Articles

Effect of metformin in addition to dietary and lifestyle

advice for pregnant women who are overweight or obese:
the GRoW randomised, double-blind, placebo-controlled
trial
Jodie M Dodd, Jennie Louise, Andrea R Deussen, Rosalie M Grivell, Gustaaf Dekker, Andrew J McPhee, William Hague

Summary
Background Maternal overweight and obesity are associated with well recognised pregnancy complications. Antenatal Lancet Diabetes Endocrinol 2018
dietary and lifestyle interventions have a modest effect on gestational weight gain without affecting pregnancy Published Online
outcomes. We aimed to assess the effects on maternal and infant outcomes of antenatal metformin given in addition December 4, 2018
http://dx.doi.org/10.1016/
to dietary and lifestyle advice among overweight and obese pregnant women.
S2213-8587(18)30310-3
See Online/Comment
Methods GRoW was a multicentre, randomised, double-blind, placebo-controlled trial in which pregnant women at http://dx.doi.org/10.1016/
10–20 weeks’ gestation with a BMI of 25 kg/m² or higher were recruited from three public maternity units in Adelaide, S2213-8587(18)30337-1
SA, Australia. Women were randomly assigned (1:1) via a computer-generated schedule to receive either metformin Discipline of Obstetrics &
(to a maximum dose of 2000 mg per day) or matching placebo. Participants, their antenatal care providers, and Gynaecology and Robinson
Research Institute
research staff (including outcome assessors) were masked to treatment allocation. All women received an antenatal
(Prof J M Dodd PhD, J Louise PhD,
dietary and lifestyle intervention. The primary outcome was the proportion of infants with birthweight greater than A R Deussen BHSc,
4000 g. Secondary outcomes included measures of maternal weight gain, maternal diet and physical activity, maternal Prof G Dekker MD,
pregnancy and birth outcomes, maternal quality of life and emotional wellbeing, and infant birth outcomes. Outcomes Prof W Hague MD) and School
of Public Health (J Louise),
were analysed on an intention-to-treat basis (including all randomly assigned women who did not withdraw consent
University of Adelaide,
to use their data, and who did not have a miscarriage or termination of pregnancy before 20 weeks’ gestation, or a Adelaide, SA, Australia;
stillbirth). The trial is registered with the Australian New Zealand Clinical Trials Registry, number Department of Perinatal
ACTRN12612001277831. Medicine (J M Dodd, W Hague)
and Department of Neonatal
Medicine (A J McPhee MD),
Findings Of 524 women who were randomly assigned between May, 28 2013 and April 26, 2016, 514 were included in Women’s and Children’s
outcome analyses (256 in the metformin group and 258 in the placebo group). Median gestational age at trial entry Hospital, North Adelaide, SA,
was 16·29 weeks (IQR 14·43–18·00) and median BMI was 32·32 kg/m² (28·90–37·10); 167 (32%) participants were Australia; Department of
Obstetrics and Gynaecology,
overweight and 347 (68%) were obese. There was no significant difference in the proportion of infants with birthweight
Flinders University, Bedford
greater than 4000 g (40 [16%] with metformin vs 37 [14%] with placebo; adjusted risk ratio [aRR] 0·97, 95% CI Park, SA, Australia
0·65 to 1·47; p=0·899). Women receiving metformin had lower average weekly gestational weight gain (adjusted (R M Grivell PhD); and Lyell
mean difference –0·08 kg, 95% CI –0·14 to –0·02; p=0·007) and were more likely to have gestational weight gain McEwin Hospital, Elizabeth
Vale, SA, Australia (G Dekker)
below recommendations (aRR 1·46, 95% CI 1·10 to 1·94; p=0·008). Total gestational weight gain, pregnancy and
Correspondence to:
birth outcomes, maternal diet and physical activity, and maternal quality of life and emotional wellbeing did not differ
Prof Jodie M Dodd, Discipline of
significantly between groups. Similar numbers of women in both treatment groups (76% [159/208] in the metformin Obstetrics & Gynaecology and
group and 73% [144/196] in the placebo group) reported side-effects including nausea, diarrhoea, and vomiting. Two Robinson Institute, University of
stillbirths (placebo group) and one neonatal death (metformin group) occurred; none of the perinatal deaths were Adelaide, and Women’s &
Children’s Hospital, North
determined to be attributable to participation in the trial.
Adelaide, SA 5006, Australia
jodie.dodd@adelaide.edu.au
Interpretation For pregnant women who are overweight or obese, metformin given in addition to dietary and lifestyle
advice initiated at 10–20 weeks’ gestation does not improve pregnancy and birth outcomes.

Funding Australian National Health and Medical Research Council.

Copyright © 2018 Elsevier Ltd. All rights reserved.

