REVIEWS

Gestational diabetes mellitus: does an

effective prevention strategy exist?
Rochan Agha-Jaffar1, Nick Oliver1, Desmond Johnston1 and Stephen Robinson2
Abstract | The overall incidence of gestational diabetes mellitus (GDM) is increasing worldwide.
Preventing pathological hyperglycaemia during pregnancy could have several benefits: a
reduction in the immediate adverse outcomes during pregnancy, a reduced risk of long-term
sequelae and a decrease in the economic burden to healthcare systems. In this Review we
examine the evidence supporting lifestyle modification strategies in women with and without
risk factors for GDM, and the efficacy of dietary supplementation and pharmacological
approaches to prevent this disease. A high degree of heterogeneity exists between trials so a
generalised recommendation is problematic. In population studies of dietary or combined
lifestyle measures, risk of developing GDM is not improved and those involving a physical activity
intervention have yielded conflicting results. In pregnant women with obesity, dietary
modification might reduce fetal macrosomia but in these patients, low compliance and no
significant reduction in the incidence of GDM has been observed in trials investigating physical
activity. Supplementation with probiotics or myoinositol have reduced the incidence of GDM but
confirmatory studies are still needed. In randomized controlled trials, metformin does not
prevent GDM in certain at-risk groups. Given the considerable potential for reducing disease
burden, further research is needed to identify strategies that can be easily and effectively
implemented on a population level.

1
Division of Diabetes,
Endocrinology and
Metabolism, G3 Medical
School Building, Imperial
College London, Norfolk
Place, London, W2 1PG, UK.
2
Department of Metabolic
Medicine, Mint Wing,
St Mary’s Hospital, Imperial
College NHS Trust, Praed
Street, London, W2 1NY, UK.
Correspondence to S.R.
Stephen.Robinson@imperial.
nhs.uk
doi:10.1038/nrendo.2016.88
Published online 24 Jun 2016
Gestational diabetes mellitus (GDM) is defined as
“diabetes diagnosed in the second or third trimester
of pregnancy that is not clearly overt diabetes” and is
associated with considerable risks to both the mother
and developing fetus1. For the mother, these include a
greater likelihood of undergoing a caesarian section,
pre-eclampsia and the development of type 2 diabetes
mellitus (T2DM); for the baby, macrosomia, shoulder
dystocia, and physiological and metabolic abnormali-
ties such as neonatal hypoglycaemia, and obesity with
insulin resistance in young adulthood2–4. Treatment,
including dietary modification and pharmacological
therapies such as metformin and insulin, have con-
sistently been shown to reduce immediate adverse
outcomes thus decreasing the requirement for neona-
tal care5,6. However, the economic burden associated
with GDM remains substantial with one model pre-
dicting that the overall cost of care for an individual
with GDM is 34% greater than for a woman without
the disease7. In light of this finding, and the increasing
incidence reflecting the rising prevalence of obesity
among women of childbearing age, measures that pre-
vent or reduce the risk of developing GDM need to be
identified.
In this Review we discuss the evidence supporting
lifestyle strategies in women with and without risk fac-
tors as well as the efficacy of dietary supplementation
and pharmacological approaches to GDM preven-
tion. Direct comparison of possible interventions to
treat GDM is problematic in part due to heterogeneity
between study populations. Additionally, the methodol-
ogies used to screen for and diagnose GDM vary across
the trials evaluated, which in turn affects the reported
incidence of GDM in cohorts and the potential effect
size associated with the intervention. Furthermore, few
trials have been adequately powered to assess the effec-
tiveness of intervention programs. Finally, the assess-
ment of lifestyle changes is itself challenging and, in
those studies in which one can determine adherence to
protocols, concordance was variable.
Pathophysiology and risk factors
Pregnancy is characterized by increasing insulin resist-
ance that correlates with advancing gestation. The
fetal–placental unit is primarily responsible for driv-
ing this increase and although the mechanisms are
not fully understood, placental production of tumour
necrosis factor α, placental lactogen, growth hormone,

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Key points fetal hyperinsulinaemia2. Elevated amino acid levels and

• The use of dietary intervention or combined lifestyle measures does not seem to
reduce the risk of developing gestational diabetes mellitus (GDM) in women with no
defined risk factors, but the evidence for increasing physical activity is conflicting
• Dietary intervention can reduce the risk of developing GDM and the proportion of
infants born with macrosomia in pregnant women with obesity; physical activity
interventions have not had the same effect
• Combined lifestyle modifications have reduced gestational weight gain in pregnant
women with obesity and have improved certain materno–fetal outcomes even if
hyperglycaemia is not improved
• In individuals at high risk of developing GDM, preliminary data have demonstrated
that probiotic and myoinositol supplementation might reduce the incidence of GDM
• The use of metformin does not seem to improve the incidence of GDM in either
pregnant women with obesity or those with polycystic ovary syndrome.
and increased cortisol and progesterone levels are all
thought to be contributory factors8,9 (FIG. 1). To main-
tain normoglycaemia in the mother, β‑cell production
of insulin increases. In longitudinal studies, this increase
has been found to be restricted to the first phase insu-
lin response in the early stages of pregnancy (that is, a
120% increase at 12–14 weeks gestation)10. By 36 weeks
gestation, both first and second phase insulin responses
increase 3–3.5 times. The resultant changes in maternal
carbohydrate and lipid metabolism ensure that adequate
nutrition is delivered to the fetus for normal fetal growth
to proceed. Placental-mediated glucose delivery to the
fetus is further facilitated by a 30% increase in maternal
basal endogenous hepatic glucose production11.
Women unable to adapt to these pregnancy-induced
physiological changes develop GDM. The pathophysi-
ology of GDM and T2DM are similar, such that GDM
could be seen to reflect an early stage of T2DM expressed
under the conditions of pregnancy12. Consistent with this
finding, the rate of progression to T2DM is increased in
those with a history of GDM13.
T2DM is a heterogeneous condition; that is, an
individual’s genetic predisposition and the interactions
with intrauterine and adult environmental factors all
contribute to its aetiology14. The pathophysiology of
T2DM relates to an insulin resistant state that is present
throughout adult life before the development of hyperg-
lycaemia15. Subtle defects in insulin secretion, including
abnormal pulsatile insulin profiles, increased release of
immature insulin and later failure of adequate first-phase
insulin secretion contribute to the development of the
initial postprandial hyperglycaemia observed in the early
stages of T2DM14. Eventually, β‑cell failure is more com-
plete and a defective second phase of insulin secretion
arises leading to fasting hyperglycaemia.
The majority of women who develop GDM also
exhibit defective β‑cell function leading to initial post-
prandial, and later fasting hyperglycaemia12,16. In longi-
tudinal studies, insulin sensitivity is reduced before the
onset of β‑cell dysfunction in those who develop GDM;
moreover, increased insulin resistance before concep-
tion might further accelerate this process9,17. Subsequent
increases in plasma levels of glucose provide substrates
for enhanced fetal growth, which is in part stimulated by
non-esterified fatty acid concentrations further contribute
to the pathophysiology of GDM18.
Although the results of epidemiological studies have
failed to firmly establish the risk factors for developing
GDM, certain consistent predictors have emerged19
(BOX 1). Non-modifiable risk factors include non-white
ethnicity, advancing maternal age, underlying polycystic
ovary syndrome (PCOS), previous pregnancies in which
GDM was present and a family history of T2DM19. Well-
established modifiable risk factors include pre-gravid or
early pregnancy excess adiposity and obesity20.
Lifestyle intervention strategies
Women with no defined risk factors
Large population studies of intervention with lifestyle
modifications are either absent or have yielded conflict-
ing results. In only one trial have the potential benefits
of dietary modulation in improving GDM risk in a
randomly selected cohort of women been investigated
(TABLE 1). In the ‘Low‑GI Diet in Pregnancy’ study, 62
pregnant women were randomly assigned to either a
low glycaemic index diet (LGI) or to a high fibre, mod-
erate-to-high glycaemic index diet (HGI)21. No dif-
ferences were found in either GDM incidence or fetal
birthweight. The proportion of infants born large for
gestational age (LGA, birthweight ≥90th centile) in the
LGI group was substantially lower (3.3% versus 33.3%
in the HGI group), which indicates that a potential ben-
efit associated with the diet exists; however, this finding
should be interpreted with caution given that the study
was not adequately powered to assess this outcome.
In trials investigating the affect of physical activity
programmes on reducing the risk of GDM in women
with no defined risk factors, conflicting results have been
reported. In a trial conducted in Spain, 342 women were
randomly assigned to either three supervised exercise ses-
sions per week or to routine antenatal care22. Women in
the intervention arm were more likely to adhere to gesta-
tional weight gain guidelines (as defined by the Institute
of Medicine (IOM))23 and the intervention was associated
with a 90% risk reduction in GDM (95% CI 0.013–0.803;
diagnosis as per the National Diabetes Data Group cri-
teria24). However, the randomization procedures, which
were not explained in the methodology section, were
unbalanced and, as a result, a selection bias might have
been introduced. 122 women were initially assigned to
the intervention group and 220 to the control, with only
257 women (101 intervention versus 156 controls) being
included in the final analysis following participant with-
drawals. In a trial conducted in Norway, 855 women who
were between 18 and 22 weeks gestation were randomly
assigned to either receive routine antenatal care or to a
12‑week program consisting of three exercise sessions per
week25. A physiotherapist supervised one of these exercise
sessions while the second two were self-directed. No dif-
ferences were recorded in incidence of GDM as defined
by the 1999 WHO criteria26.
The reasons for the conflicting results are likely to be
multifactorial. In the study conducted in Spain, all the
sessions were supervised, which might thereby improve

