TEM 1352 No.

of Pages 12

Review

Gestational Diabetes Mellitus: Mechanisms,

Treatment, and Complications
Emma C. Johns,1 Fiona C. Denison,1 Jane E. Norman,1 and Rebecca M. Reynolds1,2,*

Gestational diabetes mellitus (GDM) is the most common metabolic distur- Highlights
bance during pregnancy. The prevalence is rising and correlates with the The prevalence of GDM is rapidly
increasing and is set continue climbing
increase in maternal obesity over recent decades. The etiology of GDM is
in the context of the global obesity
complex, with genetic and environmental factors implicated in mechanistic epidemic.
and epidemiological studies. GDM begets important short- and long-term
GDM has serious adverse implications
health risks for the mother, developing fetus, and offspring. This includes for the health of current and future
the high likelihood of subsequent maternal type 2 diabetes (T2DM), and possi- generations through genetic and envir-
ble adverse cardiometabolic phenotypes in the offspring. The most clinically onmental mechanisms which remain
incompletely understood. In addition,
and cost-effective methods of screening for GDM remain uncertain. Whilst the disease poses a significant eco-
treatments with lifestyle and pharmacological interventions have demonstrated nomic burden for healthcare systems,
with variability in clinical practice often
short-term benefits, the long-term impact for the offspring of intrauterine
determined by resource limitations.
exposure to antidiabetic medication remains unclear.
The optimal timing of screening and
diagnostic thresholds for GDM remain
uncertain.

Emerging evidence suggests intrauter-

The Rising Prevalence of Gestational Diabetes Mellitus ine exposure to metformin may have
Gestational diabetes mellitus (GDM) is traditionally defined as carbohydrate intolerance of an adverse impact on the offspring of
women with GDM. There is an ongoing
variable severity with onset or first detection during pregnancy [1]. This definition encompasses
need for long-term follow-up of chil-
abnormal glucose tolerance, which normalizes following delivery, and diabetes mellitus (DM), dren exposed to metformin to clarify
which was undiagnosed prior to or began concomitantly during pregnancy. The latter includes these potential associations and pro-
type 2 diabetes mellitus (T2DM), and rarely type 1 diabetes mellitus (T1DM) or monogenic vide a more robust evidence base to
inform clinical practice.
diabetes (see Glossary) [2]. A more recent definition of GDM, ‘diabetes diagnosed in the
second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation’,
aims to provide greater clarity [3].

The prevalence of GDM varies widely depending on population characteristics and the
diagnostic criteria used. Cohort studies performed in the UK and Ireland prior to 2010
demonstrated 1–3% of pregnancies were complicated by GDM [4]. In contrast, the
prevalence of GDM varied between 9% and 26% (mean 18%) at the 15 centers involved
1
in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study when more stringent Tommy’s Centre for Maternal and
Fetal Health, MRC Centre for
diagnostic criteria were applied [5]. In 2017, it was estimated that one in every seven Reproductive Health, University of
live births worldwide were affected by GDM [6]. This represented 85% of the total 21.3 Edinburgh, Queen’s Medical Research
million live births affected by diabetes during pregnancy globally [6]. Key drivers for the Institute, Edinburgh, UK
2
BHF/University Centre for
increase in GDM prevalence include the obesity epidemic, physical inactivity, and rising Cardiovascular Science, University of
maternal age [7]. Edinburgh, Queen’s Medical Research
Institute, Edinburgh, UK

Though GDM is now one of the most common pregnancy complications, considerable
controversies remain regarding timing of screening, diagnostic thresholds, optimal manage- *Correspondence:
ment, and postpartum follow-up. r.reynolds@ed.ac.uk (R.M. Reynolds).

Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy https://doi.org/10.1016/j.tem.2018.09.004 1
© 2018 Elsevier Ltd. All rights reserved.
 TEM 1352 No. of Pages 12