Introduction associated with infant birthweights greater than 4000 g,

The worldwide prevalence of overweight and obesity
continues to grow.1 In high-income countries, roughly
50% of women enter pregnancy with a BMI greater than
25 kg/m²,2 placing both the woman and her infant at risk
of a range of well documented adverse pregnancy and
birth outcomes.3 Furthermore, high maternal BMI is
which in turn is recognised as an independent predictor
of childhood obesity, associated with a more than two-
times increased risk.4
There has been considerable research and clinical
interest in the provision of antenatal dietary and lifestyle
interventions for pregnant women, particularly women

www.thelancet.com/diabetes-endocrinology Published online December 4, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30310-3 1

 Articles
Research in context
Evidence before this study
We searched the Cochrane Pregnancy and Childbirth Group’s
Trials Register by contacting the trials search coordinator (April
13, 2016). Briefly, the Cochrane Pregnancy and Childbirth
Group’s Trials Register is maintained by the trials search
coordinator and contains trials identified from: monthly
searches of the Cochrane Central Register of Controlled Trials
(CENTRAL); weekly searches of MEDLINE (Ovid); weekly
searches of Embase (Ovid); monthly searches of CINAHL
(EBSCO); manual searches of 30 journals and the proceedings of
major conferences; weekly current awareness alerts for an
additional 44 journals and monthly BioMed Central email
alerts. Search terms from this comprehensive register include
“metformin”, “randomiz(s)ed trial”, and “pregnancy”. Antenatal
dietary and lifestyle interventions for pregnant women,
particularly those who are overweight or obese, have been
investigated as a strategy to limit gestational weight gain, but
have shown only a modest effect on weight gain in pregnancy
and very little effect on clinical outcomes. Metformin has been
proposed as a possible drug treatment for use among obese
pregnant women, although recent studies have reported
conflicting findings with regards to the effect on gestational
weight gain and some pregnancy outcomes. In the EMPOWaR
trial, the investigators reported no difference between
metformin and placebo groups in birthweight centile and no
differences in any of the secondary outcomes including
who are overweight or obese, as a strategy to limit
gestational weight gain and thereby improve preg­
nancy, birth, and infant outcomes. In an individual
­ benefit in providing treatment for women who are
participant data meta-analysis incorporating data from
36 randomised trials and more than 12 500 pregnant
women who received an antenatal dietary or lifestyle
intervention,2 a modest effect on gestational weight gain
(mean difference –0·7 kg) was identified, but with very
little effect on clinical pregnancy outcomes, consistent
with other reports.5 These findings suggest the need for
assessment of additional strategies in this population.
Metformin has been considered for use in pregnant
women who are overweight or obese, in view of the
associations between high maternal BMI and gestational
diabetes, and a similar intrauterine milieu of insulin resis­
tance, hyperglycaemia, hyperlipidaemia, and chro­ nic
inflammation.6 Metformin has insulin-sensitising
properties, reducing hepatic glucose production and
increasing peripheral glucose utilisation,7 and is used
increasingly in the treatment of women with gestational
diabetes.8
Previous trials9,10 assessing the use of metformin in
obese pregnant women have had conflicting findings with
respect to effects on gestational weight gain and some
pregnancy outcomes. Importantly, women partici­pating
in these previous randomised trials were not provided
with a dietary and lifestyle intervention. Furthermore,
2 www.thelancet.com/diabetes-endocrinology Published online December 4, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30310-3
gestational weight gain or pre-eclampsia. In the MOP trial,
investigators reported no difference in neonatal birthweight
but decreased gestational weight gain and reduced incidence of
pre-eclampsia in the group assigned to metformin.
Importantly, women participating in these previous
randomised trials were not provided with a dietary and lifestyle
intervention. Additionally, these previous trials have only
included women who were obese, whereas there might be
clinical benefit in providing treatment for women who are
overweight as well as for those who are obese.
Added value of this study
To our knowledge, this is the first trial to assess the effect of
metformin given in addition to an antenatal dietary and
lifestyle intervention, and to include women who are
overweight as well as those who are obese. The use of
metformin in addition to an antenatal dietary and lifestyle
intervention in women who are overweight or obese did not
affect the proportion of infants with a birthweight greater than
4000 g. There was no effect of metformin on total gestational
weight gain or on clinical pregnancy and birth outcomes.
Implications of all the available evidence
The use of metformin in this clinical setting should not be
advocated. Future research strategies should focus on
improving women’s health and diet to encourage weight loss
before conception.
since the risk of adverse pregnancy outcomes increases
with increasing maternal BMI,3 there might be clinical
overweight as well as for those who are obese.
The aim of the GRoW (metformin and dietary advice to
improve insulin sensitivity and promote Gestational
Restriction of Weight in pregnant women who are
overweight or obese) randomised trial was to assess the
effects on maternal and infant outcomes of antenatal
metformin in addition to dietary and lifestyle advice
among overweight and obese pregnant women.
Methods
Study design and participants
GRoW was a multicentre, randomised, double-blind,
placebo-controlled trial in which women were recruited
from the three major public maternity hospitals in
metropolitan Adelaide, SA, Australia (Women’s and
Children’s Hospital, Lyell McEwin Hospital, and Flinders
Medical Centre). Eligible women had a live singleton
pregnancy between 10 and 20 weeks’ gestation and
were overweight (BMI 25·0–29·9 kg/m²) or obese
(BMI ≥30·0 kg/m²) at their first antenatal visit. Women
with a multiple pregnancy, type 1 or 2 diabetes diagnosed
prior to pregnancy, or with significant renal or hepatic
impairment such that metformin therapy was
contraindicated, were excluded.