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Pre-pregnancy determinants Mother Placenta Fetus

of insulin resistance
Persistent Pancreatic
hyperglycaemia production
of insulin

Increased Glucose flux

glucose levels
Ethnicity

Physical inactivity Defective insulin

secretion
Substrates
Insulin resistance for fetal
Obesity growth
Hydrolysis
↑ Triglyceride to free
Dietary composition levels fatty acids
• Tumour necrosis
factor α ↑ Amino acid
• Placental lactogen turnover
Polycystic ovarian
syndrome/hypertension • Placental growth Placental
hormone hormone
• Oestrogen production Enhanced
• Progesterone fetal
• Cortisol growth

Nature Reviews | Endocrinology

Figure 1 | Factors contributing to maternal insulin resistance and fetal growth. A number of pre-pregnancy factors
can contribute to insulin resistance in the mother, which can affect the growth and health of the fetus. Placental hormone
production can also contribute to insulin resistance in the mother.

compliance, and was indeed recorded as higher than in
the trial from Norway (80% versus 55%). Furthermore,
no differences were recorded in gestational weight gain
in the Norwegian trial. By contrast, in the Spanish trial,
a significantly lower proportion of women assigned
to the intervention gained excess gestational weight
(22.8% versus 34.8%, P = 0.040) as defined by the IOM
recommendations23.
A combined approach to diet and physical activity
in minimizing gestational weight gain and prevent-
ing GDM has been evaluated by investigators in one
randomized controlled trial27, which was powered to
detect gestational weight gain as the primary outcome.
Although the intervention consisting of focused dietary
counselling, encouragement to increase physical activ-
ity and advice regarding appropriate weight gain was
associated with significantly less gestational weight gain
(13.0 ± 5.68 kg versus 16.1 ± 7.05 kg; P = 0.01), no differ-
ences were recorded in the incidence of GDM between
women in the two arms of the trial (TABLE 1).
Women with obesity
The relationship between maternal BMI and risk of GDM
is well described. An increase in early pregnancy BMI
category is associated with an increased odds ratio (OR)
of developing GDM: BMI 25–30 kg/m2, OR 1.86; BMI
30–35 kg/m2, OR 3.34; and BMI ≥35 kg/m2, OR 5.77
(REF. 20). Indeed, maternal weight has been identified
as the strongest predictor of fetal macrosomia, which
emphasizes the detrimental effect of an insulin resist-
ant state despite normal glucose tolerance28,29. Although
excess gestational weight gain has been implicated in
GDM risk, the ideal weight targets across the different
ethnic groups and BMI categories are difficult to define30.
In light of this difficultly, and the increasing incidence of
obesity among women of childbearing age worldwide31–33,
considerable focus has been placed on preventing the
associated adverse outcomes (TABLES 2,3).
In a feasibility study conducted in Denmark, 50
white women who were pregnant and had obesity but
without diabetes mellitus were randomly assigned to
receive either active dietary intervention (consisting of
ten, 1 h educational sessions with a trained dietician)
or standard dietary advice34 (TABLE 2). In the interven-
tion arm of the trial, no women were diagnosed with
GDM. In the control group, 10% of patients were diag-
nosed with GDM and subsequently excluded from the
analysis, owing to the potential for confounding. Since
this trial, the results from two randomized controlled
trials have indicated that the risk of developing GDM
can be reduced with dietary modulation. In a study in
the USA powered to detect gestational weight gain as
the primary outcome, 257 pregnant women with obesity
were randomly assigned to receive either conventional
management or an active nutritional and behavioural
intervention from 12 weeks gestation35. Those in the
intervention arm gained significantly less weight
(5.0 ± 6.8 kg versus 14.1 ± 7.3 kg; P <0.001) during preg-
nancy and a nonsignificant reduction in the incidence
of GDM was noted (9.5% versus 16.4%). This reduc-
tion reached significance in a sub-analysis of those
who adhered to the programme within the interven-
tion arm (4% versus 19%, P <0.01). In a trial conducted
in Australia that was powered to detect a difference in
GDM incidence as the primary outcome, 132 pregnant
women who were overweight or obese were randomly

