(1):
67-72.
336. Tarry-Adkins JL, Aiken CE, Ozanne SE. Neonatal, infant, and
childhood growth following metformin versus insulin treatment
for gestational diabetes: a systematic review and meta-analysis.
PLoS Med. 2019;16(8):e1002848.
337. Feig DS, Donovan LE, Zinman B, et al. Metformin in women
with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial. Lancet Diabetes
Endocrinol. 2020;8(10):834-844.
338. Niromanesh S, Alavi A, Sharbaf FR, et al. Metformin compared
with insulin in the management of gestational diabetes
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
300.
randomized controlled trials examining the impact of modified
dietary interventions on maternal glucose control and neonatal
birth weight. Diabetes Care. 2018;41(7):1346-1361.
Major CA, Henry MJ, De Veciana M, et al. The effects of carbohydrate restriction in patients with diet-controlled gestational
diabetes. Obstet Gynecol. 1998;91(4):600-604.
American College of Obstetrics and Gynecology. Practice
Bulletin No. 137: gestational diabetes mellitus. Obstet Gynecol.
2013;122(2 Pt 1):406-416.
Metzger BE, Buchanan TA, Coustan DR, et al. Summary and
recommendations of the Fifth International Workshop-Conference
on Gestational Diabetes Mellitus. Diabetes Care. 2007;30(suppl
2):S251-S260.
American Diabetes Association. Standards of medical care in diabetes-2011. Diabetes Care. 2011;34(suppl 1):S11-S61.
Battaglia FC, Meschia G. An Introduction to Fetal Physiology.
Academic Press; 1986.
Harding JE, Johnston BM. Nutrition and fetal growth. Reprod
Fertil Dev. 1995;7(3):539-547.
Sweeting A, Markovic TP, Mijatovic J, et al. The carbohydrate
threshold in pregnancy and gestational diabetes: how low can we
go? Nutrients. 2021;13(8):2599.
Morisaki N, Nagata C, Yasuo S, et al. Optimal protein intake
during pregnancy for reducing the risk of fetal growth restriction: the Japan Environment and Children’s Study. Br J Nutr.
2018;120(12):1432-1440.
Rizzo T, Metzger BE, Burns WJ, et al. Correlations between antepartum maternal metabolism and intelligence of offspring. N Engl
J Med. 1991;325(13):911-916.
Shaw GM, Yang W. Women’s periconceptional lowered carbohydrate intake and NTD-affected pregnancy risk in the
era of prefortification with folic acid. Birth Defects Res.
2019;111(5):248-253.
Mijatovic J, Louie JCY, Buso MEC, et al. Effects of a modestly
lower carbohydrate diet in gestational diabetes: a randomized
controlled trial. Am J Clin Nutr. 2020;112(2):284-292.
Shubert PJ, Gordon MC, Landon MB, et al. Ketoacids attenuate
glucose uptake in human trophoblasts isolated from first-trimester
chorionic villi. Am J Obstet Gynecol. 1996;175(1):56-62.
Catalano PM, Mele L, Landon MB, et al. Inadequate weight gain
in overweight and obese pregnant women: what is the effect on
fetal growth? Am J Obstet Gynecol. 2014;211(2):137 e1-137 e7.
Faucher MA, Barger MK. Gestational weight gain in obese women
by class of obesity and select maternal/newborn outcomes: a systematic review. Women Birth. 2015;28(3):e70-e79.
Viecceli C, Remonti LR, Hirakata VN, et al. Weight gain adequacy and pregnancy outcomes in gestational diabetes: a metaanalysis. Obes Rev. 2017;18(5):567-580.
Kainer F, Weiss PA, Huttner U, et al. Levels of amniotic fluid insulin and profiles of maternal blood glucose in pregnant women
with diabetes type-I. Early Hum Dev. 1997;49(2):97-105.
de Veciana M, Major CA, Morgan MA, et al. Postprandial versus
preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med.