The study protocol (appendix)11 was approved by the
Women’s and Children’s Health Network Human
Research Ethics Committee, with local institutional
approval at each site. Participating women provided
written informed consent.
Randomisation and masking
All women presenting for antenatal care at the partici­
pating centres had their height and weight measured
and BMI calculated at their first antenatal appointment.
Eligible women were then counselled by a research
assistant. Those women who consented to participate
were randomly assigned (1:1) to metformin or placebo,
by use of a central online randomisation service. The
computer-generated randomisation schedule util­ ised
blocks of four and was prepared by an investigator not
involved with recruitment or clinical care. Stratifi­cation
occurred for parity (0 vs 1 or more), BMI at ante­natal
booking visit (25·0–29·9 kg/m² vs ≥30·0 kg/m²), and
collaborating centre.
Metformin tablets (500 mg) and placebo tablets
identical in appearance were packaged by an independent
pharmaceutical packaging company (Pharmaceutical
Packaging Professionals, Port Melbourne, VIC,
Australia) and coded in accordance with the
randomisation schedule. Participants, their antenatal
care providers, and research staff (including outcome
assessors) were masked to treatment allocation.
Procedures
All participants received a 16-week supply of tablets
(metformin 500 mg or identical placebo) and a further
12-week supply at 28 weeks’ gestation. Women com­
menced tablets from randomisation, starting with one
tablet per day for 1 week, and increasing to a maximum
of two tablets twice per day (maximum dose metformin
2000 mg per day) over 4 weeks as tolerated, and then
continuing until birth. At 36 weeks’ gestation, women
completed a questionnaire to ascertain com­pliance with
medication and the occurrence of any side-effects.
All participating women received dietary and lifestyle
advice delivered over three face-to-face sessions (two
with a dietitian, shortly after trial entry and at 28 weeks,
and one with a research assistant at 36 weeks) and
three telephone calls from the research assistant at 20,
24, and 32 weeks. Dietary advice was consistent with
Australian standards.12,13 Women were advised to main­
tain a balance of carbohydrates, fat, and protein, while
specifically encouraging a reduction in the intake of
energy-dense and non-core foods high in refined
carbohydrates and saturated fats, increased intake of
fibre, and consumption of two servings of fruit,
five servings of vegetables, and three servings of dairy
each day.12,13
Tailoring of the intervention was informed by stage
theories of health decision making.14 Initially, there was
a planning session with a research dietitian, in which
www.thelancet.com/diabetes-endocrinology Published online December 4, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30310-3 3
Articles
women were provided with written information, an See Online for appendix
individual diet and physical activity plan, recipe book,
and example menu plans. Participants were encouraged
to set achievable goals for dietary and exercise change
and were supported to make these lifestyle changes and
to self-monitor their progress using a SMART (Specific,
Measurable, Achievable, Relevant, and Timely) goals
approach. These principles were reinforced at
subsequent face-to-face visits with the dietitian and
research assistant, and during the telephone contacts.
All participants completed a food frequency question­
naire, exercise diary, and quality-of-life and emotional
wellbeing assessments at trial entry and at 28 and
36 weeks’ gestation. Consistent with state-wide clinical
practice guidelines for South Australia, all women were
screened for gestational diabetes at about 28 weeks’
gestation.15 During the course of the trial, diagnostic
criteria for gestational diabetes changed across the state
from a positive 75 g oral glucose tolerance test with a
fasting blood glucose concentration of 5·5 mmol/L or
above, or a 2 h blood glucose concentration of
7·8 mmol/L above, to a fasting blood glucose of
5·1 mmol/L or above, a 1 h blood glucose concentration
of 10·0 mmol/L or above, or a 2 h blood glucose con­
centration of 8·5 mmol/L or above.15 Women diagnosed
with gestational diabetes remained in the study and
were offered treatment with further dietary modification
and metformin or insulin added as required to maintain
appropriate glycaemic control.15 Women who required
metformin for the treatment of gestational diabetes
were prescribed this medication in addition to their
study medication. All other care during pregnancy and
birth was done in accordance with local hospital
practices.15
Outcomes
The primary outcome was the proportion of infants with
birthweight greater than 4000 g.
Several categories of secondary outcomes were also
assessed. First, maternal weight gain outcomes assessed
were total gestational weight gain (defined as the
difference between pregnancy weight obtained at
36 weeks’ gestation or nearest to birth and early
pregnancy weight); average weekly gestational weight
gain (calculated as total gestational weight gain divided
by actual time in weeks between measurements); and
gestational weight gain below, within, or above the US
Institute of Medicine (IoM) recom­mendations according
to early pregnancy BMI (defined as 7·0 to 11·5 kg for
women who were overweight and 5·0 to 9·0 kg for
women who were obese).16 Second, maternal diet and
physical activity, as measured by questionnaires
completed at trial entry and at 28 and 36 weeks’ gestation
(using the Harvard Semi-Quantitative Food Frequency