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Box 1 | Risk factors for developing GDM
• Non-modifiable factors
• Non-white ethnicity
• Underlying polycystic ovary syndrome
• Previous pregnancies complicated by GDM
• Family history type 2 diabetes mellitus
• Maternal age
• Modifiable factors
• Pre-gravid obesity or maternal excess adiposity
• Dietary factors and levels of physical activity in the
pre-conception period
GDM, gestational diabetes mellitus
assigned to either a four-step multidisciplinary antena-
tal care approach or to routine antenatal care36. Those
in the intervention arm attended specialized antenatal
clinics where they were weighed and reviewed by an
obstetrician, food technician and a clinical psychologist.
The intervention was associated with significant reduc-
tions in mean gestational weight gain (7.0 ± 0.65 kg ver-
sus 13.8 ± 0.67 kg; P <0.001) and an 83% reduction in
GDM incidence (95% CI 0.03–0.95). In this study, a
high background incidence of GDM (29% in the control
group) was found, which indicates that these individuals
were particularly at risk of developing the disease.
In a meta-analysis conducted in 2012, the inves-
tigators evaluated the effect of lifestyle interventions
on pregnancy-related outcomes37. When specifically
assessing dietary intervention and GDM risk, the
authors combined the results from the three trials dis-
cussed in the previous paragraph. They determined
that dietary intervention in any form resulted in a 61%
risk reduction in GDM (relative risk (RR) 0.39, 95% CI
0.23–0.69, I2 21%). However, since this meta-analysis,
the findings from the LIMIT study38 have been pub-
lished. In the LIMIT trial, 2,212 women who were
overweight were randomly assigned to receive either
dietary advice with individualized meal plans, or
routine antenatal care. No differences were detected
in gestational weight gain, incidence of GDM or the
proportion of infants born LGA. Despite these find-
ings, significant reductions in the proportion of infants
born macrosomic (that is, a birth weight ≥4,000 g) were
observed in the intervention group38. This considera-
tion is important given that dietary advice and meal
plans could easily be replicated in the wider antenatal
setting compared with the more intensive strategies in
trials that demonstrated reductions in GDM. The find-
ing also highlights the potential role of macro­nutrients
and healthy diets in improving fetal outcomes even
in the absence of improving maternal glycaemia and
reducing gestational weight gain.
Exercise alone does not seem to prevent GDM in
pregnant women who are overweight or obese (TABLE 2).
In a feasibility study conducted in Australia, the effects
of targeting an energy expenditure of 900 kcal per week
using individualized exercise programmes in 50 women
with obesity were investigated39. Increases in self-reported
physical activity (as assessed by the Pregnancy Physical
Activity Questionnaire)40 in the intervention arm were
demonstrated at 28  weeks gestation. Although this
increased activity was associated with reduced fasting glu-
cose and fasting insulin levels at 36 weeks gestation, no dif-
ferences were seen in insulin resistance or GDM incidence
as defined by the Australasian Diabetes in Pregnancy
Society criteria (fasting plasma glucose ≥5.5 mmol/l
and/or 120 min post 75 g glucose load ≥8.0 mmol/l)41.
In the FitFor2 Trial42 conducted in the Netherlands, 121
women with an early pregnancy BMI ≥25 kg/m2 and a sec-
ond risk factor for developing GDM (defined as one of the
following: history of macrosomia, history of prior preg-
nancy with GDM or a first degree relative with T2DM),
were randomly assigned to attend either two 60‑min
group exercise sessions per week or to no lifestyle inter-
vention. No significant differences in glycaemic meas-
ures (that is, fasting plasma glucose and HbA1c), insulin
sensitivity or incidence of GDM were found between
the two groups. The background incidence of GDM in the
control groups in both trials (21.6% and 23% for Australia
and the Netherlands, respectively) indicates that these
cohorts were at particular high risk of developing the
disease. However, as the women recruited in these trials
were already either overweight or had obesity, they were
more likely to have entered pregnancy with higher lev-
els of insulin resistance. Consequently, the interventions
might not have been sufficient to overcome this issue,
particularly in the context of the profound increase in
insulin resistance associated with pregnancy. Moreover,
in the FitFor2 study42, the required sample size was not
achieved and only 16% of the women attended at least
50% of the exercise sessions, meaning that drawing any
firm conclusions from the data is difficult.
The two trials that have investigated a combined
approach to dietary modification and physical activ-
ity in pregnant women with obesity, and which were
powered to detect a reduction in the incidence of
GDM, have yielded conflicting results (TABLE 3). In the
UPBEAT trial43 conducted in the UK, 1,440 pregnant
women with obesity were randomly assigned to either
routine antenatal care or lifestyle intervention. Women
in the intervention group were reviewed weekly, either
individually or in group-led sessions, for a total of
8 weeks from study inclusion at 15.0–18.6 weeks gesta-
tion, during which time recommended dietary intake
and physical activity were discussed. In the interven-
tion arm, despite self-reported improvements in the
glycaemic index of foods the individuals consumed,
the self-reported increased level of physical activ-
ity achieved and a 0.55 kg (95% CI −1.08 to −0.02)
reduction in gestational weight gain, no differences
were found in the incidence of GDM. By contrast, in
the RADIEL trial44, a study conducted in Finland, the
investigators reported that input from midwives and
dieticians at 14, 23 and 35 weeks gestation, reduced the
risk of developing GDM (RR 0.64, 95% CI 0.38–1.09).
Women in the intervention arm were encouraged to
maintain their weight in the first two trimesters of preg-
nancy and engage in 150 min of moderate level physi-
cal activity. Differences in the baseline demographics

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Table 1 | RCTs for interventions reducing GDM and adverse outcomes in women with no defined risk factors
Trial Population Gestational Protocol GDM Group characteristics Outcomes
age for criteria
enrolment Arms n BMI GDM Significant outcomes
(weeks) (%)

Low GI • n = 62 12–16 • LGI diet or a high fibre–low ND LGI 32 • 24.4 0.0 GI (P = 0.051), proportion
diet in • Australia sugar HGI diet • (± 0.7)* of infants born LGA
pregnancy21 • Five dietary education (P = 0.01) and neonatal
sessions ponderal index (P = 0.03)
• No control group HGI 30 • 26.6 3.3 all lower in LGI group
• (± 0.9)*
Cordero • n = 272 10–12 • Two supervised sessions NDDG‡ I 101 • 22.5 1.0* Significant reduction in
et al.22 • Spain in gym (60 min moderate • (± 3.2) proportion of women
intensity) with excess GWG in
• One supervised session intervention group (22.8%
pool-based activity (50 min C 156 • 23.6 8.8* versus 34.8%; P = 0.040) §
moderate intensity) • (± 4.0)
Stafne • n = 855 18–22 • 12 week exercise program WHO|| I 429 • 24.7 7 None
et al.25 • Norway (3 days/ week) • (± 3.0)
• One session supervised by
physiotherapist
• Two home-based C 239 • 25.0 6
unsupervised sessions • (± 3.4)

Dietary • n = 100 6–16 • Focused dietary ND I 57 • 25.5 NSD Significantly less GWG
counselling • USA counselling • (± 6.0) in intervention arm:
in • Unsupervised moderate- 13.0 ± 5.68 kg versus
pregnancy27 intensity exercise (3‑5 16.1 ± 7.05 kg, P = 0.01.
times/ week) GDM incidence similar
• Education regarding target C 43 • 25.6 NSD on sub-analysis of those
weight gain (IOM§) • (± 5.1) who adhered to IOM
• Weighed at each visit. If not guidelines
in target, lifestyle reviewed
All continuous data are expressed as mean (± standard deviation). *Significance of P <0.05. ‡National Diabetes Data Group (NDDG) criteria24. §As defined by Institute
of Medicine Guidelines (IOM)23. ||WHO criteria 1999 (REF. 26). C, control group; GDM, Gestational diabetes mellitus; GWG, gestational weight gain; GI glycaemic
index; HGI high glycaemic index; I intervention group; LGI low glycaemic index; LGA large for gestational age; ND, not described; NSD, no significant difference.

