DIABETES IN PATIENT SUBGROUPS

Gestational diabetes

Whats new?

Zoe A Stewart
C

Helen R Murphy

Abstract
Maternal hyperglycaemia is associated with increased risk of adverse perinatal outcome, in particular, infant birth weight that is large for gestational age, increased infant fat mass, pre-eclampsia and preterm
delivery, and an increased need for caesarean section. However, there
is controversy regarding the diagnosis and treatment of specific levels
of hyperglycaemia during pregnancy. This article summarizes the latest
evidence-based recommendations for the diagnosis and classification of
gestational diabetes mellitus (GDM). It considers the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommendations and epidemiological evidence from the landmark Hyperglycaemia
and Adverse Pregnancy Outcome (HAPO) study. It reviews the evidence
in support of intensive treatment of hyperglycaemia in pregnancy and
provides suggestions for post-partum management to delay and/or prevent progression to type 2 diabetes.

diagnostic criteria.5 The recognition that the relationship between

glycaemia and maternalefetal outcome is a continuum has created
controversy regarding appropriate diagnostic thresholds.

Keywords diabetes; gestational diabetes; hyperglycaemia in pregnancy;

large for gestational age; macrosomia; pregnancy

Risk factors for developing GDM

Introduction







Body mass index greater than 30 kg/m2

Previous large for gestational age (LGA) infant over 4.5 kg
Gestational diabetes in a previous pregnancy
Family history of diabetes (first-degree relative)
Ethnic origin with high prevalence of type 2 diabetes (e.g.
South Asian (in particular Indian, Pakistani and Bangladeshi), Black Caribbean, Middle Eastern)
Retrospective analyses also suggest increased rates of GDM with
advancing maternal age and in women who have a history of
infertility, polycystic ovary syndrome or conception using assisted reproductive technologies.6e8 However, although these factors increase the risk of GDM, 30e50% of affected women have
no known risk factors.

Diabetes mellitus is the commonest medical condition complicating pregnancy, affecting up to 5% of pregnancies in England
and up to 25% of pregnancies in Asia.1 Gestational diabetes
mellitus (GDM) accounts for 87.5% of diabetic pregnancies. It is
defined as any degree of glucose intolerance with onset or first
recognition during pregnancy.2 Hyperglycaemia during pregnancy is associated with increased risk of pre-eclampsia, premature delivery, caesarean section delivery, and of the later
development of overt (predominantly type 2) diabetes in the
mother. Risks to the offspring include the perinatal and longerterm consequences of increased adiposity and birth weight that
is large for gestational age (LGA).3 Although serious perinatal
complications such as death, shoulder dystocia, bone fracture or
nerve palsy are rare (1e4%), macrosomia (infant birth weight
>4 kg) and LGA are common, affecting 10e20% GDM offspring.
LGA infants are themselves at increased longer-term risk of insulin resistance, obesity and diabetes, with female offspring
having a higher chance of developing gestational diabetes during
future pregnancy.4
Hyperglycaemia should be considered as a continuous risk
variable for all pregnant women in a similar way to other continuous variables such as weight and blood pressure, rather than
being dichotomized into distinct diagnoses based on arbitrary

Screening for GDM

Whether screening for GDM should be universal or targeted at
high-risk groups remains controversial. The International Association of Diabetes and Pregnancy Study Groups (IADPSG)
Consensus Panel,9 supported by the World Health Organization10
and the Australasian Diabetes in Pregnancy Society advise universal screening of pregnant women at 24e28 weeks gestation
using a 2- or 3-hour 75-g oral glucose tolerance test (OGTT), and
earlier screening for women at high risk of GDM. While the
OGTT represents the gold standard diagnostic test for GDM, a
non-fasting 1-hour 50-g glucose challenge test (GCT), recommended by the 2013 National Institutes of Health (NIH)
consensus group,11 is a cheaper and less burdensome initial
alternative, and widely used in clinical practice. In the NIHrecommended protocol, women with a positive GCT should
have an OGTT before GDM is diagnosed (known as the two-step
approach). The American Diabetes Association recommends

Zoe A Stewart MBBS BMedSc is an Honorary Clinical and Research Fellow

at the University of Cambridge, Cambridge, UK. Competing interests:
none declared.
Helen R Murphy MD FRACP is an Honorary Consultant/Senior Research
Associate at the University of Cambridge, Cambridge, UK. Competing
interests: none declared.