Questionnaire17 and the Short Questionnaire to Assess
Health-Enhancing Physical Activity18). Third, maternal
pregnancy and birth outcomes assessed were
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hypertension (defined as a systolic blood pressure
≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on
two occasions 4 h or more apart) and pre-eclampsia
(based on criteria from the Australasian Society for the
Study of Hypertension in Pregnancy19); clinical diagnosis
of gestational diabetes;15 antepartum haemorrhage
requiring admission; preterm prelabour ruptured
membranes; chorioamnionitis; induction of labour;
caesarean section; postpartum haemorrhage (defined as
blood loss >600 mL); 3rd or 4th degree perineal trauma;
wound infection; endo­ metritis; thromboembolic
disease; antenatal admission; antibiotic use during
delivery; and maternal death. Fourth, maternal quality of
life and emotional wellbeing, as measured by question­
naires completed by participants at trial entry and at
28 and 36 weeks’ gestation relating to quality of life
(SF12 Health Survey Questionnaire20), anxiety (Short
Form Spielberger State Trait Inventory21), and depression
(Edinburgh Postnatal Depression Scale22).
Finally, the secondary outcomes also included
additional infant birth outcomes. These infant outcomes
were preterm birth before 37 weeks; perinatal mortality
(defined as an intrauterine fetal death after trial entry
and after 20 weeks’ gestation but prior to birth, or the
death of a liveborn infant before hospital discharge
[excluding lethal congenital anomalies]); infant birth­
weight (inclu­ding weight <2500 g, and weight >4500 g);
large for gestational age (defined as weight greater than
the 90th centile for gestational age and infant sex); small
for gestational age (defined as weight less than the
10th centile for gestational age and infant sex); hypo­
glycaemia requiring treatment; infant admis­sion to the
neonatal intensive care unit or special care baby unit;
hyperbilirubinaemia requiring photo­ therapy; nerve
palsy; fracture; birth trauma; shoulder dystocia; and
new­ born anthropometric measures (including birth
length; biceps, triceps, abdominal, supra­ iliac, sub­
scapular, and thigh skinfold thicknesses; head, chest,
abdominal, and right upper arm circum­ferences; and
z scores for birthweight, birth length, and circumference
measures) taken within the first few days (median 2·0
days [IQR 1·0–4·0]) after birth in accordance with a
specifically developed protocol.23
The study protocol (appendix) also specified a health
economic analysis of health-care costs to determine the
cost of the intervention per live birth. Another secondary
outcome, fetal growth and adiposity measures deter­
mined by ultrasound at 28 and 36 weeks’ gestation,
will be reported elsewhere. Infant follow-up at 6 and
18 months, including weight, length, and circumference
and skinfold measurements will also be reported
elsewhere.
Safety was assessed with a questionnaire completed at
36 weeks asking about compliance with study medication
and side-effects experienced. Additionally, a multi­discip­
lin­ary adverse events committee masked to treat­ment
allocation reviewed all serious adverse events.
4 www.thelancet.com/diabetes-endocrinology Published online December 4, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30310-3
Statistical analysis
The primary clinical outcome was the proportion of
infants born with birthweight greater than 4000 g, which
was estimated to occur in 15·5% of offspring of women
eligible for the trial.12 To detect a change from
15·5% to 7·35% (ie, a reduction of about 47%; alpha
0·05, power 80%),12 and accounting for a 5% rate of
attrition (based on our experience with the LIMIT
study12), we estimated that a sample size of 524 women
would be required.
All analyses followed a prespecified statistical analysis
plan (appendix). Baseline characteristics of all randomly
assigned women were examined descriptively. Primary
and secondary outcomes were analysed on an intention-
to-treat basis (including all randomly assigned women
who did not withdraw consent to use their data, and who
did not have a miscarriage or termination of pregnancy
before 20 weeks’ gestation, or a stillbirth), according to
the treatment allocated (metformin or placebo) at
random­isation. Continuous outcomes were analysed by
use of linear regression and binary outcomes were
analysed by use of log binomial regression. Outcomes
measured at multiple timepoints included a time-by-
treatment interaction term, with generalised estimating
equations used to account for correlation between
repeated measures. Results for continuous outcomes are
reported as adjusted differences in means (metformin
minus placebo) and results for binary outcomes are
reported as adjusted risk ratios (aRRs; metformin vs
placebo). No adjustments were made for multiple
comparisons (secondary outcomes were considered
exploratory rather than confirmatory).
As specified in the statistical analysis plan (appendix),
the primary analyses were adjusted analyses based on
imputed data. Unadjusted analyses, and analyses on
unimputed data (not presented), were also done as
secondary sensitivity analyses. Adjusted models included
the stratification variables (centre, maternal BMI, and
parity) as well as smoking status, socioeconomic status
(as defined by the Australian Bureau of Statistics’ 2011
Socio-Economic Index for Areas—Index of Relative
Socio-Economic Disadvantage quintile24), and maternal
age at trial entry as covariates.
There were no missing values for the primary outcome
or for other infant birthweight outcomes; many other