between the cohorts from the UK and Finland might
account for the latter strategy being successful in reduc-
ing GDM: the mean baseline BMI was lower in Finland
than the UK (32.3 kg/m2 versus 36.3 kg/m2). Ethnicity
might also have affected the results. This aspect was
not commented on in the RADIEL trial (one presumes
that most women were of white European origin); how-
ever, in the UPBEAT trial, 40% of participants were of
non-white ethnicity. In addition, the glucose threshold
for diagnosing GDM was lower in the UPBEAT trial
than the RADIEL. The 5th International Association
of Diabetes and Pregnancy Study Group (IADPSG)45
criteria were used in the UPBEAT trial (one or more
pathological values required for diagnosis with 75 g
oral glucose tolerance test (OGTT): fasting plasma
glucose (FPG) ≥5.1 mmol/l; 60 min ≥10.0 mmol/l;
120 min ≥8.5  mmol/l). Criteria adapted from the
Hyperglycaemia and Adverse Pregnancy Outcomes
Study Group2 were used in the RADIEL trial (one or
more pathological values in a 75 g OGTT with the fol-
lowing diagnostic thresholds: FPG ≥5.3 mmol/l; 60 min
≥10.0 mmol/l; 120 min ≥8.5mmol/l). However, the
positive results reported by the RADIEL trial should
be interpreted with caution as the reduction in risk of
GDM only reached significance after adjusting for mul-
tiple confounding factors including age, pre-pregnancy
BMI, a prior history of GDM and gestational age44.
Five other trials have been conducted that have eval-
uated the benefits of combined lifestyle interventions in
pregnant women with obesity and while all have been
associated with reduced gestational weight gain, none
have improved the risk of developing GDM46–50 (TABLE 3).
However, two of these trials have shown positive effects
on materno-fetal outcomes other than improving glycae-
mia. For example, one trial demonstrated an improve-
ment in hypertensive disorders during pregnancy. In
‘The Bumps and Beyond’ (REF. 46) intervention program
178 pregnant women with obesity (BMI ≥35 kg/m2 at
inclusion) were randomly assigned to either routine
antenatal care or to between two and four weekly educa-
tional sessions provided by health advisers and specialist
midwives. During these sessions the participants were
encouraged to engage in physical activity at least three
times per week and follow dietary advice. The interven-
tion was associated with a 95% reduction in gestational
hypertension (OR 0.103, 95% CI 0.034–0.307) and a
90% reduction in pre-eclampsia (OR 0.115, 95% CI
0.014–0.940). In the TOP study47, a trial conducted
in Denmark, 452 women with obesity were randomly
assigned to one of three trial arms: combined physical
activity and dietary intervention, intervention with
physical activity alone or routine antenatal care. Both
the dietary and physical activity interventions were
delivered via educational sessions with encouragement

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Table 2 | RCTs for a single interventions reducing GDM and adverse outcomes in overweight and obese pregnant women
Trial Population Gestational Protocol GDM Group characteristics Outcomes
age for criteria
enrolment Arms n BMI GDM Significant
(weeks) (%) outcomes

Wolff • n = 50 12–18 Ten 1 h dietary ND I 23 • 34.9 0 Reduced GWG in

et al.34 • BMI ≥30 consultations with • (± 4) the intervention arm:
• White ethnicity aim of restricting 6.6 (± 5.5) versus 13.3
• Denmark GWG to 6–7 kg (± 7.5) kg, P = 0.002
C 27 • 34.6 10
• (± 3)
Thornton • n = 257 12–28 Active nutritional ND I 116 • 37.4 9.5 Intervention
et al.35 • Singleton and behavioural • (± 7.0) associated with
pregnancy intervention: reduced GWG:
• BMI ≥30 18–24 kcal/kg from 5.0 (± 6.8) versus
• USA inclusion until 14.1 (± 7.3) kg,
delivery P <0.001. Reduced
C 116 • 38.2 16.4 GDM incidence on
• (± 7.5) sub-analysis of group
that complied with
intervention: 2.2%
versus 34.6%, P <0.01

Quinlivan • n = 124 Not Four step approach; WHO‡ I 63 58%§ 6.0* Reduction in GWG
et al.36 • BMI ≥25 specified continuity obstetric observed in the
• Australia care provider, regular intervention arm:
weight assessment, C 61 51%§ 29.0* 7.0 (± 0.7) versus 13.8
food technician and (± 0.7) kg, P <0.001
clinical psychology
input
LIMIT • n = 2212 10–20 Individualized meal 75 g I 1108 • 31.0 14 Lower rates of
Trial38 • Singleton plans provided by OGTT FPG • (28.1–35.9) macrosomia in
pregnancy dietician with advice 5.5 mmol/l; intervention group
• BMI ≥25 regarding lifestyle 2 h 15% versus 19%;
• Australia at six different time 7.8 mmol/l P = 0.04||
points C 1104 • 31.1 11
• (27.7–35.6)
Callaway • n = 50 ≤12 Individualized ADIPS¶ I 25 • 36% 16 None
et al.39 • BMI ≥30 exercise programme. • ≥35kg/m2
• Australia Targeted energy
expenditure
900 kcal per week. C 25 • 36% 23
No supervised • ≥35kg/m2
sessions. Monthly
physiotherapy review
FitFor2 • n = 121 Not 60 min aerobic or ND I 49 • 33.0 14.6 None
trial42 • BMI ≥25 specified strength work twice • (± 3.7)
• One or more of: per week from
previous GDM 15 weeks gestation
or macrosomia until 6 weeks
1st degree postpartum. All C 52 • 33.9 21.6
relative with sessions supervised • (± 5.6)
T2DM
• Finland
Continuous data are expressed as mean (± standard deviation). *P <0.05. ‡WHO criteria 1999 (REF. 26). §BMI ≥25 kg/m2. ||Birthweight ≥4000 g. ¶Australasian
Diabetes in Pregnancy Society (ADIPS) criteria41. C, Control group; FPG, fasting plasma glucose; GDM, Gestational diabetes mellitus; GWG, gestational weight
gain; GA, gestational age (at inclusion); I, intervention group; OGTT, oral glucose tolerance test; T2DM, type 2 diabetes mellitus.

to maintain a hypocaloric diet and increase daily phys-
ical activity as appropriate. Those patients receiving the
combined intervention had a significantly lower rate of
unplanned or emergency caesarian sections (11% versus
22% in the physical activity arm and 24% in the control
arm, P = 0.015).
Three remaining trials have evaluated combined life-
style measures (TABLE 3). The LiP trial48 demonstrated a
median 149 g increase (P = 0.039) in fetal birthweight with
an intervention programme that comprised one session
with a physiotherapist and self-directed physical activity
for 30–60 min per day in pregnant women with obesity.
The intervention was not associated with an increase in the
proportion of infants born LGA. The investigators in this
trial postulated that this unexpected finding might be
associated with improved placental function in those par-
ticipants assigned to the intervention arm of the trial48. In
the DALI lifestyle pilot study49 the investigators compared

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Table 3 | RCTs for interventions reducing GDM and adverse outcomes in overweight and obese pregnant women
Trial Population Entry Protocol GDM Group characteristics Outcomes
criteria and criteria
Arm n BMI GDM Significant outcomes
Gestational
(%)
age for
enrolment
UPBEAT • n = 1,555 • BMI ≥30 Weekly health trainer IADPSG* I 783 • 36.3 25 Intervention associated with
study43 • UK • 15–19 weeks sessions for 8 weeks. • (± 5.0) reduced GWG: 7.19 (± 4.6)
Diet and physical versus 7.76 (± 4.6); P = 0.041
activity addressed C 772 • 36.3 26 and increased incidence of
• (± 4.6) NNH: 4 versus 2%; P = 0.02