MEDICINE 43:1

There is ongoing controversy about universal versus selective

screening for gestational diabetes mellitus (GDM). International
guidelines advise universal screening for all pregnant women at
24e28 weeks gestation using a 75-g oral glucose tolerance
test (OGTT). Health economic analyses are currently awaited
The current World Health Organization (WHO) and International
Association of Diabetes and Pregnancy Study Groups guidelines
for diagnosing GDM (fasting plasma glucose (FPG) 5.1, 1-hour
10.0, 2-hour 8.5 mmol/litre) may result in a two- to threefold
increase in the number of women diagnosed with GDM
compared with the previous WHO/National Institute for Health
and Care Excellence criteria (FPG 7.0, 2-h 7.8 mmol/litre)
Metformin appears to be safe and effective treatment in late
gestation, with no adverse outcomes noted in offspring up to 2
years of age

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DIABETES IN PATIENT SUBGROUPS

universal screening using either the IADPSG or NIH strategy.12 A

recent Cochrane review found insufficient evidence to make a
recommendation regarding universal GDM screening or specific
screening protocols for GDM.13
Guidelines published by the National Institute for Health and
Care Excellence (NICE) in 2008,14 currently under review,
recommend screening only high-risk women and suggest that,
before deciding, women should be informed that:
 most women respond to diet and lifestyle changes and only
10e20% require insulin and/or oral medication
 undiagnosed GDM is associated with a small risk of birth
complications such as shoulder dystocia
 diagnosed GDM may lead to increased monitoring and
planned intervention during pregnancy/labour.7

Diagnosis of GDM
The IADPSG recommendations for the diagnosis of GDM are
based on findings from the HAPO study9 (Table 1). Widespread
adoption of these criteria is likely to increase the number of
women diagnosed with GDM by two- to threefold. However,
these criteria are associated with adverse maternal and neonatal
outcomes,16e18 and although the cost implications are significant, so too is the opportunity for intervention to reduce
maternal and fetal complication rates. Nevertheless, this benefit
may not apply in all contexts; a recent epidemiological study in a
Chinese population found that implementation of the IADPSG
criteria doubled the prevalence of GDM, but that women in
whom GDM was diagnosed solely on the basis of IADPSG criteria
were not at increased risk of complications.19 Given the significant cost and resource implications of screening and treatment,
particularly in resource-poor settings, context-specific health
economic evaluation is important.

Epidemiology: Hyperglycaemia and Adverse Pregnancy Outcome

(HAPO) study
The objective of the Hyperglycaemia and Adverse Pregnancy
Outcome (HAPO) study was to clarify the maternal glucose
concentration threshold associated with adverse perinatal
outcome.15 It was a landmark multinational, multicultural,
epidemiological study in which 25,000 women had a 75-g oral
glucose tolerance test (OGTT) performed during the third
trimester. OGTT results were available to women and health
professionals only when overt diabetes was diagnosed (fasting
plasma glucose >5.8 mmol/litre or a 2-hour value of >11.1
mmol/litre). Primary outcomes were birth weight over the 90th
percentile (LGA), delivery by caesarean section, neonatal hypoglycaemia and cord C-peptide over the 90th percentile (a marker
of fetal hyperinsulinaemia). Secondary outcomes were preeclampsia, preterm delivery, shoulder dystocia/birth injury,
hyperbilirubinaemia and neonatal care admission. The key
finding was of a continuous linear relationship between maternal
hyperglycaemia (on fasting, 1-hour and 2-hour post-OGTT
values) and increased frequency of primary or secondary outcomes. Importantly, this association was independent of other
risk factors, including maternal obesity, and did not differ between countries or centres.

Treatment of maternal hyperglycaemia: evidence from

randomized trials
Near normoglycaemia is the established goal for glycaemic
management during pregnancy, and the associations established
by HAPO support this. However, formal demonstration in intervention studies that treatment of GDM improves pregnancy
outcomes, and investigation of what degree of hyperglycaemia
warrants treatment and which treatments are most effective, are
critical. This has been addressed by three large-scale, rigorously
conducted, randomized controlled trials.