outcomes (including infant anthropometry and infant
and maternal delivery data) had less than 1% missing
data; however, infant skinfold thickness measurement
and other maternal antenatal measures had between
20% and 46% missing data across the study cohort
(appendix). Multiple imputation by the fully conditional
specification (chained equations) method was used to
create 100 complete datasets for analysis.25 The
imputation model included all outcomes, all stratification
variables, mater­ nal baseline height, weight, and
gestational age, and maternal weight at 36 weeks’
gestation. Estimates were derived in the standard manner
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by combining the estimates from each imputation using onset fetal growth restriction and pre-eclampsia). There
Rubin’s rules.25 As there were no missing values for the was one neonatal death in the metformin group following
primary outcome, no missing-not-at-random sensitivity extremely preterm birth (before 22 weeks). None of the
analyses were done. perinatal deaths were determined to be attributable to
Secondary analyses for the primary outcome and participation in the trial.
secondary infant anthropometric outcomes were The baseline characteristics of women at trial entry
prespecified to test for evidence of modification of the were similar in the two treatment groups (table 1). Across
effect of treatment by maternal BMI category (overweight the whole study cohort, median gestational age at trial
vs obese). entry was 16·29 weeks (IQR 14·43–18·00) and median
Statistical analyses were done with SAS version 9.4 or BMI was 32·32 kg/m² (28·90–37·10); 167 (32%)
Stata version 14. participants were overweight and 347 (68%) were obese.
We also did a post-hoc meta-analysis incorporating the Adequate data were available for all 514 infants for the
findings of the GRoW trial into our previously reported primary outcome of birthweight greater than 4000 g.
Cochrane systematic review,26 which was done in 404 (79%) of 514 participants provided data for
accordance with standard Cochrane methods, to assess experience of adverse effect, with no differences
the impact of metformin on gestational weight gain, identified between treatment groups (table 2). Of 354
birth­weight, and risk of pre-eclampsia. Briefly, (69%) participants who provided data for medication
randomised and quasi-randomised trials assessing compliance, 296 (84%) took the maximum of four tablets
metformin use (compared with placebo or no metformin) per day (appendix).
in pregnant women who were overweight or obese, There was no significant difference in the proportion
defined as an early pregnancy or pre-pregnancy BMI of of infants with birthweight greater than 4000 g between
25·0 kg/m² or higher, were identified from a search of the metformin and placebo groups (40 [16%] of 256 in the
the Cochrane Pregnancy and Childbirth’s Trials Register.
Two review authors independently assessed risk of bias 3546 eligible women approached to participate
for each study, with statistical analyses done with Review
Manager 5. A fixed-effect meta-analysis was used to
combine data where trials were judged to be sufficiently 3022 declined to participate
259 did not want to
similar, and a random-effects meta-analysis was used to participate in research
produce an overall summary if substantial statistical 481 did not want to take
study medication
heterogeneity was detected. For the present report, we 547 too busy or unable
incorporated the data from the present trial into the to attend for study
visits
existing systematic review and meta-analysis using 531 other reasons*
Review Manager 5. For dichotomous data (risk of pre- 1204 were not interested,
eclampsia), results are presented as summary risk ratio did not give a reason,
or could not be
with 95% CIs; for continuous data (gestational weight contacted
gain and birthweight), results are presented as mean
difference with 95% CIs.
524 consented and randomly assigned
The GRoW trial is registered with the Australian New
Zealand Clinical Trials Registry, number
ACTRN12612001277831.
261 assigned to metformin 263 assigned to placebo
Role of the funding source
The funder had no role in the study design, data
0 withdrew consent 1 withdrew consent
collection, analysis, interpretation, or writing of the 5 had miscarriage before 2 had miscarriage before
report. The corresponding author had full access to the 20 weeks or termination of 20 weeks or termination of
pregnancy pregnancy
data and final responsibility for the decision to submit 0 had stillbirth after 20 weeks 2 had stillbirth after 20 weeks
for publication. 256 liveborn infants 258 liveborn infants
1 neonatal death 0 neonatal death
0 maternal death 0 maternal death
Results
Between May 28, 2013 and April 26, 2016, 3546 eligible
women were approached to participate; 524 women were 256 woman and infant pairs 258 woman and infant pairs
included in the analysis included in the analysis
randomly assigned, 261 to metformin and 263 to placebo
(figure). 514 women and infant pairs were included in
the analyses (256 in the metformin group and 258 in the Figure: Trial profile
*Other reasons includes any reason not covered by the other categories,
placebo group). No maternal deaths occurred. There including partner or family against participation, did not think they were
were two stillborn infants, both in the placebo group (one overweight, were already participating in another research project, and did not
secondary to acute chorioamnionitis and one due to early think that they needed lifestyle intervention.