RADIEL • n = 293 • Previous GDM 3 lifestyle sessions HAPO‡ I 144 • 32.3 13.9 Significant reduction in
study44 • Finland +/- BMI ≥30 targeting: no weight • (± 4.9) incidence GDM (P = 0.04) and
• <20 weeks gain in 1st and 2nd GWG at 23.4 weeks (−0.5 kg;
trimesters; ≥150 min 95% CI −1.1 to 0.05, P = 0.039)
moderate intensity C 125 • 32.6 21.6 following adjustment for
activity per week • (± 4.5) confounders
McGiveron • n = 178 • BMI ≥35 2–4 weekly educational ND I 89 • 38.4 NSD Intervention associated
et al.46 • UK • 16–18 weeks sessions for healthy • (± 3.2) with reduced GWG: 4.5
diet and maintaining (± 4.6) versus 10.3 (± 4.4) kg;
physical activity three C 89 • 39.4 NSD P <0.001
times per week • (± 4.1)
DALI • n = 150 • BMI ≥29 Randomized to HE, ND HE 50 • 34.8 28 Significant reductions in
Lifestyle • European • <20 weeks PA, or HE plus PA. • (± 5.9) GWG and fasting glucose
pilot countries§ Interventions were demonstrated in HE versus
study49 delivered by five PA 50 • 34.5 42 PA group: 3.5 (± 3.9) versus
face‑to‑face and four • (± 4.5) 5.2 (± 3.1) kg/m2; P = 0.03 and
optional telephone HE+ 50 • 34.1 31 4.3 (± 0.4) versus 4.6 (± 0.4)
coaching sessions. PA • (± 4.7) mmol/l; P = 0.01
GWG <5 kg targeted
• TOP • n = 425 • Age ≥18 years Pedometer to assess ND PA+ 142 • 34.4 3.8 No significant difference
study47 • Denmark • BMI ≥30 step count on seven • (± 4.2) between intervention
D
• Singleton consecutive days each groups. PA decreased GWG
pregnancy month (target 11,000). PA 142 • 34.1 1.6 by a mean of 1.38 kg (versus
2‑weekly review • (± 4.4) C), P = 0.040. Reduced
regarding hypocaloric emergency or unplanned
diet (1200–1675 kcal) C‑section rate in women
and target GWG (<5 kg) C 141 • 33.7 5.2 receiving PA+D: 11%, versus
• (± 3.5) 22% (for PA) and 24% (for C),
P = 0.015 across
all three groups
• LiP • n = 304 • 10–14 weeks Limiting GWG to OGTT|| I 150 • 33.4 6.0 Intervention associated with
study48 • Denmark • BMI 30–45 5 kg. Four dietary • (31.7– reduced GWG: 7.0 (4.7–10.6)
sessions, one exercise 36.5) versus 8.6 (5.7–11.5) kg;
session/ week with P = 0.01
physiotherapist; C 154 • 33.3 5.2
encouraged moderate • (31.7–
physical daily activity 36.9)

Harrison • n = 228 • BMI ≥25 Lifestyle counselling ADIPS¶ I 121 • 30.4 22.3 Intervention associated with
et al.50 • Australia • Risk of GDM sessions at four time • (± 5.6) reduced GWG: 6.0 (± 2.8)
• 12–15 weeks points to promote versus 6.9 (± 3.3) kg; P <0.05
healthy diet and C 107 • 30.3 32.7
physical activity. • (± 5.9)

Hui et al.51 • n = 116 • <20 weeks Attended CDA# I1 30 • 21.6 0 Individuals in group 1
• Canada • Group 1: ≤24.9 community-based • (± 2.2) intervention arm significantly
BMI weekly exercises or more likely to achieve target
• Group 2: ≥25.0 used DVD (30–45 C1 27 • 22.6 0 GWG: 37% versus 10%;
BMI minute sessions, 3–5 • (± 1.9) P = 0.03 **
times per week) for PA
I2 29 • 29.5 4
Individual dietary • (± 5.1)
sessions at baseline and
2 months later C2 27 • 29.7 10
• (± 1.3)
Continuous data are expressed as mean (± standard deviation). *Criteria proposed by the 5th International Association of Diabetes and Pregnancy Study Groups
(IADPSG)45. ‡Criteria adapted from the Hyperglycaemia and Adverse Pregnancy Outcomes Study (HAPO)2. §Austria, Belgium, Denmark, Ireland, Italy, Netherlands,
Poland, Spain and UK. ||75g oral glucose tolerance test (OGTT) 120 minute value ≥9.0 mmol/l. ¶Australasian Diabetes in Pregnancy Society (ADIPS) criteria41. #Canadian
Diabetes Association (CDA) diagnostic criteria87. **Institute of Medicine Guidelines23. C, control group; D, diet; GA gestation age; GDM gestational diabetes mellitus;
GWG, gestational weight gain; HE, healthy eating; I, intervention group; NNH, neonatal hypoglycaemia; NSD, no significant difference; PA, physical activity.

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the efficacy of three interventions (healthy eating, physical
activity and combined healthy eating with physical activ-
ity) in 150 women with an early pregnancy BMI ≥29 kg/m2,
in limiting gestational weight gain to 5 kg. Women
assigned to the healthy eating group gained 2.6 kg less
gestational weight (95% CI −4.9 to −0.2; P = 0.03) and
fasting glucose values were 0.3 mmol/l lower (95% CI
−0.4 to −0.1; P = 0.01) than those assigned to the physical
activity group; however, the differences in incidence of
GDM were not significant. No differences were observed
between combined lifestyle measures and the other two
interventions. A trial conducted in Australia that ran-
domly assigned women to either standard antenatal care
or to lifestyle sessions provided at four time points (14–16,
20, 24 and 28 weeks gestation) during pregnancy, found
no improvements in any materno-fetal outcomes50.
Finally, in a trial conducted in Canada, the investiga-
tors compared methods of lifestyle intervention in 116
women according to category of BMI51 (TABLE 3). The
intervention included the combination of two dietary
educational sessions and either a home-based exercise
programme or community-based weekly exercise pro-
grammes. Women who had an early pregnancy BMI
≤24.9 kg/m2 gained less gestational weight in the inter-
vention arm than those in the same BMI category who
were randomized to routine antenatal care (12.90 ± 3.72 kg
versus 16.23 ± 3.72 kg, P = 0.03) and the mean fetal birth-
weight born to this subgroup was significantly lower
(3356 g versus 3633 g, P = 0.047). No differences were
recorded in outcomes in women with a suboptimal BMI.
Other at risk groups
The National Institute for Health and Clinical Excellence
in the UK recommends screening all pregnant women to
ascertain if they have risk factors for developing GDM52.
In addition to the recommendation that women with a
BMI ≥30 kg/m2 are tested for GDM using a 75 g OGTT,
women who have a family history of T2DM, and/or a pre-
vious pregnancy complicated by GDM or macrosomia,
are also advised to be assessed by OGTT.
The effects of either dietary intervention or lifestyle
counselling in reducing GDM incidence in women at
risk have been evaluated in three randomized controlled
trials (TABLE 4). The NELLI trial53, conducted in Finland
was powered to detect a reduction in GDM incidence as
the primary outcome and recruited 399 women with at
least one risk factor for GDM (BMI ≥25 kg/m2, previous
pregnancy complicated by either GDM or macrosomia
(birthweight ≥4500 g), family history of diabetes mel-
lisus or maternal age ≥40 years). Those in the interven-
tion arm received lifestyle counselling at five different
time points from study inclusion (8–12 weeks gestation)
until 37 weeks gestation: women randomized to the
control arm received no counselling beyond usual care.
Gestational weight gain was similar between the two
groups. In a post hoc analysis of those who adhered to the
programme, the incidence of GDM was reduced (27.3%
versus 33.0%, P = 0.43) and a significant reduction in
the proportion of infants born LGA was also seen (7.3%
versus 19.5%, P = 0.03)53. However, the investigators pro-
vided no data regarding the baseline maternal demo-
graphics of the subgroups and the potential impact of
confounding factors is, therefore, not known. In the
ROLO study54, the effects of an LGI diet in reducing
neonatal birthweight in 800 women who had previously
delivered an infant with a birth weight ≥4000 g were
evaluated. Women in the intervention arm received a
2‑h educational session on the components of the diet
at inclusion, with refresher sessions at 28 and 34 weeks
gestation: those randomized to the control arm received

Table 4 | RCTs on the effects of interventions in women with other pre-defined risk factors
Trial Population Entry criteria Protocol GDM criteria Group characteristics Outcomes