Treatment of severe maternal hyperglycaemia

The Australian Carbohydrate Intolerance Study in Pregnant
Women (ACHOIS)20 showed that women with GDM (75% White)
treated with dietary advice and insulin had a reduced rate of
serious perinatal complications (a composite primary outcome
measure comprising infant death, shoulder dystocia, bone fracture
and nerve palsy). However, the rates of serious complications were
low (1% treatment versus 4% control group) and much attention

IADPSG criteria for GDM and overt diabetes in pregnancy9

Hyperglycaemia during pregnancy
Gestational diabetesa
Fasting plasma glucose
1-hour plasma glucose
2-hour plasma glucose

5.1 mmol/litre
10.0 mmol/litre
8.5 mol/litre

Overt diabetes in pregnancy

Fasting plasma glucose
Glycated haemoglobin (HbA1c)
Random plasma glucose

7.0 mmol/litre
6.5% (DCCT/UKPDS standardized)
11.1 mmol/litre and confirmed by either
fasting plasma glucose or HbA1c

DCCT, Diabetes Control and Complications Trial; GDM, gestational diabetes mellitus; IADPSG, International Association of Diabetes and Pregnancy Study Groups; UKPDS,
United Kingdom Prospective Diabetes Study.
a
One or more of these values after a 75-g oral glucose tolerance test is consistent with GDM.

Table 1

MEDICINE 43:1

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DIABETES IN PATIENT SUBGROUPS

Effects of treatment of mild GDM on maternal and perinatal morbidity

Variable
Maternal outcomes
Caesarean delivery (%)
Pre-eclampsia or pregnancy-induced
hypertension (%)
Weight gain (kg)
BMI at delivery (kg/m2)
Neonatal outcomes
Shoulder dystocia (%)
Birth weight (g)
Birth weight >4000 g (%)
Birth weight 90th percentile (LGA) (%)
Fat mass (g)
Birth weight 10th percentile (SGA) (%)

Treatment

Control

Relative risk (97% CI)

26.9
8.6

33.8
13.6

0.79 (0.64e0.99)
0.63 (0.42e0.96)

2.5  4.5
31.1  4.5

5.0  3.3
32.3  5.2

1.5%
3302  502.4
5.9
7.1
427  198
7.5

4%
3408  589
14.3
14.5
464  222
6.4

P value

0.02
0.01
<0.001
<0.001

0.37 (0.14e0.97)
0.41 (0.26e0.66)
0.49 (0.32e0.76)
1.18 (0.7e1.99)

0.02
<0.001
<0.001
<0.001
0.003
0.49

LGA, large for gestational age; SGA, small for gestational age.

Table 2

Metformin versus insulin

was focused on the secondary outcomes, showing reduced

maternal weight gain, reduced pre-eclampsia, reduced infant birth
weight and improved health-related quality of life for women in the
treatment group. It is important to note that, in the post-HAPO era,
the ACHOIS cohort could be considered as severely hyperglycaemic (fasting plasma glucose (FPG) <7.8 and median glucose
8.8 mmol/litre following 75-g OGTT).

Metformin is a logical option for the treatment of maternal

hyperglycaemia as it improves insulin sensitivity, and is not
associated with hypoglycaemia or maternal weight gain. However,
it does cross the placenta and could have effects on fetal physiology. Metformin was more acceptable to women than insulin
injections, and effective in a large cohort of mixed ethnicity when
used alone or in conjunction with insulin therapy.23 Almost half
those who commenced metformin subsequently required combined treatment with insulin. The lowest risk of infant complications was seen in women with capillary glucose fasting less than
4.9 and postprandial less than 6.5 mmol/litre, suggesting that these
should be the appropriate glycaemic control targets. Follow-up
studies suggest that metformin is a safe and effective treatment
in pregnancy, with no adverse outcomes noted in offspring up to
two years of age.24 Of note, neither maternal BMI, treatment with
metformin versus insulin, nor baseline OGTT was related to
outcome, suggesting that the level of glucose control achieved is
the key predictor of maternal/fetal outcome.25 Subsequent studies
suggest that, whereas metformin and insulin appear similarly
effective, rates of preterm delivery, maternal weight gain,
caesarean section and neonatal hypoglycaemia may be lower
when metformin rather than insulin is used to treat GDM.26