Screening Early in Pregnancy Glossary

Early pregnancy screening, performed in the first trimester or at the initiation of antenatal care, is Allele: a gene variant which may
generally recommended to exclude pre-existing DM in women at high risk [2,3,8–10]. The occur at a given site on a
populations in whom screening is recommended by national guideline bodies are summarized chromosome.
Epigenome: the set of chemical
in Table 1. There is no consensus on the preferred early screening tool for pre-existing DM: changes to the genome (an
fasting plasma glucose, random plasma glucose, HbA1c, and 75-g 2-hour oral glucose organism’s entire DNA sequence)
tolerance test (OGTT) are each recommended as screening tools in one or more national that modify gene expression but do
not change the DNA sequence itself.
guidelines [2,3,8,10–12]. Results indicative of DM according to World Health Organization
Genome-wide association study:
(WHO) diagnostic criteria outside pregnancy (i.e., fasting glucose 7 mmol/l, 2 hour 75-g an observational study of all the
genetic variants in a population to
determine genetic variants which are
associated with a specific
phenotype.
Table 1. Guideline Recommendations for Early Pregnancy Diabetes Mellitus Screening Population Glucose challenge test: a
Organization Recommended population Refs preliminary screening test for GDM
which involves administration of a
IADPSG All women or high-risk women; decision based on local circumstances and the [8]
50-g oral glucose load followed by
background frequency of abnormal glucose tolerance in local population
measurement of the plasma glucose
WHO Screening should be determined by individual countries/health services based on [9] level 1 hour later. Women with a
prevalence of glucose intolerance in local population, resources, and competing glucose level above a predefined
priorities threshold will proceed to an OGTT
as a diagnostic test for GDM.
ADA Women with one or more risk factor for DM: [3]
Impaired glucose tolerance: blood
 First-degree relative with DM
glucose levels which are higher than
 High-risk race/ethnicity
normal, but have not reached the
 History of cardiovascular disease
diabetic range. Defined as a blood
 Hypertension (140/90 mmHg or taking antihypertensive therapy) glucose level of between 7.8 mmol/l
 High-density lipoprotein (HDL) <35 mg/dl (0.9 mmol/l); triglycerides >250 mg/dl (140 mg/dl) and 11.0 mmol/l
(2.82 mmol/l) (196 mg/dl) 2 hours after a 75-g
 Polycystic ovarian syndrome (PCOS) OGTT.
 Physical inactivity Large for gestational age: birth
 Other clinical conditions associated with insulin resistance (e.g., acanthosis weight greater than or equal to the
nigricans, severe obesity) 90th percentile for a given
Women with previous GDM should have screening for DM at least every 3 years gestational age.
Loci: the plural of locus; a fixed site
on a chromosome at which an allele
ACOG Overweight or obese women (BMI 25 kg/m2 or 23 kg/m2 in Asian Americans) with [11] is located.
one or more additional risk factor: Macrosomia: excessive birth
 Physical inactivity weight, usually defined as more than
 First-degree relative with DM 4 kg.
 High-risk race or ethnicity Metabolic syndrome: a cluster of
 Previous macrosomic baby 4 kg common conditions including
 Previous GDM obesity, hypertension, dyslipidemia,
 Hypertension (140/90 mmHg or taking antihypertensive therapy) insulin resistance, and T2DM, which
 HDL <35 mg/dl (0.9 mmol/l); triglycerides >250 mg/dl (2.82 mmol/l) are associated with an increased risk
 PCOS of cardiovascular events.
 HbA1c 5.7%, impaired glucose tolerance or impaired fasting glucose on Monogenic diabetes: a group of
previous testing rare forms of diabetes caused by a
 Other clinical conditions associated with insulin resistance (e.g., acanthosis mutation in a single gene. For
nigricans, pre-pregnancy BMI >40 kg/m2) example, maturity onset diabetes of
 History of cardiovascular disease the young is most commonly caused
by a mutation in the HNF1A gene.
SIGN, NICE One or more risk factor for DM: [2,10] Oral glucose tolerance test: a test
 BMI >30 kg/m2 used to diagnose GDM and also
 Previous macrosomic baby 4.5 kg diabetes outside of pregnancy.
 Previous GDM Plasma glucose levels are measured
 First-degree relative with DM fasting and once or more following
 Family origin with high prevalence of DM the ingestion of an oral glucose load.
Several variations of the test exist
Diabetes Canada Women at high risk of undiagnosed T2DM [12]