Arm n BMI GDM Significant

(%) outcomes

NELLI • n = 399 • 8–12 weeks Lifestyle educational IADPSG§ I 219 • 26.3 15.8 Fewer infants born
study53 • Finland gestation sessions at five time • (± 4.9) LGA in intervention
• One risk factor points regarding arm: 12.1 versus 19.7;
for GDM‡ achieving 800 MET P = 0.042
mins per week and C 180 • 26.4 12.4
dietary counselling • (± 4.3)
ROLO • n = 800 Previous fetal Education regarding Carpenter-Coustan|| I 383 • 26.8 2.0 Significantly
study54 • Ireland macrosomia LGI diet in one 2 h • (± 5.1) less GWG in
(≥4000 g) session at 15 weeks; intervention group:
meetings with dietician C 398 • 26.8 2.0 12.2 ± 4.4 versus
at 28 and 34 weeks • (± 4.8) 13.7 ± 4.9 kg; P = 0.01
The GI • n = 139 One risk factor LGI diet or HF diet Modified ADPS LGI 65 • 25.2 13.8 No significant
baby 3 • Australia for GDM¶ criteria# • (± 5.2) outcomes
study56
HF 60 • 25.2 15.0
• (± 5.2)
Continuous data are expressed as mean (± standard deviation). ‡BMI ≥25 kg/m2, previous pregnancy complicated by GDM or macrosomia (≥4500 g), family history
of diabetes or age ≥40 years. §Criteria proposed by the 5th International Association of Diabetes and Pregnancy Study Groups (IADPSG) 2010 (REF. 45).
||
Carpenter–Coustan criteria55. ¶BMI ≥30 kg/m2, family history of T2DM, previous history of GDM, glucose intolerance, delivery of macrosomic infant (≥4000 g),
high-risk ethnic group. #Modified Australasian Diabetes in Pregnancy Society 1998 (REF. 57). C, control group; GDM, gestational diabetes mellitus; GI, glycaemic
index; GWG, gestational weight gain; HF, high fibre; I, intervention group; LGA, large for gestational age; LGI, low GI, MET, metabolic equivalent task; T2DM, type 2
diabetes mellitus.

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routine antenatal care. No differences were recorded
in the incidence of GDM as defined by the Carpenter–
Coustan criteria55 (two or more values above the follow-
ing thresholds in a 3 h 100 g OGTT: FPG ≥5.3 mmol/l;
60 min ≥10.0 mmol/l; 120 min ≥8.6 mmol/l; 180 min
≥7.8 mmol/l), mean fetal birthweight or in the proportion
of infants born macrosomic (that is with a birthweight
≥4000 g)54. Finally, in the GI Baby 3 Study56,, 139 women
at high risk of developing GDM were randomly assigned
to either an LGI diet or a high-fibre moderate glycaemic-
index diet. No differences were found in the incidence of
GDM (as defined by modified Australasian Diabetes in
Pregnancy Society criteria), gestational weight gain, fetal
birthweight or neonates born LGA57. These findings high-
light the difficulty in preventing GDM in women with
defined risk factors. However, the potential to improve
adverse materno–fetal outcomes in the absence of an
effect on glucose tolerance, is once again suggested.
Potential for future strategies
The results of the Diabetes Prevention Programme
(DPP)58 in the USA have shown that lifestyle interven-
tion in a non-pregnant population with impaired glucose
tolerance reduced progression to T2DM by 58% when
compared with placebo. The average weight loss achieved
within the lifestyle intervention arm in the DPP was 7%
over a 3‑year period. Losing a similar amount of weight
in early pregnancy would be difficult. It could be argued
that women who are overweight should aim to achieve this
pre-conceptually. However, in population-based surveys
from the UK, 45% of pregnancies are unplanned and only
48% of the women who plan pregnancy take the appro-
priate supplementation, which indicates that in most cases
adequate medical advice is neither being sought nor given
in the pre-conceptual period59,60. A key factor in the suc-
cess of the DPP58 was the provision of personal exercise
trainers, but these require considerable financial resources.
Indeed, when considering the trials that demonstrated
reductions in GDM incidence, the majority of the inter-
vention programmes employed did use considerable
resources in terms of physical activity supervision or in
the intensity of the dietary counselling sessions.
Non-pharmacological prevention
The potential for dietary supplements in reducing the
risk of GDM have been explored in a number of stud-
ies (TABLE 5). Polyunsaturated fatty acids in fish oils have
been associated with reduced insulin resistance in obser-
vational studies61. In the DOMInO trial62, 2,399 women
were randomly assigned to receive either docosahexa­
enoic acid (DHA)-enriched fish oil capsules (1500 mg
daily) or matched vegetable oil capsules from enrolment
at <21 weeks gestation through to birth. Although the
study was adequately powered, no significant reduction
in either of the two primary outcomes — incidence of
pre-eclampsia or GDM — were found.
The use of probiotics to prevent GDM has also been
suggested owing to their beneficial effects on insulin
sensitivity in non-pregnant adults, and that maternal gut
microbiota might influence metabolic programming in
offspring63,64. The ‘Probiotics and Pregnancy outcome’
study65 conducted in Finland, randomly assigned 256
women in the first trimester of pregnancy to one of three
groups: dietary intervention with probiotic supplemen-
tation, dietary intervention with placebo or routine ante-
natal care. Probiotic supplementation (with Lactobacillus
rhamnosus GG and Bifidobacterium lactis Bb12) was
associated with both reduced insulin resistance in the
antenatal and postpartum periods, as well as a reduction
in GDM incidence. In this study, 13% of women assigned
to the probiotic group developed GDM compared to
36% in the diet/placebo and 34% in the control groups
(P = 0.003) as defined by the criteria recommended by the
4th International Workshop–Conference on Gestational
Diabetes Mellitus66. Although these results are important,
they need to be interpreted with caution. Baseline demo-
graphics in each of the three groups were not defined.
Moreover, the study was not adequately powered, and
given the background incidence of GDM (34% in con-
trol group) indicating a particularly at‑risk group, further
research is needed to ensure the results are replicable in
the wider antenatal setting.
Supplementation with myoinositol, a B complex
vitamin, can improve insulin resistance in women with
established GDM67. The effects of this compound in
preventing GDM in cohorts with a single defined risk
factor (that is, a first degree relative with T2DM, fasting
hyperglycaemia in early pregnancy, early pregnancy BMI
25–30.0 kg/m2 or ≥30.0 kg/m2) have been evaluated in
four randomized controlled trials68–71 (TABLE 5). In each
trial, myoinositol (4 g and 400 μg folic acid) was com-
pared with a matched placebo (400 μg folic acid alone).
Preliminary data from these trials have been encourag-
ing, and 65–67% significant reductions in the incidence
of GDM with myoinositol supplementation have been
found (using the 5th IADPSG diagnostic criteria)45.
Furthermore, myoinositol was associated with a lower
incidence of pregnancy induced hypertension (0% ver-
sus 5.8%, P = 0.02), a lower proportion of fetal macroso-
mia (0% versus 70%, P = 0.007), and a lower incidence
of neonatal hypoglycaemia (0% versus 26%, P = 0.038).
However, these data should be interpreted with caution as
the effects of myoinositol in overweight non-obese preg-
nant women, obese pregnant women and those with a
family history of T2DM were investigated in open label
trials68,69,71; only the studies in women with fasting hyper-
glycaemia were double blind70. Furthermore, those with
fasting hyperglycaemia seem to be a particularly high-
risk group of patients (that is, background incidence of
GDM in the control group 71%) and the inclusion cri-
teria meant that participants already had a diagnosis of
GDM during trial randomization.
Pharmacological prevention
Metformin, an insulin-sensitising biguanide agent,
reduces the incidence of T2DM in adults who have
impaired glucose tolerance by 31% (95% CI 17–43)58.
In this trial, lifestyle intervention was more effective
than metformin (850 mg twice daily) at reducing T2DM
(by 58%; 95% CI 48–66). However, in a sub-analysis of
women with previous pregnancies that were compli-
cated by GDM, metformin was as effective at reducing