Treatment of mild-to-moderate maternal hyperglycaemia

The subsequent multicentre, randomized trial of treatment for
mild gestational diabetes was performed in a cohort of women
with milder hyperglycaemia (FPG <5.3 and median glucose 8.2
mmol/litre following the higher-dose 100-g OGTT).21 This group
was predominantly multiparous (75%), overweight or obese
(mean BMI 30  5 kg/m2) and of mixed ethnicity (25% White).
More than 99% of women were treated with diet and lifestyle
with only a small subgroup (<1%) requiring insulin. Treatment
was not associated with a reduction in serious perinatal complications (again a composite measure of stillbirth, perinatal
death and perinatal morbidity). However, there were significant
improvements in infant birth weight, neonatal fat mass, shoulder
dystocia, delivery by caesarean section, pre-eclampsia, pregnancy-induced hypertension and maternal weight gain, all of
which were pre-specified secondary outcomes (Table 2). The
benefits of nutritional advice on reducing maternal weight gain
and fetal growth acceleration were particularly striking. This
provides compelling evidence that the benefits of intensive
multidisciplinary team management of gestational diabetes lie in
halting the growing epidemic of obesity in mothers and their
infants, rather than preventing the rare perinatal complications
of death, bone fracture and nerve palsy. The same study found
that there was no increase in adverse outcomes for women with a
1-hour GCT result up to 7.8 mmol/litre compared with those who
had a GCT result of less than 6.7 mmol/litre, suggesting that
treatment may not be warranted for women with milder glucose
intolerance.22

MEDICINE 43:1

Prevention of type 2 diabetes in women with past GDM

The incidence of type 2 diabetes in women with GDM is 70%
higher than in the background population. Depending on
ethnicity, the rate of progression from GDM to type 2 diabetes is
50e70% over 5e10 years of follow-up. Hence continual followup, annual screening for overt diabetes using fasting plasma
glucose, HbA1c or OGTT, and preventive measures are important. Indeed, a recent study found that screening for GDM was
cost effective only when it provided an opportunity to intervene
and prevent future type 2 diabetes. Women with higher BMIs
and/or higher intra-partum or post-partum weight gain are most

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DIABETES IN PATIENT SUBGROUPS

at risk of type 2 diabetes, every 1-kg increase in pre-pregnancy

weight being associated with a 40% increase in risk.27 The Diabetes Prevention Program (DPP) suggested that metformin and
lifestyle intervention are equally effective in reducing risk of
progression to type 2 diabetes by around 50%.28
A

19

20

REFERENCES
1 Tutino G, Tam W, Yang X, Chan J, Lao T, Ma C. Diabetes and pregnancy: perspectives from Asia. Diabet Med 2014; 31: 302e18.
2 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2009; 32: S62e7.
3 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 Tri-Hospital Gestational Diabetes
Project. Am J Obstet Gynecol 1995; 173: 146e56.
4 Hillier TA, Pedula KL, Schmidt MM, Mullen JA, Charles MA, Pettitt DJ.
Childhood obesity and metabolic imprinting: the ongoing effects of
maternal hyperglycemia. Diabetes Care 2007; 30: 2287e92.
5 Murphy HR, Hadden DR. Hyperglycaemia in pregnancy: whats in a
name? Diabet Med 2014; 31: 252e3.
6 Wang YA, Nikravan R, Smith HC, Sullivan EA. Higher prevalence of
gestational diabetes mellitus following assisted reproduction technology treatment. Hum Reprod 2013; 28: 2554e61.
7 Kjerulff L, Sanches-Ramos L, Duffy D. Pregnancy outcomes in women
with polycystic ovary syndrome: a metaanalysis. Am J Obstet Gynecol
2011; 204. 558.e1e558.e6.
8 Makgoba M, Savvidou M, Steer P. An analysis of the interrelationship
between maternal age, body mass index and racial origin in the
development of gestational diabetes mellitus. Br J Obstet Gynaecol
2011; 119: 276e82.
9 International Association of Diabetes and Pregnancy Study Groups
Consensus Panel recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010; 33: 676e82.
10 World Health Organization. Diagnostic criteria and classification of
hyperglycaemia first detected in pregnancy 2013.
11 VanDorsten JP, Dodson WC, Espeland MA, et al. NIH consensus
development conference: diagnosing gestational diabetes mellitus.
NIH Consens State Sci Statements 2013; 29: 1e31.
12 American Diabetes Association. Standards of medical care in diabetes e 2014. Diabetes Care 2014; 37: s14e80.
13 Tieu J, McPhee A, Crowther C, Middleton P. Screening and subsequent
management for gestational diabetes for improving maternal and
infant health. Cochrane Database Syst Rev 2014; http://dx.doi.org/
10.1002/14651858.CD007222. Art. No.: CD007222.
14 The Guideline Development Group. Management of diabetes from
preconception to the postnatal period: summary of NICE guidance. Br
Med J 2008; 336: 714e7.
15 The HAPO Study Cooperative Research Group. Hyperglycemia and
adverse pregnancy outcomes. N Engl J Med 2008; 358: 1991e2002.
16 Shang M, Lin L. IADPSG criteria for diagnosing gestational diabetes
mellitus and predicting adverse pregnancy outcomes. J Perinatol
2014; 34: 100e4.
17 OSullivan EP, Avalos G, OReilly M, Dennedy MC, Gaffney G, Dunne F.
Atlantic Diabetes in Pregnancy (DIP): the prevalence and outcomes of
gestational diabetes mellitus using new diagnostic criteria. Diabetologia 2011; 54: 1670e5.
18 Falavigna M, Prestes I, Schmidt MI, Duncan BB, Colagiuri S, Roglic G.
Impact of gestational diabetes mellitus screening strategies on