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OGTT, or random glucose 11.1 mmol/l or HbA1c 48 mmol/mol), should be considered to involving different glucose loads,
represent ‘diabetes in pregnancy’ and appropriate management initiated [9]. intervals, and durations of sampling.
Polyhydramnios: an excessive
amount of amniotic fluid surrounding
The ability to diagnose GDM in the first trimester as opposed to the second or third trimester of the fetus in the amniotic sac,
pregnancy remains controversial. The International Association of Diabetes in Pregnancy Study associated with an increased risk of
Groups (IADPSG) revoked their 2010 recommendation that fasting plasma glucose pregnancy complications, including
preterm birth.
5.1 mmol/l in early pregnancy should be considered diagnostic of GDM, following evidence Prediabetes: an umbrella term used
that this was poorly predictive of OGTT outcomes in the third trimester [8,13]. For example, a to describe those who have blood
retrospective cohort study in China, including data from 17 186 pregnant women, reported glucose levels higher than normal but
have not reached the diabetic range,
37% of participants with fasting plasma glucose between 5.10 and 5.59 mmol/l at the first
and who have an increased risk of
antenatal visit were subsequently diagnosed with GDM based on a 75-g OGTT between 24 and T2DM. It includes those with
28 weeks’ gestation [14]. Studies assessing the diagnostic utility of an OGTT between 12 and impaired glucose tolerance.
15 weeks and 18 and 20 weeks’ gestation are ongoing [15,16]. Shoulder dystocia: an emergency
complication of labor when, following
delivery of the infant’s head, the
Screening Later in Pregnancy anterior shoulder becomes stuck
Screening for GDM later in pregnancy is performed between 24 and 28 weeks’ gestation using behind the mother’s pubic
an OGTT. A ‘one-step’ 2-hour 75-g OGTT is endorsed by the IADPSG, WHO, and national symphysis. Assistance is required to
release the shoulder and allow
guideline committees [2,3,8–10]. Alternative ‘two-step’ methods involving a glucose chal- delivery of the infant.
lenge test followed by an OGTT for those with a positive result are also recommended as an Single nucleotide polymorphism:
alternative [American Diabetes Association (ADA)] or preferable [American College of Obste- the most common type of genetic
tricians and Gynaecologists (ACOG), Diabetes Canada] screening method in the US and variation; a change at a single
nucleotide position in the genome,
Canada [3,11,12]. Whilst universal screening in the third trimester is advocated by several where each variant is present in at
groups (IADPSG, ADA, ACOG, Diabetes Canada), guidelines in the UK suggest limiting least 1% of the population.
screening to women with clinical risk factors for GDM [Scottish Intercollegiate Guidelines
Network (SIGN), National Institute for Health and Care Excellence (NICE)] [2,3,8,10–12].

The diagnostic thresholds for GDM (Table 2) have evolved over recent decades and remain a
source of active discussion. The IADPSG Consensus Panel issued updated diagnostic criteria
in 2010 based on the results of the HAPO Study and these have been widely accepted by
national and international organizations [8]. HAPO, an international cohort study involving a
diverse group of more than 25 000 women, demonstrated a strong, continuous relationship
between maternal glucose levels and primary outcomes, including increased birth weight [17].
This included glucose levels below those diagnostic of diabetes, which were not previously

Table 2. Diagnostic Thresholds for GDM Using OGTT at 24–28 weeks’ Gestation
Guideline committee Glucose load Fastinga mmol/l 1-houra mmol/l 2-houra mmol/l 3-houra mmol/l Refs
(g) (mg/dl) (mg/dl) (mg/dl) (mg/dl)

IADPSG/WHO/ADA/Diabetes 75 5.1 (92) 10.0 (180) 8.5 (153) – [2,3,8,9,12]

Canada/SIGNb

NICEb 75 5.6 (101) – 7.8 (140) – [10]

ADA (Carpenter-Coustan) c
100 5.3 (95) 10.0 (180) 8.6 (155) 7.8 (140) [3]

ADA (NDDG)c 100 5.8 (105) 10.6 (190) 9.2 (165) 8.0 (145) [3]

Diabetes Canada d
75 5.3 (95) 10.6 (190) 9.0 (162) – [12]

NDDG, National Diabetes Data Group.

a
Plasma glucose levels: fasting, 1 hour, 2 hours, and 3 hours following oral glucose load.
b
GDM diagnosed if one or more glucose value met or exceeded.
c
Following an abnormal 50-g 1-hour glucose challenge test; GDM diagnosed if two or more plasma glucose levels met or exceeded.
d
Following an abnormal 50 g 1-hour glucose challenge test; GDM diagnosed if one or more plasma glucose level met or exceeded.

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known to be harmful. Diagnostic thresholds for GDM were (somewhat arbitrarily) set at glucose
values associated with estimated odds of 1.75 for birth weight, cord C-peptide, and percent
infant body fat >90th percentiles, compared with the odds of these outcomes at mean glucose
values for the entire study cohort [8]. The prevalence of GDM increased three- to fourfold at two
European centers following the change from the two-step ADA (Carpenter-Coustan) screening
approach to adopt the IADPSG criteria [18,19].

Mechanisms
Several changes in glucose regulation occur during normal pregnancy to facilitate nutrient
supply to the developing fetus. Hyperinsulinemic-euglycemic clamp studies in healthy lean
women show that, compared with pre-pregnancy, insulin sensitivity is reduced by 56% and
basal endogenous glucose production is increased by 30% in the third trimester [20,21]. In
those with normal glucose tolerance, the pancreatic beta cells adapt to these changes by
producing increased amounts of insulin, allowing maintenance of normal blood glucose levels.
For example, the first- and second-phase insulin response to an intravenous glucose tolerance
test was increased approximately threefold in late pregnancy, relative to pre-pregnancy, in one
small study of normal controls [22]. The insulin resistance associated with normal pregnancy
resolves within days of delivery, as demonstrated in postpartum glucose clamp studies,
suggesting these changes are mediated by placental factors [23].