1995;333(19):1237-1241.
Hernandez TL. Glycemic targets in pregnancies affected by diabetes: historical perspective and future directions. Curr Diab Rep.
2015;15(1):565.
Abell SK, Boyle JA, Earnest A, et al. Impact of different glycaemic
treatment targets on pregnancy outcomes in gestational diabetes.
Diabet Med. 2019;36(2):177-183.
Garner P, Okun N, Keely E, et al. A randomized controlled trial
of strict glycemic control and tertiary level obstetric care versus
routine obstetric care in the management of gestational diabetes:
a pilot study. Am J Obstet Gynecol. 1997;177(1):190-195.
Langer O, Levy J, Brustman L, et al. Glycemic control in gestational diabetes mellitus--how tight is tight enough: small for gestational age versus large for gestational age? Am J Obstet Gynecol.
1989;161(3):646-653.
Endocrine Reviews, 2022, Vol. 43, No. 5
339.
340.
341.
342.
344.
345.
346.
347.
348.
349.
350.
351.
352.
353.
354.
355.
356.
357.
358. Gabbe SG, Landon MB, Warren-Boulton E, et al. Promoting
health after gestational diabetes: a National Diabetes Education
Program call to action. Obstet Gynecol. 2012;119(1):171-176.
359. Ehrlich SF, Hedderson MM, Feng J, et al. Change in body mass
index between pregnancies and the risk of gestational diabetes in
a second pregnancy. Obstet Gynecol. 2011;117(6):1323-1330.
360. Kim C, Newton KM, Knopp RH. Gestational diabetes and the
incidence of type 2 diabetes: a systematic review. Diabetes Care.
2002;25(10):1862-1868.
361. Bellamy L, Casas JP, Hingorani AD, et al. Type 2 diabetes mellitus
after gestational diabetes: a systematic review and meta-analysis.
Lancet. 2009;373(9677):1773-1779.
362. Dornhorst A, Bailey PC, Anyaoku V, et al. Abnormalities of
glucose tolerance following gestational diabetes. Q J Med.
1990;77(284):1219-1228.
363. Aroda VR, Christophi CA, Edelstein SL, et al. The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: the
Diabetes Prevention Program outcomes study 10-year follow-up.
J Clin Endocrinol Metab. 2015;100(4):1646-1653.
364. Pirc LK, Owens JA, Crowther CA, et al. Mild gestational diabetes
in pregnancy and the adipoinsular axis in babies born to mothers
in the ACHOIS randomised controlled trial. BMC Pediatr.
2007;7:18.
365. Landon MB, Rice MM, Varner MW, et al. Mild gestational diabetes mellitus and long-term child health. Diabetes Care.
2015;38(3):445-452.
366. Dabelea D, Pettitt DJ. Intrauterine diabetic environment confers
risks for type 2 diabetes mellitus and obesity in the offspring, in
addition to genetic susceptibility. J Pediatr Endocrinol Metab.
2001;14(8):1085-1091.
367. Pettitt DJ, Baird HR, Aleck KA, et al. Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy. N
Engl J Med. 1983;308(5):242-245.
368. Gillman MW, Rifas-Shiman S, Berkey CS, Field AE, Colditz GA.
Maternal gestational diabetes, birth weight, and adolescent obesity. Pediatrics. 2003;111(3):e221-e226.
369. Plagemann A, Harder T, Kohlhoff R, et al. Overweight and obesity in infants of mothers with long-term insulin-dependent diabetes or gestational diabetes. Int J Obes Relat Metab Disord.
1997;21(6):451-456.
370. Pribylova H, Dvorakova L. Long-term prognosis of infants of
diabetic mothers. Relationship between metabolic disorders in
newborns and adult offspring. Acta Diabetol. 1996;33(1):30-34.
371. Silverman BL, Metzger BE, Cho NH, et al. Impaired glucose tolerance in adolescent offspring of diabetic mothers: relationship to
fetal hyperinsulinism. Diabetes Care. 1995;18(5):611-617.