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Table 5 | RCTs on the effects of dietary supplementation in preventing GDM and adverse outcomes
Trial Population Entry Protocol GDM Group characteristics Outcomes
criteria criteria
Arm n BMI GDM Significant outcomes
(%)
Zhou • n = 2,399 <20 weeks • Double blind 50 g GCT‡ IMP 1,197 • 26.2 13.8 Higher proportion of
et al.62 • Australia gestation • DHA-enriched fish • (23.2– macrosomia in DHA
oil capsules versus 30.5) group: 16.3 versus
vegetable oil capsule 12.8%; P = 0.02
(1500 mg) C 1,202 • 26.3 13.8
• (22.9–
30.8)
Luoto • n = 256 • 1st • Open label International D+IMP 85 ND 13* None
et al.65 • Finland trimester • Randomisation to one Workshop-
• No of 3 groups: diet and Conference
metabolic probiotics, diet and on GDM§ D+P 86 ND 36*
diseases placebo or placebo
only. C 85 ND 34*
D’Anna • n = 220 • First • Open-label IADPSG ||
IMP 99 • 22.8 6.1* Fewer infants born
et al.68 • Italy degree • 4 g myo-inositol +  • (± 3.1) macrosomic (≥4000 g) in
relative 400 μg folic acid versus myoinositol group: 0%
T2DM 400 μg folic acid versus 7%; P = 0.007
• White C 98 • 23.6 15.3*
• BMI ≤30 • (± 3.1)
Materelli • n = 75 • Fasting • Double blind of IADPSG|| IMP 35 • 23.5 6.0* Myoinositol associated
et al.70 • Italy glucose: myoinositol + folic acid • (± 3.4) with lower: GWG
5.1–7.0 (4,000 mg + 400 μg) (2.3 ± 1.1 kg/m2
mmol/l versus folic acid only versus 3.8 ± 2.4 kg/m2;
• BMI ≤35 (400 μg) C 38 • 24.7 71.0* P = 0.001). Requirement
• (± 4.2) for insulin therapy (3.0%
versus 21.0%, P = 0.053).
Incidence of NNH (0%
versus 26%; P = 0.038) .
Mean BWC (42 versus
57; P = 0.001)
Santamaria • n = 220 • BMI 25–30 • Open-label IADPSG|| IMP 95 • 26.9 11.6* None
et al.71 • Italy • White • 4g myoinositol + 400 μg • (± 1.3)
folic acid versus
400 μg folic acid C 102 • 27.1 27.4*
• (± 1.3)
D’Anna • n = 220 • BMI ≥30 • Open-label IADPSG|| IMP 107 • 33.8 14.0* Myoinositol associated
et al.69 • Italy • 4 g myoinositol +  • (30.0– with reduction in
400 μg folic acid 46.9) GWG (5.9 0 ± 4.7 versus
versus 400 μg folic 4.6 ± 4.5 kg; P = 0.04);
acid C 107 • 33.8 33.6* HOMA‑IR, PIH (0 versus
• (30.0– 6%, P = 0.02), and
46.0) admission to NICU
(0 versus 5%; P = 0.03).
Continuous data are expressed as mean (± standard deviation). *P <0.05. ‡50 g glucose challenge test. If ≥7.7 mmol/l for diagnostic OGTT: FPG >5.5 mmol/l and 2 h
8.0 mmol/l. §4th International Workshop-Conference on GDM66. ||Criteria proposed by the 5th International Association of Diabetes in Pregnancy Study Group
(IADPSG) criteria45. C, control group; BWC, birthweight centile; DHA, docosahexaenoic acid; GA, gestational age; GDM, gestational diabetes mellitus; GWG,
gestational weight gain; IMP, investigational medicinal product; ND, not described; NICU, neonatal intensive care unit; NNH, neonatal hypoglycaemia; PIH,
pregnancy induced hypertension; RCT, randomized-controlled trial; T2DM, type 2 diabetes mellitus;.

the incidence of T2DM as lifestyle intervention. Intensive
lifestyle modifications, including 150 min of moderate
activity per week (for example, brisk walking) combined
with a healthy low-calorie, low-fat diet, and metformin
therapy each reduced the incidence of T2DM by ~50% in
parous women who had a history of GDM72. However,
in parous women with pregnancies uncomplicated by
hyperglycaemia this reduction was 49% and 14% for
lifestyle intervention and metformin, respectively72. In
the TRIPOD study, troglitazone treatment (400 mg per
day) reduced the incidence of T2DM in Latin-American
parous women with previous GDM (5.4% versus 12.2%
in the drug and placebo group respectively, P = 0.009)73. In
this study, the benefits with troglitazone were associated
with a reduction in endogenous insulin secretion illus-
trating the importance of reducing insulin resistance in
disease process modification.
Strong evidence supports the safe use of metformin
(up to 2.5–3.0 g total daily doses) both before conception
and in the antepartum period74. Furthermore, potential
advantages are associated with the use of metformin
compared with insulin to treat hyperglycaemia, includ-
ing, consistently less gestational weight gain (pooled
mean difference −1.14 kg; 95% CI −2.22 to −0.006),

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Table 6 | RCTs with pharmacological agents for preventing GDM and adverse pregnancy outcomes
Trial Population Entry Protocol GDM Group Characteristics Outcomes
criteria and criteria
GA (weeks) Arm n BMI GDM Significant outcomes
(%)
Vanky • n = 273 • PCOS ‡ • Double blind WHO§ IMP 135 • 29.5 17.6 Less GWG in metformin
et al.80 • Norway • 5–12 • Metformin versus • (± 7.0) group: −2.2kg; P = 0.001.
placebo Per-protocol analysis:
• 7‑day washout period reduced preterm delivery in
if taking metformin metformin group: 2.8 versus
before conception 10.2; P = 0.03
and before C 138 • 28.5 16.9
randomization • (± 7.2)
EMPOWaR • n = 449 • BMI ≥30 • Double blind IADPSG|| IMP 226 • 37.8 18.0 Metformin associated with
trail81 • UK • White • Metformin versus • (± 4.9) reduction in CRP and IL‑6.
• 12–16 placebo maximum Fewer neonates required
daily dose 2500 g admission to neonatal unit
• Randomization in the metformin group (7.0
stratified by study site C 223 • 37.7 24.0 versus 13.0%; P = 0.02)
and BMI category • (± 5.6)
Syngelaki • n = 400 • BMI ≥35 • Double blind WHO§ IMP 202 38.6 12.4 Metformin associated with
et al.82 • UK • 12–16 • Metformin versus (36.5–41.5) significant reductions in
placebo maximum GWG: 4.6 (1.3–7.2) versus 6.3
daily dose 3.0 g (2.9–9.2) kg (P <0.001) and
C 198 38.4 11.3 pre-eclampsia incidence: 3.0
(36.3–41.9) versus 11.3%; P = 0.001
Continuous data are expressed as mean (± standard deviation). ‡PCOS diagnosed by Rotterdam criteria77. §WHO criteria 199926. ||5th International Association of
Diabetes and Pregnancy Study Groups (IADPSG) criteria45. C, control group; CRP, C‑reactive protein; GA, gestational age; GDM, gestational diabetes mellitus; GWG
gestational weight gain; LGA, large for gestational age. IMP, investigational medicinal product; PCOS, polycystic ovary syndrome; RCT, randomized-controlled trial.