Pathophysiology of GDM
GDM is characterized by the inability of pancreatic beta cells to respond adequately to the
increased insulin requirements of pregnancy resulting in varying degrees of hyperglycemia. The
key pathophysiological features of insulin resistance and defective insulin secretion mirror those
observed in T2DM. The pathophysiology of GDM has been studied in detail by Catalano et al.,
using hyperinsulinemic-euglycemic clamp studies, the results of which are summarized in his
2014 review [24]. In brief, these studies demonstrated significantly decreased insulin sensitivity
in GDM relative to control subjects, which was present prior to conception and persisted across
pregnancy [24]. A reduction in insulin sensitivity of approximately 50–60% in late pregnancy,
compared with pre-pregnancy, was demonstrated in those with GDM and similarly in those
with normal glucose tolerance [22,25]. Pregnancy therefore appears to unmask previously
unknown beta cell failure due to the exacerbation of pre-existing insulin resistance.

Obesity
GDM shares several nonmodifiable risk factors with T2DM, including advanced age, family
history of diabetes, and ethnicity with a high prevalence of diabetes (including South Asian,
Middle-Eastern, and black Caribbean) [26]. Obesity is the most salient modifiable risk factor for
the condition and presents a particular public health challenge given its rapidly increasing
prevalence globally [27]. The contribution of these genetic and environmental risk factors
highlights the potential for complex mechanistic pathways underlying GDM. A meta-analysis
of 20 cohort studies from North America, Europe, and Australia estimated that the risk of GDM
was approximately two, four, and eight times higher in overweight, obese, and severely obese
women, respectively, relative to women of normal body mass index (BMI) [27]. A population
based analysis including data from 23 904 women in the US described the prevalence of GDM
stratified by BMI (Table 3) [28]. It was estimated that the population attributable fraction of GDM
relating to overweight and obesity was 46% [95% confidence interval (CI)] 36–56%].

Genetic Factors
The high prevalence of T2DM in women with previous GDM raises the possibility of a shared
genetic pathway. Multiple genes associated with pancreatic beta cell development, function,

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Table 3. Prevalence of GDM Stratified by BMI in a Sample of 23 904 Women

BMI (kg/m2) Category GDM prevalence (%) Refs

13–18.4 Underweight 0.7

18.5–25 Normal weight 2.3

[28]
25–29.9 Overweight 4.8

30–34.9 Obese 5.5

35–64.9 Severely obese 11.5

and survival have been identified to influence risk of T2DM in genome-wide association
studies (GWAS). For example, variations in TCFL7, CDKAL1, and MTNR1B loci have been
demonstrated to increase risk of T2DM in ethnically diverse populations [29]. Mutations in
TCF2, a transcription factor which encodes hepatic nuclear factor 1b, were initially identified in a
subtype of monogenic diabetes. The influence of TCF2 variance in T2DM remains uncertain,
with evidence of both reduced and increased T2DM risk reported in GWAS in populations of
varying ethnicity [30,31].

The prevalence of 11 genetic loci known to increase susceptibility to T2DM were examined in a
cohort of Danish women with previous GDM (n = 283) and middle-aged control subjects with
normal glucose tolerance (n = 2446) [32]. When adjusted for age and BMI, three of the
susceptibility alleles were significantly associated with an increased risk of GDM: TCF7L2
rs7903146 [odds ratio (OR) 1.44, 95% CI 1.19–1.74, P = 0.00017], CDKAL1 rs7756992 [OR
1.22, 95% CI 1–1.49, P = 0.049], and TCF2 rs7501939 [OR 1.22, 95% CI 1.01–1.48,
P = 0.039]. A significant cumulative effect for GDM risk was observed when more than 1 of
the 11 alleles were present in combination (OR 1.18, 95% CI 1.10–1.27 per risk allele,
P = 3.2  10 6).

A later study in Finland evaluated 69 single nucleotide polymorphisms (SNPs) associated

with T2DM in women with previous GDM (n = 533) and control subjects with normal glucose
tolerance (n = 407) [33]. Several risk variants were associated with GDM in age-adjusted
analyses, with the strongest association observed in two MTNR1B SNPs: rs10830963 (OR
1.62, 95% CI 1.34–1.96, P = 1.3  10 7) and rs1387153 (OR 1.38, 95% CI 1.14–1.66,
P = 3.6  10 4). Nominally statistically significant associations between seven other SNPs
and increased risk of GDM were also observed, including TCF7L2 rs7903146 (OR 1.3, 95% CI
1.03–1.64, P = 0.016) and GCKR rs780094 (OR 1.25, 95% CI 1.03–1.51, P = 0.028).