372. Crume TL, Ogden L, West NA, et al. Association of exposure to diabetes in utero with adiposity and fat distribution in a multiethnic
population of youth: the Exploring Perinatal Outcomes among
Children (EPOCH) Study. Diabetologia. 2011;54(1):87-92.
373. West NA, Crume TL, Maligie MA, et al. Cardiovascular risk
factors in children exposed to maternal diabetes in utero.
Diabetologia. 2011;54(3):504-507.
374. Hillier TA, Pedula KL, Schmidt MM, et al. Childhood obesity and
metabolic imprinting: the ongoing effects of maternal hyperglycemia. Diabetes Care. 2007;30(9):2287-2292.
375. Whincup PH, Kaye SJ, Owen CG, et al. Birth weight and risk of type
2 diabetes: a systematic review. JAMA. 2008;300(24):2886-2897.
376. Guerrero-Romero F, Aradillas-Garcia C, Simental-Mendia LE,
et al. Birth weight, family history of diabetes, and metabolic syndrome in children and adolescents. J Pediatr. 2010;156(5):719723, 23 e1.
377. Harder T, Roepke K, Diller N, et al. Birth weight, early weight
gain, and subsequent risk of type 1 diabetes: systematic review
and meta-analysis. Am J Epidemiol. 2009;169(12):1428-1436.
378. Reece EA. The fetal and maternal consequences of gestational
diabetes mellitus. J Matern Fetal Neonatal Med. 2010;23(3):
199-203.
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
343.
mellitus: a randomized clinical trial. Diabetes Res Clin Pract.
2012;98(3):422-429.
Khin MO, Gates S, Saravanan P. Predictors of metformin failure
in gestational diabetes mellitus (GDM). Diabetes Metab Syndr.
2018;12(3):405-410.
Rowan JA, Rush EC, Obolonkin V, et al. Metformin in gestational
diabetes: the offspring follow-up (MiG TOFU): body composition
at 2 years of age. Diabetes Care. 2011;34(10):2279-2284.
Rowan JA, Rush EC, Plank LD, et al. Metformin in gestational
diabetes: the offspring follow-up (MiG TOFU): body composition
and metabolic outcomes at 7-9 years of age. BMJ Open Diabetes
Res Care. 2018;6(1):e000456.
Hanem LGE, Stridsklev S, Juliusson PB, et al. Metformin use in
PCOS pregnancies increases the risk of offspring overweight at
4 years of age: follow-up of two RCTs. J Clin Endocrinol Metab.
2018;103(4):1612-1621.
Brown J, Martis R, Hughes B, et al. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational
diabetes. Cochrane Database Syst Rev. 2017;1:CD011967.
Balsells M, Garcia-Patterson A, Sola I, et al. Glibenclamide,
metformin, and insulin for the treatment of gestational diabetes: a
systematic review and meta-analysis. BMJ. 2015;350:h102.
Poolsup N, Suksomboon N, Amin M. Efficacy and safety of
oral antidiabetic drugs in comparison to insulin in treating
gestational diabetes mellitus: a meta-analysis. PLoS One.
2014;9(10):e109985.
Nachum Z, Zafran N, Salim R, et al. Glyburide versus metformin
and their combination for the treatment of gestational diabetes mellitus: a randomized controlled study. Diabetes Care.
2017;40(3):332-337.
Sacco F, Calderone A, Castagnoli L, et al. The cell-autonomous
mechanisms underlying the activity of metformin as an anticancer
drug. Br J Cancer. 2016;115(12):1451-1456.
Barbour LA, Davies JK. Comment on Nachum et al. Glyburide
versus metformin and their combination for the treatment of gestational diabetes mellitus: a randomized controlled study. Diabetes
Care. 2017;40:332-337. Diabetes Care. 2017;40(8):e115.