increased levels of self-reported maternal satisfaction
(evaluated using questionnaires) and a reduced inci-
dence of neonatal hypoglycaemia (pooled risk ratio 0.78
(95% CI 0.60–1.01)) in pregnant women75,76.
PCOS is characterized by hyperandrogenism, hyper-
insulinaemia and polycystic ovaries77. Women with
PCOS tend to enter pregnancy with higher levels of insu-
lin resistance than those without the disease, which pre-
disposes them to developing GDM78. 60–80% of women
who have PCOS also have obesity78, only compounding
this risk further. Furthermore, these pregnancies are
more likely to be complicated by early term miscarriage,
stillbirth and pre-eclampsia than those pregnancies of
individuals without PCOS, even in the absence of devel-
oping hyperglycaemia78. In one prospective cohort study,
1,000–2,000 mg metformin per day reduced the risk of
developing GDM (OR 0.17, 95% CI 0.07–0.37) and
pre-eclampsia (OR 0.35, 95% CI 0.13–0.94) in patients
with PCOS79. However, in a randomized controlled trial
conducted in Norway of metformin versus matched pla-
cebo (up to 1,000 mg twice daily), which began before
12 weeks gestation, in 257 pregnant women who had
PCOS, no benefit was found for metformin in prevent-
ing either GDM or pre-eclampsia80 (TABLE 6). The dispar-
ity in these findings could relate to the time at which the
intervention was started. In the study in which a benefit
of metformin was observed, these women were already
receiving the drug before conception79.
The potential for metformin to improve outcomes in
pregnant women with obesity has been evaluated in two
randomized controlled trials81 (TABLE 6). The EMPOWaR
trial81 powered to detect differences in fetal birthweight,
randomly assigned 449 pregnant white women who had
obesity to receive either metformin or matched placebo
(up to 2,500 mg daily in two to three divided doses)
before 16 weeks gestation. Fetal birthweight was simi-
lar between the two groups. Importantly, no differences
were detected in either the proportion of women who
developed GDM (18.0% versus 24.0%, P = 0.27) or the
proportion of infants who were born LGA. In the MOP
trial82, which was similarly powered to detect differences
in fetal birthweight as the primary outcome, a total daily
dose of 3.0 g metformin versus matched placebo was
assessed. Although fetal birthweight centile (51.8; inter-
quartile range (IQR) 23.9–82.1) versus 56.6 (IQR 26.8–
81.4); P = 0.66) and incidence of GDM (12.4% versus
11.3%; P = 0.74) was similar in the two groups, those
assigned to the metformin arm gained significantly less
gestational weight (4.6 kg (IQR 1.3–7.2) versus 6.3kg
(IQR 2.9–9.2); P <0.001) and had a lower incidence of
pre-eclampsia (OR 0.24, 95% CI 0.10–0.61; P = 0.001)
than those receiving placebo. The negative results from
these trials, and those investigating lifestyle interven-
tions in pregnant women with obesity, suggest that
addressing risk factors, in particular obesity before con-
ception, might be a more effective strategy to address
the risk of metabolic disorders in the mother and infant.
GDM prevention strategies before conception
No randomized controlled trials have been developed
that investigate the use of GDM prevention strategies
before conception. Observational data have indicated
that associations exist between lifestyle factors during
this preconception period or in early pregnancy, and

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risk of developing GDM19,83. Replacing 1–5% of energy
derived from carbohydrates with fat is associated with
an increased risk of GDM, and higher consumption of
cholesterol (≥300 mg per day), haem iron (≥1.1 mg per
day), processed meats (increment of one serving per day)
and eggs (≥7 per week) have similarly been suggested to
increase GDM risk. A lower intake of carbohydrates has
been associated with a lower risk84. In a meta-analysis,
increased physical activity has been associated with a 55%
reduction in the risk of GDM during the preconception
period (pooled OR 0.45; 95% CI 0.28–0.75, P <0.0001)
compared with a 25% reduction during early pregnancy
(pooled OR 0.76, 95% CI 0.70–0.83; P = 0.77)85. Finally,
in a retrospective analysis from the Nurses’ Health
Study II, the relationship between low risk factors in
the pre-conceptual period, defined as a healthy body
weight, adherence to a healthy dietary pattern, regular
exercise of 150 min per week and abstinence from smok-
ing, and GDM risk was analysed86. Each risk factor was
significantly and independently associated with a lower
risk of developing GDM as follows: healthy body weight
RR 0.44 (95% CI 0.38–0.50); adherence to a healthy
diet RR 0.81 (95% CI 0.70–0.94); regular exercise RR 0.85
(95% CI 0.73–0.99); and non-smoking RR 0.71 (95% CI
0.58–0.87). Women who adhered to all four healthy life-
style patterns had an 83% reduction in GDM incidence
(95% CI 0.12–0.25). Modifying behaviour and reducing
weight either before or in the very early stages of preg-
nancy might, therefore, have a positive effect on the
pregnancy, and perhaps to a greater extent than when
the interventions are implemented later in the pregnancy.
Further research is needed to identify the effective means
of lifestyle modification both in the pre-conception
period and during pregnancy, with an evaluation as to
whether these can improve materno–fetal outcomes.
Conclusions
The incidence of GDM and its complications are increas-
ing, which reflects the increasing prevalence of obe-
sity among pregnant women. Preventing pathological
hyperglycaemia during pregnancy has several potential
benefits: a reduction of associated immediate maternal
and fetal adverse outcomes, improvements in the risk
of long-term sequelae and reductions in the economic
burden to healthcare systems worldwide.
The evidence regarding intervention with lifestyle
strategies in preventing GDM in women with and with-
out risk factors is conflicting and probably relates to
the large degree of heterogeneity across the trials both
in terms of cohort demographics and the diagnostic
criteria used to define the condition. The results of pop-
ulation-based studies of dietary or combined lifestyle
measures have not demonstrated any improvements
in the risk of developing GDM and trials involving
physical activity strategies have yielded conflicting
results. In women with obesity, dietary modification
might improve GDM risk and fetal macrosomia, but
low compliance and no significant reductions in the
incidence of GDM have been observed in trials inves-
tigating physical activity. Combined lifestyle measures
have been associated with significant reductions in
gestational weight gain in pregnant women with obe-
sity; however, reductions in the incidence of GDM
have been reported in only one randomized controlled
trial following adjustment for multiple baseline covar-
iates. Fish oil supplementation has not influenced
the incidence of GDM and the use of probiotics only
seems to benefit women at very high risk of GDM.
Although supplementation with myoinositol has had
a positive effect on GDM, confirmatory studies are
needed. Finally, in randomized controlled trials with
metformin, this drug does not seem to prevent GDM
in certain at-risk groups though it might still prove of
benefit in other groups.
Given the significant potential for reducing the
disease burden, research should continue to identify
strategies that can be easily implemented within a pop-
ulation, particularly during the preconception period.
Until such time, standard recommendations should
be followed.

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Acknowledgments
The authors wish to acknowledge support from the Novo
Nordisk UK Research Charitable Foundation for a clinical
research fellowship awarded to R.A.-J.
Author contributions
R.A.-J. and S.R. researched data for the article. R.A.-J.wrote
the manuscript. All authors made substantial contribution
to discussion of the content, and reviewed and edited the
manuscript before submission.
Competing interests statement
The authors declare no competing interests.
Review criteria
Articles were identified through searches of PubMed from
1961 through to December 2015 using the following search
terms: “lifestyle”, “intervention”, “exercise”, “diet” and “sup-
plements” in combination with “gestational diabetes mellitus”
and “prevention”. The full text articles for abstracts outlining
randomized controlled trials were examined. Only articles
analysing the effect of the intervention on GDM, as either a
primary or secondary outcome, were included. References
from relevant articles were reviewed to ensure that all cita-
tions had been included.

14 | ADVANCE ONLINE PUBLICATION www.nature.com/nrendo

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