The influence of two risk variants, TCF7L2 rs7903146 and GCK rs1799884, was examined in
3811 European and 1706 Thai participants from the HAPO cohort [34]. In the European
subgroup, a significant association between TCF7L2 rs7903146 and blood glucose levels at
baseline, 1 hour, and 2 hours during an OGTT at 24–32 weeks’ gestation was observed (fasting
0.02 mmol/l higher per T-allele, 95% CI 0.002–0.03, P = 0.03; 1-hour glucose 0.16 mmol/l
higher per T-allele, 95% CI 0.08–0.24, P < 0.0001; 2-hour glucose 0.13 mmol/l higher per T-
allele, 95% CI 0.07–0.19, P < 0.0001). There was no significant association observed in the
Thai subgroup. TCF7L2 rs7903146 was associated with increased odds of GDM diagnosis
according to IADPSG criteria in the European subgroup only (per T-allele OR 1.15, 95% CI
1.00–1.31, P = 0.04). GCK rs1799884 was less consistently associated with OGTT results
based on ethnicity but was associated with increased odds of GDM diagnosis according to

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IADPSG criteria in both subgroups (European per T-allele OR 1.29, 95% CI 1.09–1.50,
P = 0.001; Thai per T-allele OR 1.42, 95% CI 1.06–1.77, P = 0.007). The only GWAS of
GDM to date, performed in the Korean population, showed a strong association between
GDM and the risk alleles MTNR1B rs10830962 (OR 1.454, 95% CI 1.315–1.608,
P = 2.49  10 13) and CDKAL1 rs7754840 (OR 1.518, 95% CI 1.372–1.680,
P = 6.65  10 16) [35].

Intrauterine Environment
Several epidemiological studies have reported that offspring risk of T2DM is more closely
associated with maternal than paternal diabetes [36–38]. The risk of offspring GDM was also
more closely associated with maternal diabetes in an American cohort, where 30 (33%) women
with GDM reported a history of maternal diabetes and a nondiabetic father, compared with 9
(12%) women with pregestational diabetes and 5 (6%) control subjects (x2 = 32.4; P < 0.001)
[39]. Longitudinal follow-up of 2527 offspring (mean age 54 years) born to parents in the
Framingham Heart Study demonstrated the risk of T2DM was 3.5-fold greater for those with
diabetes in one parent regardless of gender, and 6-fold greater in those with diabetes in both
parents, compared with those without parental diabetes [40]. However, the risk of T2DM in
offspring of mothers diagnosed with diabetes aged <50 years was noted to be greatly elevated
(OR 9.7, 95% CI 4.3–22.0). These observations may relate to genetic transmission of diabetes
susceptibility variants but also raise the possibility that the intrauterine environment has
contributed to offspring diabetes risk.

In order to escape the confounding of genetic factors, the impact of in utero exposure to a
diabetic environment was examined in an observational study of 19 nuclear families from the
Pima Indian community in Arizona [41]. The risk of offspring diabetes was significantly higher in
siblings born after the mother’s diagnosis of T2DM compared with siblings born before the
mother developed T2DM (OR 3.7, 95% CI 1.3–11.3, P = 0.02). There was no difference
between siblings in terms of diabetes risk when timing of paternal diagnosis of T2DM was
examined. The similarities in pathophysiology of T2DM and GDM suggest these findings may
be of relevance to those exposed to GDM in utero.

Mechanistic studies suggest that GDM exposes the fetus to a proinflammatory environment.
Elevations in serum leukocyte count and levels of inflammatory cytokines, including interleukin
(IL)-6 and tumor necrosis factor (TNF)-a, in women with GDM compared with control subjects
have been reported [42,43]. Placental mRNA and protein expression of inflammatory mediators
also appear to be upregulated in GDM, particularly in the presence of obesity [44]. Environ-
mental exposure to a proinflammatory environment within the uterus may impact diabetes risk
by influencing the fetal epigenome at this early stage, although further work is required to fully
understand these mechanisms [45,46].

Complications
Hyperglycemia is associated with a well-documented range of adverse pregnancy outcomes for
the mother and fetus. The linear association between dysglycemia less severe than overt DM and
short-term adverse pregnancy outcomes was shown definitively in the landmark HAPO study [17].
Since then, evidence has accumulated to support the HAPO findings and also to suggest that
GDM is associated with a range of long-term adverse outcomes for the mother and the offspring.