Rao U, de Vries B, Ross GP, et al. Fetal biometry for guiding the
medical management of women with gestational diabetes mellitus
for improving maternal and perinatal health. Cochrane Database
Syst Rev. 2019;9:CD012544.
Schaefer-Graf UM, Kjos SL, Fauzan OH, et al. A randomized
trial evaluating a predominantly fetal growth-based strategy to
guide management of gestational diabetes in Caucasian women.
Diabetes Care. 2004;27(2):297-302.
Schaefer-Graf UM, Wendt L, Sacks DA, et al. How many
sonograms are needed to reliably predict the absence of fetal
overgrowth in gestational diabetes mellitus pregnancies? Diabetes
Care. 2011;34(1):39-43.
Kjos SL, Schaefer-Graf UM. Modified therapy for gestational diabetes using high-risk and low-risk fetal abdominal circumference
growth to select strict versus relaxed maternal glycemic targets.
Diabetes Care. 2007;30(suppl 2):S200-S205.
Nelson L, Wharton B, Grobman WA. Prediction of large for gestational age birth weights in diabetic mothers based on early thirdtrimester sonography. J Ultrasound Med. 2011;30(12):1625-1628.
McLean A, Katz M, Oats J, et al. Rethinking third trimester ultrasound measurements and risk of adverse neonatal outcomes
in pregnancies complicated by hyperglycaemia: a retrospective
study. Aust N Z J Obstet Gynaecol. 2021;61(3):366-372.
American College of Obstetricians and Gynecologists. ACOG
Committee Opinion No. 560: medically indicated late-preterm
and early-term deliveries. Obstet Gynecol. 2013;121(4):908-910.
Metcalfe A, Hutcheon JA, Sabr Y, et al. Timing of delivery in
women with diabetes: a population-based study. Acta Obstet
Gynecol Scand. 2020;99(3):341-349.
Hunt KJ, Logan SL, Conway DL, et al. Postpartum screening
following GDM: how well are we doing? Curr Diab Rep.
2010;10(3):235-241.
791
792
399. Syngelaki A, Pastides A, Kotecha R, et al. First-trimester screening
for gestational diabetes mellitus based on maternal characteristics
and history. Fetal Diagn Ther. 2015;38(1):14-21.
400. Savvidou M, Nelson SM, Makgoba M, et al. First-trimester prediction of gestational diabetes mellitus: examining the potential
of combining maternal characteristics and laboratory measures.
Diabetes. 2010;59(12):3017-3022.
401. Lamain-de Ruiter M, Kwee A, Naaktgeboren CA, et al. Prediction
models for the risk of gestational diabetes: a systematic review.
Diagn Progn Res. 2017;1:3.
402. Sweeting AN, Wong J, Appelblom H, et al. A novel early pregnancy risk prediction model for gestational diabetes mellitus.
Fetal Diagn Ther. 2019;45(2):76-84.
403. Sweeting AN, Wong J, Appelblom H, et al. A first trimester prediction model for gestational diabetes utilizing aneuploidy and
pre-eclampsia screening markers. J Matern Fetal Neonatal Med.
2018;31(16):2122-2130.
404. Aronson JK, Ferner RE. Biomarkers-a general review. Curr Protoc
Pharmacol. 2017;76:9 23 19 17.
405. Allinson JL. Clinical biomarker validation. Bioanalysis.
2018;10(12):957-968.
406. Sattar N, Wannamethee SG, Forouhi NG. Novel biochemical
risk factors for type 2 diabetes: pathogenic insights or prediction
possibilities? Diabetologia. 2008;51(6):926-940.
407. O’Malley EG, Reynolds CME, Killalea A, et al. The use of
biomarkers at the end of the second trimester to predict
Gestational Diabetes Mellitus. Eur J Obstet Gynecol Reprod Biol.
2020;250:101-106.
408. Richardson AC, Carpenter MW. Inflammatory mediators in
gestational diabetes mellitus. Obstet Gynecol Clin North Am.
2007;34(2):213-224, viii.