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Metformin (n=256) Placebo (n=258) Metformin Placebo

(n=208*) (n=196†)
Maternal age (years) 29·87 (5·54) 30·17 (5·37)
Study centre Any reported side-effect 159 (76%) 144 (73%)

Women’s and Children’s Hospital 110 (43%) 112 (43%) Nausea 74 (36%) 65 (33%)

Lyell McEwin Hospital 117 (46%) 118 (46%) Vomiting 49 (24%) 46 (23%)

Flinders Medical Centre 29 (11%) 28 (11%) Abdominal pain 50 (24%) 48 (24%)

Gestational age at entry (weeks) 16·29 (14·43–18·00) 16·29 (14·57–18·14) Diarrhoea 62 (30%) 44 (22%)

BMI (kg/m )2
32·50 (28·71–37·54) 32·05 (29·10–36·80) Fatigue 92 (44%) 98 (50%)

BMI category Weakness 33 (16%) 30 (15%)

25·0–29·9 kg/m 2
83 (32%) 84 (33%) Skin rash 14 (7%) 19 (10%)

≥30·0 kg/m 2
173 (68%) 174 (67%) Loss of appetite 47 (23%) 40 (20%)

Public patient 252 (98%) 254 (98%) Data are the number (%) of women who reported at least one specified adverse
event during the study period up to completion of the questionnaire at 36 weeks.
Weight (kg) 92·89 (19·76) 91·80 (19·79)
Data are for all randomly assigned women who did not withdraw consent to use
Height (cm) 165·27 (6·76) 164·87 (6·79) their data, and who did not have a miscarriage or termination of pregnancy
Race before 20 weeks’ gestation, or stillbirth. *Excludes 48 (19%) of 256 participants
White 210 (82%) 221 (86%) who did not complete the questionnaire assessing compliance with medication
and experience of adverse effects. †Excludes 62 (24%) of 258 participants who did
East Asian 5 (2%) 7 (3%) not complete the questionnaire assessing compliance with medication and
Indian 12 (5%) 6 (2%) experience of adverse effects.
Other 24 (9%) 19 (7%)
Table 2: Adverse effects
Unknown 5 (2%) 5 (2%)
Smoker 24 (9%) 43 (17%)
Nulliparous 88 (34%) 92 (36%) (table 4), including diagnosis of gestational diabetes,
Previous preterm birth 13 (5%) 13 (5%) irrespective of the diagnostic criteria used (appendix).
Previous pre-eclampsia 13 (5%) 10 (4%) Furthermore, following diagnosis of gestational diabetes,
Previous stillbirth or neonatal death 1 (<1%) 6 (2%)
there were no significant differences between the
Previous caesarean section 48 (19%) 67 (26%)
treatment groups with respect to use of either metformin
Family history of diabetes 83 (32%) 78 (30%)
or insulin therapy (appendix).
Family history of hypertension 105 (41%) 104 (40%)
Overall the risks of maternal labour complications did
not differ significantly between the treatment groups
Family history of heart disease 58 (23%) 61 (24%)
(table 5). Although there was a significant reduction in
Index of socioeconomic disadvantage*
risk of caesarean birth among women in the metformin
Quintile 1 (most disadvantaged) 76 (30%) 95 (37%)
group compared with those in the placebo group, this
Quintile 2 78 (30%) 74 (29%)
finding was partly the result of a difference in the number
Quintile 3 31 (12%) 30 (12%)
of women undergoing an elective repeat caesarean birth
Quintile 4 52 (20%) 43 (17%)
(30 women in the metformin group vs 44 women in the
Quintile 5 (least disadvantaged) 19 (7%) 16 (6%)
placebo group). Self-reported maternal quality of life and
Data are mean (SD), median (IQR), or n (%). Data are for all randomly assigned women who did not withdraw consent emotional wellbeing did not differ between groups
to use their data, and who did not have a miscarriage or termination of pregnancy before 20 weeks’ gestation, or a
stillbirth. *Socioeconomic index of relative social disadvantage (as defined by the Australian Bureau of Statistics’
(appendix).
2011 Socio-Economic Index for Areas—Index of Relative Socio-Economic Disadvantage quintile24). Mean gestational age at birth was similar in the
two treat­ment groups, as was mean infant birthweight
Table 1: Baseline characteristics
(table 3). There were no significant differences between
the two groups with respect to other infant outcomes
metformin group vs 37 (14%) of 258 in the placebo group; (table 3) or newborn anthropometric measures
aRR 0·97, 95% CI 0·65 to 1·47; p=0·899; table 3). (appendix) apart from infant abdominal circumference at
Compared with the placebo group, women in the birth, which was 0·5 cm smaller in the metformin group
metformin group had lower average weekly gestational (p=0·049; appendix), although this could be a chance
weight gain and were more likely to have weight gain finding and the small difference is of questionable
below the IoM recommendations; total gestational clinical significance.
weight gain was not significantly different between the A prespecified secondary analysis identified some
treatment groups (table 4). Women in both groups were evidence of effect modification by maternal BMI category,
successful in improving the quality of their dietary with the use of metformin associated with a significant
intake, but dietary patterns and physical activity did not reduction in the proportion of infants with birthweight
differ between the two treatment groups at trial entry or greater 4000 g and reductions in total gestational weight
over the course of pregnancy (appendix). There were no gain and weight gain above IoM recommendations
significant differences between the two treatment groups among overweight women but not among obese women
with respect to maternal risk of pregnancy complications (appendix).