Offspring Complications
Offspring born to mothers with GDM are at increased risk of multiple immediate complications,
including macrosomia, preterm birth, birth injury, shoulder dystocia, neonatal

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hypoglycemia, neonatal unit admission, and respiratory distress [17,47–51]. It remains uncer-
tain whether GDM is associated with an increased risk of perinatal death. A cohort study
capturing all births in France during 2012, including 57 629 births with maternal GDM, showed
the odds of perinatal mortality were increased by 30% in infants born at term (at or beyond 37
weeks) with maternal GDM, compared with the nondiabetic population [47]. A more conser-
vative estimate in the same cohort, excluding deliveries which were considered to potentially
represent pregestational diabetes (i.e., women to whom any antidiabetic medication was
dispensed in the year following delivery), showed this risk persisted only in those with diet-
treated GDM. On the contrary, large population-based cohort studies, including over 1 million
participants in Ontario, Canada (1996–2010) and Sweden (1991–2003), demonstrated peri-
natal mortality in offspring from GDM mothers (on treatment) was significantly lower than
[relative risk (RR) 0.63, 95% CI 0.43–0.93] or similar to (OR 0.8, 95% CI 0.58–1.10) the
nondiabetic population, respectively [51,52]. Doubt also exists over the relationship between
GDM and risk of congenital anomaly. Whilst a large body of evidence supports an association
between pregestational diabetes and increased risk of congenital malformations, this is due to
the impact of hyperglycemia on embryogenesis during the first eight gestational weeks (i.e.,
before GDM is diagnosed). A study performed across five Irish centers reported there was no
difference in rates of congenital anomaly observed in the offspring of 5500 women with GDM or
normal glucose tolerance (2.3% versus 1.5%, P > 0.05) [48]. However, GDM was associated
with an elevated risk of congenital anomaly in the Ontario cohort [absolute risk (AR) 37.5 per
1000 births in GDM, AR 29.04 per 1000 births in nondiabetic population], and of cardiac
malformations in the French cohort (OR 1.3, 95% CI 1.1–1.4; insulin-treated GDM group),
compared with the nondiabetic population [47,52]. These positive findings may be accounted
for by the inclusion of women with unrecognized T2DM and failure of these studies to adjust for
important confounding factors, including maternal obesity (known to increase risk of congenital
anomaly in the GDM population) and ethnicity [53].

The long-term impact of intrauterine exposure to GDM on offspring health remains uncertain.
Studies in childhood have shown evidence of an adverse cardiovascular phenotype, including
increases in adiposity, insulin resistance, systolic blood pressure, and risk of circulatory disease
compared with offspring with no parental diabetes [54,55]. Studies in adult offspring have
demonstrated reduced insulin sensitivity and increased risk of prediabetes/diabetes, meta-
bolic syndrome, and higher BMI compared with the background population [56,57].

Maternal Complications
The risks of multiple serious perinatal complications are increased in women with GDM,
including gestational hypertension, pre-eclampsia, polyhydramnios, Caesarean section,
and shoulder dystocia [17,47,48,50,51]. The likelihood of recurrent GDM in a subsequent
pregnancy was estimated as 48% in a meta-analysis of 18 studies [58]. Recurrence was more
likely in non-white European ethnic groups (Hispanic, African American, and Asian) and
multiparous participants. Obesity, advanced maternal age, and early gestation of diagnosis
in the index pregnancy have also been implicated as risk factors for recurrent GDM [59].

The risk of T2DM in women following GDM was seven times that of women with normal glucose
tolerance in pregnancy in one meta-analysis [60]. It has been estimated that as many as one-
third of T2DM cases occurring in parous women were pre-dated by GDM [61]. A systematic
review of 28 studies showed the cumulative incidence of T2DM increased rapidly in the 5 years
following the index pregnancy and approached a plateau beyond 10 years of follow-up [62].
The cumulative incidence of T2DM observed ranged from 2.6% to 70% across follow-up
periods ranging from 6 weeks to 28 years following delivery. In analyses adjusted to account for

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variable T2DM screening rates and follow-up durations, five studies reported incidence of 50%
or higher in the 5–10 years following the index pregnancy. Interestingly, the pattern of
cumulative incidence appeared to be similar in different ethnic groups after adjustment for
interstudy variability. Higher fasting glucose level on OGTT was the factor found to associate
most closely with risk of progression of GDM to T2DM, although a risk threshold could not be
identified due to variations in statistical analysis between included studies [62]. It has generally
been observed that increasing maternal BMI, early gestational age at GDM diagnosis, and
postpartum impaired glucose tolerance are predictors for future development of T2DM [57].

Treatment
Treatment of GDM aims to reverse hyperglycemia and reduce the risk of the associated
adverse pregnancy outcomes. The ability of medical intervention to impact positively on fetal
and maternal morbidity was first demonstrated in the landmark Australian Carbohydrate
Intolerance Study in Pregnant Women (ACHOIS) [63]. Intervention with dietary advice, blood
glucose monitoring, and insulin therapy if required was associated with a 67% reduction in the
primary composite outcome of infant death, shoulder dystocia, bone fracture, and nerve palsy,
compared with usual care. Reductions in average birthweight and rates of macrosomia were
also noted. Similar benefits were also demonstrated in the Maternal-Fetal Medicine Units
Network randomized trial performed in 958 women diagnosed with ‘mild’ GDM (i.e., normal
fasting glucose levels on OGTT). A similar intervention package was associated with reductions
in clinical outcomes, including macrosomia, Caesarean delivery, shoulder dystocia, and pre-
eclampsia compared with standard care (Table 4) [64].