409. Eleftheriades M, Papastefanou I, Lambrinoudaki I, et al. Elevated
placental growth factor concentrations at 11-14 weeks of gestation to predict gestational diabetes mellitus. Metabolism.
2014;63(11):1419-1425.
410. Lovati E, Beneventi F, Simonetta M, et al. Gestational diabetes mellitus: including serum pregnancy-associated plasma
protein-A testing in the clinical management of primiparous women? A case-control study. Diabetes Res Clin Pract.
2013;100(3):340-347.
411. White SL, Lawlor DA, Briley AL, et al. Early antenatal prediction of gestational diabetes in obese women: development of prediction tools for targeted intervention. PLoS One.
2016;11(12):e0167846.
412. Rasanen JP, Snyder CK, Rao PV, et al. Glycosylated fibronectin as
a first-trimester biomarker for prediction of gestational diabetes.
Obstet Gynecol. 2013;122(3):586-594.
413. Watanabe N, Morimoto S, Fujiwara T, et al. Prediction
of gestational diabetes mellitus by soluble (pro)renin receptor during the first trimester. J Clin Endocrinol Metab.
2013;98(6):2528-2535.
414. Theriault S, Giguere Y, Masse J, et al. Early prediction of gestational diabetes: a practical model combining clinical and biochemical markers. Clin Chem Lab Med. 2016;54(3):509-518.
415. Syngelaki A, Kotecha R, Pastides A, et al. First-trimester biochemical markers of placentation in screening for gestational diabetes
mellitus. Metabolism. 2015;64(11):1485-1489.
416. Gobl CS, Bozkurt L, Rivic P, et al. A two-step screening algorithm
including fasting plasma glucose measurement and a risk estimation model is an accurate strategy for detecting gestational diabetes mellitus. Diabetologia. 2012;55(12):3173-3181.
417. Australasian Diabetes in Pregnancy Society. Diagnostic testing
for gestational diabetes mellitus (GDM) during the COVID 19
pandemic: antenatal and postnatal testing advice: a statement
from the Australasian Diabetes in Pregnancy Society (ADIPS).
Last updated April 7, 2020. Accessed June 12, 2021. https://www.
adips.org/documents/COVID19-WITHQLDGUIDELINES07042
01150ADIPSADSADEADAupdated.pdf
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022
379. Ornoy A. Prenatal origin of obesity and their complications: gestational diabetes, maternal overweight and the paradoxical effects
of fetal growth restriction and macrosomia. Reprod Toxicol.
2011;32(2):205-212.
380. Page KA, Romero A, Buchanan TA, et al. Gestational diabetes
mellitus, maternal obesity, and adiposity in offspring. J Pediatr.
2014;164(4):807-810.
381. Grunnet LG, Hansen S, Hjort L, et al. Adiposity, dysmetabolic traits,
and earlier onset of female puberty in adolescent offspring of women
with gestational diabetes mellitus: a clinical study within the Danish
National Birth Cohort. Diabetes Care. 2017;40(12):1746-1755.
382. Logan KM, Emsley RJ, Jeffries S, et al. Development of early adiposity in infants of mothers with gestational diabetes mellitus.
Diabetes Care. 2016;39(6):1045-1051.
383. Catalano PM, Farrell K, Thomas A, et al. Perinatal risk factors for
childhood obesity and metabolic dysregulation. Am J Clin Nutr.
2009;90(5):1303-1313.
384. Chung WK, Erion K, Florez JC, et al. Precision medicine in diabetes: a consensus report from the American Diabetes Association
(ADA) and the European Association for the Study of Diabetes
(EASD). Diabetes Care. 2020;43(7):1617-1635.
385. Cheney C, Shragg P, Hollingsworth D. Demonstration of heterogeneity in gestational diabetes by a 400-kcal breakfast meal tolerance test. Obstet Gynecol. 1985;65(1):17-23.