MEDICINE 43:1

21

22

23

24

25

26

27
28

perinatal outcomes: a simulation study. Diabetes Res Clin Pract

2013; 99: 358e65.
Liao S, Mei J, Song W, et al. The impact of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) fasting
glucose diagnostic criterion on the prevalence and outcomes of
gestational diabetes mellitus. Diabet Med 2014; 31: 341e51.
Crowther C, et al. Effect of treatment of gestational diabetes mellitus
on pregnancy outcomes. N Engl J Med 2005; 352: 2477e86.
Landon M, Spong C, Thom E, et al. A multicenter, randomized trial of
treatment for mild gestational diabetes. N Engl J Med 2009; 361:
1339e48.
Figueroa D, Landon M, Mele L, Al E. Relationship between 1-hour
glucose challenge test results and perinatal outcomes. Obstet
Gynecol 2013; 121: 1241e7.
Rowan J, Hague W, Gao W, Battin M, Moore M. Metformin versus
insulin for the treatment of gestational diabetes. N Engl J Med 2008;
358: 2003e15.
Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM.
Metformin in gestational diabetes: the offspring follow-up (MiG TOFU):
body composition at 2 years of age. Diabetes Care 2011; 34: 2279e84.
Rowan J, Gao W, Hague W, McIntyre H. Glycemia and its relationship
to outcomes in the metformin in gestational diabetes trial. Diabetes
Care 2010; 33: 9e16.
Lautatzis M-E, Goulis DG, Vrontakis M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus
or polycystic ovary syndrome: a systematic review. Metab Clin Exp
2013; 62: 1522e34.
Kim C. Maternal outcomes and follow-up after gestational diabetes
mellitus. Diabet Med 2014; 31: 292e301.
Ratner R, Christophi C, Metzger B, et al. Prevention of diabetes in
women with a history of gestational diabetes: effects of metformin and
lifestyle interventions. J Clin Endocrinol Metab 2008; 93: 4774e9.

Practice points
C

Treatment reduces the risk of serious perinatal complications in

women with severe hyperglycaemia in pregnancy (fasting plasma
glucose (FPG) <7.8 mmol/litre)
Treatment has beneficial effects on maternal weight gain, infant
birth weight, caesarean delivery, pre-eclampsia, pregnancyinduced hypertension and neonatal adiposity, in women with
both mild (FPG <5.3 mmol/litre) and more moderate (FPG <7.8
mmol/litre) hyperglycaemia in pregnancy
The level of glycaemic control achieved is more important than
maternal obesity or treatment modality (metformin versus insulin). Proposed capillary glucose targets for tight glycaemic control
are fasting <4.9 mmol/litre and postprandial <6.5 mmol/litre
Both lifestyle interventions and metformin reduce the incidence of
type 2 diabetes by approximately 50% in women with previous
gestational diabetes

Acknowledgements
HRM is supported by a National Institute for Health Research (NIHR)
research fellowship (CDF-2013-06-035). ZAS is supported by the
Gates Cambridge Trust and Jean Hailes for Womens Health Australia.

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2014 Elsevier Ltd. All rights reserved.