Management of GDM should occur in a multidisciplinary setting with joint diabetes and
obstetric input. Education in lifestyle modification and capillary blood glucose monitoring should
be provided by diabetes specialist nurses and dieticians. Fasting and 1- or 2-hour postprandial
capillary blood glucose monitoring is recommended in national guidelines [2,10,12,65].

Table 4. Selected Neonatal and Maternal Outcomes from the Maternal-Fetal Medicine Units Network Trialc
Treatment group Control group Relative risk P value Refs

Neonatal outcomesa n = 485 n = 473

Composite perinatal end point:b 149/460 (32.4) 163/440 (37.0) 0.87

Birth weight (g) 3302  502.4 3408  589.4 <0.001

Birth weight >4000 g: 28/477 (5.9) 65/454 (14.3) 0.41 (0.26–0.66) <0.001

Large for gestational age: 34/477 (7.1) 66/454 (14.5) 0.49 (0.32–0.76) <0.001

Fat mass (g) 427.0  197.9 464.3  222.3 0.003 [64]

Maternal outcomes n = 476 n = 455

Caesarean delivery: 128 (26.9) 154 (33.8) 0.79 (0.64–0.99) 0.02

Shoulder dystocia: 7 (1.5) 18 (4.0) 0.37 (0.14–0.97) 0.02

Preeclampsia: 12 (2.5) 25 (5.5) 0.46 (0.22–0.97) 0.02

Preeclampsia or gestational hypertension: 41 (8.6) 62 (13.6) 0.63 (0.42–0.96) 0.01

Weight gain (kg) 2.8  4.5 5.0  3.3 <0.001

a
There were 10 women in the treatment group and 19 women in the control group for whom at least some delivery data were missing.
b
The composite perinatal outcome included stillbirth, neonatal death, hypoglycemia, hyperbilirubinemia, elevated cord c-peptide level, and birth trauma.
c
Data are presented as n/N (%), n (%), or mean  SD.

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 TEM 1352 No. of Pages 12

Glucose monitoring targets vary between guidelines but are influenced by those utilized in
ACHOIS and Maternal-Fetal Medicine Units Network trials [2,10,12,65].

Lifestyle Intervention
Lifestyle intervention, comprising dietary modification, physical activity, and weight manage-
ment, is an essential component of GDM management. It is estimated that this strategy may be
sufficient to achieve blood glucose targets in as many as 70–85% of women diagnosed using
ADA criteria [65]. Targets for gestational weight gain should be determined on an individual
basis to optimize maternal and fetal outcomes. An Institute of Medicine guideline recommends
weight gain targets based on pre-pregnancy BMI but does not provide specific advice for GDM
[66]. A recent meta-analysis of randomized controlled trials reported that dietary intervention is
associated with improvements in mean maternal fasting glucose (13 studies; 4.07 mg/dl,
95% CI 7.58 to 0.57, P = 0.02) and postprandial glucose (9 studies; 7.78 mg/dl, 95% CI
12.27 to 3.29, P = 0.0007) compared with control subjects, with reduced requirement for
pharmacological treatment (RR 0.49, 95% CI 0.27–0.88, P = 0.02) [67]. Reduction in mean
birthweight ( 170.62 g, 95% CI 333.64 to 7.60, P = 0.04) and rates of macrosomia (RR
0.49, 95% CI 0.27–0.88, P = 0.02) were also observed. A Cochrane review comparing lifestyle
intervention with usual care or diet alone found that intervention was associated with reduced
risk of large for gestational age offspring (RR 0.6, 95% CI 0.5–0.71) [68]. Other positive
findings associated with intervention included an increased likelihood of achieving maternal
postpartum weight goals and decreased neonatal adiposity. A further Cochrane review,
evaluating the role of combined diet and exercise interventions to prevent GDM, reported a
trend to a reduced risk of GDM with this strategy which did not reach statistical significance (RR
0.85, 95% CI 0.71–1.01) [69].

Pharmacological Therapy
If blood glucose targets are not achieved with lifestyle intervention, the addition of glucose-
lowering therapy is warranted. Insulin is recommended as the first-line pharmacological therapy
for GDM in the US and Canada, whereas oral therapy is the preferred first-line strategy in the UK
unless blood glucose levels are markedly elevated [2,10,12,65]. Insulin is typically administered
as multiple daily injections, although continuous subcutaneous insulin infusion is acknowledged
as a potential alternative in US national recommendations [65]. There is growing evidence to
suggest insulin analogues (short and long acting) are safe alternatives to human insulin during
pregnancy [70].