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Metformin Placebo (n=258) Unadjusted Unadjusted Adjusted treatment Adjusted

(n=256) treatment effect p value effect (95% CI) p value
(95% CI)
Birthweight >4000 g 40 (15·63%) 37 (14·34%) 1·09 (0·72 to 1·65) 0·684 0·97 (0·65 to 1·47) 0·899
Birthweight (g) 3487·80 3471·80 16·00 0·739 –13·01 0·785
(531·37) (556·67) (–78·10 to 110·09) (–106·45 to 80·44)
Gestational age at birth (weeks) 39·12 (1·64) 38·93 (1·85) 0·19 (–0·11 to 0·49) 0·222 0·10 (–0·20 to 0·40) 0·532
Large for gestational age 50 (19·53%) 56 (21·71%) 0·90 (0·64 to 1·26) 0·543 0·87 (0·62 to 1·23) 0·428
Small for gestational age 10 (3·91%) 8 (3·10%) 1·26 (0·51 to 3·14) 0·620 1·37 (0·55 to 3·45) 0·502
Birthweight >4500 g 5 (1·95%) 7 (2·71%) 0·72 (0·23 to 2·24) 0·570 0·64 (0·21 to 1·97) 0·433
Birthweight <2500 g 4 (1·56%) 11 (4·26%) 0·37 (0·12 to 1·14) 0·082 0·42 (0·13 to 1·31) 0·135
Stillbirth* 0 2 (0·77%) ·· ·· ·· 0·499
Neonatal death* 1 (0·39%) 0 ·· ·· ·· 0·496
Admission to NICU or SCBU 32 (12·55%) 43 (16·67%) 0·75 (0·49 to 1·15) 0·189 0·78 (0·51 to 1·20) 0·260
Hypoglycaemia requiring treatment 19 (7·45%) 24 (9·30%) 0·80 (0·45 to 1·43) 0·451 0·87 (0·49 to 1·55) 0·632
Hyperbilirubinaemia requiring 16 (6·27%) 20 (7·75%) 0·81 (0·43 to 1·53) 0·513 0·76 (0·41 to 1·40) 0·379
phototherapy†
Nerve palsy‡ 0 0 ·· ·· ·· ··
Fracture* 1 (0·39%) 0 ·· ·· ·· 0·497
Birth trauma* 3 (1·18%) 0 ·· ·· ·· 0·122
Shoulder dystocia 7 (2·73%) 7 (2·71%) 1·01 (0·36 to 2·83) 0·988 0·96 (0·34 to 2·66) 0·935
Results presented are based on imputed data, unless otherwise specified. Birthweight and gestational age at birth are continuous outcomes, for which data are mean (SD)
and treatment effect estimates are differences in means (metformin minus placebo); all other outcomes are binary, for which data are n (%; with numbers calculated from
proportions averaged across imputations) and treatment effect estimates are risk ratios (metformin vs placebo). Data are for all randomly assigned women who did not
withdraw consent to use their data, and who did not have a miscarriage or termination of pregnancy before 20 weeks’ gestation, or stillbirth. Adjusted analyses included
stratification variables (centre, parity, BMI category), maternal smoking status, age at consent, and socioeconomic status quintile as covariates. NICU=neonatal intensive care
unit. SCBU=special care baby unit. *Insufficient events for analysis or imputation; p value from Fisher’s exact test on un-imputed data. †Poisson model with robust variance
estimation used for adjusted analysis because binomial model did not converge. ‡No events in either group so no modelling was possible.