386. Powe CE, Allard C, Battista MC, et al. Heterogeneous contribution of insulin sensitivity and secretion defects to gestational diabetes mellitus. Diabetes Care. 2016;39(6):1052-1055.
387. Catalano PM, Tyzbir ED, Roman NM, et al. Longitudinal changes
in insulin release and insulin resistance in nonobese pregnant
women. Am J Obstet Gynecol. 1991;165(6 Pt 1):1667-1672.
388. Powe CE, Hivert MF, Udler MS. Defining heterogeneity
among women with gestational diabetes mellitus. Diabetes.
2020;69(10):2064-2074.
389. Benhalima K, Van Crombrugge P, Moyson C, et al.
Characteristics and pregnancy outcomes across gestational diabetes mellitus subtypes based on insulin resistance. Diabetologia.
2019;62(11):2118-2128.
390. Sweeting A, Park F, Hyett J. The first trimester: prediction and
prevention of the great obstetrical syndromes. Best Pract Res Clin
Obstet Gynaecol. 2015;29(2):183-193.
391. Coustan DR, Nelson C, Carpenter MW, et al. Maternal age and
screening for gestational diabetes: a population-based study.
Obstet Gynecol. 1989;73(4):557-561.
392. Lavin JP Jr. Screening of high-risk and general populations for gestational diabetes. Clinical application and cost analysis. Diabetes.
1985;34(suppl 2):24-27.
393. Weeks JW, Major CA, de Veciana M, et al. Gestational diabetes:
does the presence of risk factors influence perinatal outcome? Am
J Obstet Gynecol. 1994;171(4):1003-1007.
394. Cosson E, Benbara A, Pharisien I, et al. Diagnostic and prognostic
performances over 9 years of a selective screening strategy for gestational diabetes mellitus in a cohort of 18,775 subjects. Diabetes
Care. 2013;36(3):598-603.
395. Chevalier N, Fenichel P, Giaume V, et al. Universal two-step screening
strategy for gestational diabetes has weak relevance in French
Mediterranean women: should we simplify the screening strategy for
gestational diabetes in France? Diabetes Metab. 2011;37(5):419-425.
396. Moses RG, Moses J, Davis WS. Gestational diabetes: do lean
young Caucasian women need to be tested? Diabetes Care.
1998;21(11):1803-1806.
397. Avalos GE, Owens LA, Dunne F, et al. Applying current
screening tools for gestational diabetes mellitus to a European
population: is it time for change? Diabetes Care. 2013;36(10):
3040-3044.
398. Teede HJ, Harrison CL, Teh WT, et al. Gestational diabetes:
development of an early risk prediction tool to facilitate
opportunities for prevention. Aust N Z J Obstet Gynaecol.
2011;51(6):499-504.
Endocrine Reviews, 2022, Vol. 43, No. 5
Endocrine Reviews, 2022, Vol. 43, No. 5
418. Royal College of Obstetricians. Guidance for maternal medicine in the evolving coronavirus Covid-19 pandemic. Published
July 10, 2020. Accessed June 30, 2021. https://www.rcog.org.
uk/globalassets/documents/guidelines/2020-07-10-guidance-formaternal-medicine.pdf
419. Simmons D, Rudland VL, Wong V, et al. Options for screening for
gestational diabetes mellitus during the SARS-CoV-2 pandemic.
Aust N Z J Obstet Gynaecol. 2020;60(5):660-666.
793
420. McIntyre HD, Gibbons KS, Ma RCW, et al. Testing for
gestational diabetes during the COVID-19 pandemic.
An evaluation of proposed protocols for the United
Kingdom, Canada and Australia. Diabetes Res Clin Pract.
2020;167:108353.
421. Meek CL, Lindsay RS, Scott EM, et al. Approaches to screening
for hyperglycaemia in pregnant women during and after the
COVID-19 pandemic. Diabet Med. 2021;38(1):e14380.
Downloaded from https://academic.oup.com/edrv/article/43/5/763/6511028 by guest on 03 November 2022