Metformin and glibenclamide (known as glyburide in the US and Canada) are the only oral
agents used in the treatment of GDM. In the large randomized Metformin in Gestational
Diabetes (MiG) trial, there was no difference in the rate of perinatal complications (32.0%
versus 32.2%) or adverse events between metformin and insulin treatment groups [71].
However, 46% of patients in the metformin group required the addition of insulin therapy to
achieve target blood glucose levels. In another large randomized trial, glibenclamide and insulin
were associated with similar maternal and fetal perinatal outcomes [72]. In this case only 4% of
women in the glibenclamide group required addition of insulin to maintain acceptable blood
glucose levels. In a randomized pilot study, insulin appeared superior to glibenclamide as add-
on therapy for women with GDM, not achieving glycemic targets with metformin monotherapy
[73]. Insulin was associated with improved glycemic control and fewer episodes of hypoglyce-
mia than glibenclamide.

Meta-analyses comparing the safety and efficacy of metformin and glibenclamide have drawn
differing conclusions. A 2015 meta-analysis suggested metformin was associated with

Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy 9

 TEM 1352 No. of Pages 12

superior outcomes when compared with glibenclamide, including less maternal weight gain, Outstanding Questions
reduced birth weight, and reduced rates of macrosomia [74]. However, this finding was based Which early pregnancy screening
on only two randomized trials. A Cochrane review examined the role of oral therapies for GDM in techniques for GDM best predict posi-
tive diagnostic results in late preg-
11 trials and concluded there is insufficient evidence to draw an informed conclusion regarding nancy (i.e., how reliably can we infer
the benefits of any particular oral therapy over another [75]. a diagnosis of GDM in early
pregnancy)?
The long-term impacts of intrauterine exposure to metformin and glibenclamide are unknown.
Does the addition of early pregnancy
Whilst glibenclamide appears to cross the placenta in low concentrations, concerns have been
screening and/or universal late preg-
raised regarding its ability to alter placental glucose transporter expression, potentially leading nancy screening for GDM improve
to increased fetal insulin production and beta cell fatigue in the long-term [76]. Metformin maternal and fetal perinatal outcomes
crosses the placenta readily and similar plasma concentrations have been observed in the fetal compared with late pregnancy screen-
ing performed in ‘high risk’ groups
and maternal circulation [77]. A recent case control study involving data from 11 European
only?
congenital anomaly databases reported that there was no increase in the risk of all non-genetic
congenital anomalies combined following exposure to metformin in the first trimester of Which late pregnancy GDM screening
pregnancy [78]. An increase in the risk of pulmonary valve atresia (adjusted OR 3.54, 95% strategy is associated with the greatest
CI 1.05–12.00) following metformin exposure was reported, however the authors acknowledge benefits in clinical outcomes?

this may represent a chance finding in the context of multiple statistical testing. The current
What are the most clinically and cost-
evidence of outcomes in the offspring of metformin-treated mothers, including increased
effective methods of GDM screening
weight in childhood, is summarized in detail in a recent review by Lindsay and Loeken [79]. and management in low- and middle-
income countries?
Postnatal Management
Women with GDM should undergo screening in the postnatal period to exclude overt diabetes To what extent does epigenetic trans-
mission mediate the influence of envi-
or impaired glucose tolerance. There is no robust evidence to support the mechanism of ronment, including obesity and
screening: a fasting plasma glucose or 75-g OGTT between 4 weeks and 6 months following maternal DM, on offspring risk of
delivery may be offered, depending on the national guideline followed [2,10,12,65]. Regular GDM?
screening for T2DM or impaired glucose tolerance should be offered with HbA1c or fasting
glucose on a 1 to 3 yearly basis [2,10,65]. In one longitudinal study including 350 women with How does intervention to improve or
reverse hyperglycemia in GDM influ-
impaired glucose tolerance and previous GDM, intensive lifestyle intervention and metformin ence the future metabolic health of
were associated with reduced progression to overt DM, compared with placebo, over a 10- offspring?
year follow-up period [80]. On this basis, intensive lifestyle intervention with or without the
addition of metformin is recommended by Diabetes Canada for women identified to have Which pharmacological therapies for
GDM offer the greatest short- and
impaired glucose tolerance or prediabetes on postpartum screening [12].
long-term benefits to women with
GDM?
Concluding Remarks
Despite known short- and long-term complications of GDM for both mother and child, there What is the long-term impact of in
remain uncertainties regarding the optimal time for screening women, which diagnostic utero exposure to oral antidiabetic
therapies, particularly metformin, for
threshold to use, and best management pathways [81]. Better understanding offers a real
the offspring of women with GDM?
opportunity to optimize health of women and their children (see Outstanding Questions).
How can we optimize the postnatal
Acknowledgements management of women with GDM,
We acknowledge the support of Tommy’s and the British Heart Foundation. including those with normal or
impaired glucose tolerance, to reduce
the risk of recurrent GDM and progres-
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