Table 3: Infant outcomes

Metformin Placebo Unadjusted treatment Unadjusted Adjusted treatment Adjusted

(n=256) (n=258) effect (95% CI) p value effect (95% CI) p value
Total gestational weight gain (kg) 7·48 (6·95) 8·72 (6·91) –1·23 (–2·45 to –0·01) 0·048 –1·18 (–2·37 to 0·01) 0·053
Average weekly gestational weight 0·38 (0·34) 0·47 (0·35) –0·08 (–0·14 to –0·02) 0·006 –0·08 (–0·14 to –0·02) 0·007
gain (kg)
Gestational weight gain below IoM 100 (39·20%) 70 (27·00%) 1·45 (1·09 to 1·93) 0·010 1·46 (1·10 to 1·94) 0·008
recommendations16*
Gestational weight gain above IoM 83 (32·27%) 101 (39·10%) 0·83 (0·64 to 1·07) 0·145 0·84 (0·65 to 1·09) 0·185
recommendations16*
Preterm birth before 37 weeks’ gestation 13 (5·08%) 18 (6·98%) 0·73 (0·36 to 1·45) 0·368 0·79 (0·40 to 1·58) 0·504
Hypertension 19 (7·42%) 16 (6·23%) 1·19 (0·63 to 2·26) 0·592 1·25 (0·66 to 2·35) 0·496
Pre-eclampsia 13 (5·08%) 11 (4·28%) 1·19 (0·54 to 2·60) 0·667 1·22 (0·56 to 2·66) 0·618
Gestational diabetes* 72 (27·93%) 62 (23·95%) 1·17 (0·85 to 1·60) 0·335 1·19 (0·88 to 1·62) 0·253
Antenatal admission 48 (18·75%) 62 (24·03%) 0·78 (0·56 to 1·09) 0·146 0·82 (0·59 to 1·15) 0·254
Antepartum haemorrhage requiring 1 (0·39%) 7 (2·69%) ·· ·· ·· 0·068
admission†
Preterm prelabour ruptured membranes† 5 (1·95%) 3 (1·15%) ·· ·· ·· 0·502
Results presented are based on imputed data, unless otherwise specified. Total gestational weight gain and average weekly gestational weight gain are continuous outcomes,
for which data are mean (SD) and treatment effect estimates are differences in means (metformin minus placebo); all other outcomes are binary, for which data are n (%;
with numbers calculated from proportions averaged across imputations) and treatment effect estimates are risk ratios (metformin vs placebo). Data are for all randomly
assigned women who did not withdraw consent to use their data, and who did not have a miscarriage or termination of pregnancy before 20 weeks’ gestation, or stillbirth.
Adjusted analyses included stratification variables (centre, parity, BMI category), maternal smoking status, age at consent, and socioeconomic status quintile as covariates.
IoM=US Institute of Medicine. *Poisson model with robust variance estimation used for adjusted analysis because binomial model did not converge. †Insufficient events for
analysis or imputation; p value from Fisher’s exact test on un-imputed data.

Table 4: Maternal antepartum outcomes

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Metformin Placebo (n=258) Unadjusted risk Unadjusted Adjusted risk ratio Adjusted
(n=256) ratio (95% CI) p value (95% CI) p value
Chorioamnionitis* 3 (2·22%) 5 (3·40%) ·· ·· ·· 0·725
Induction of labour 104 (40·63%) 87 (33·72%) 1·20 (0·96 to 1·51) 0·107 1·19 (0·95 to 1·49) 0·139
Antibiotic use during delivery† 135 (52·73%) 147 (56·98%) 0·93 (0·79 to 1·08) 0·334 0·95 (0·81 to 1·11) 0·493
Caesarean section (all)† 87 (33·98%) 111 (43·02%) 0·79 (0·63 to 0·99) 0·037 0·80 (0·64 to 1·00) 0·049
Elective caesarean section‡ 44 (17·19%) 54 (20·93%) 0·82 (0·57 to 1·18) 0·281 0·72 (0·51 to 1·00) 0·053
Emergency caesarean section 43 (16·80%) 57 (22·09%) 0·76 (0·53 to 1·09) 0·131 0·79 (0·56 to 1·11) 0·168
Postpartum haemorrhage 66 (25·79%) 58 (22·55%) 1·14 (0·84 to 1·56) 0·393 1·15 (0·85 to 1·57) 0·367
>600 mL
3rd or 4th degree perineal 6 (2·34%) 3 (1·15%) ·· ·· ·· 0·336
trauma*
Wound infection* 3 (1·17%) 3 (1·16%) ·· ·· ·· >0·999
Endometritis* 3 (1·17%) 3 (1·16%) ·· ·· ·· >0·999
Thromboembolic disease* 1 (0·39%) 0 ·· ·· ·· 0·497
Results presented are based on imputed data, unless otherwise specified. Data are n (%; with numbers calculated from proportions averaged across imputations), unless
otherwise indicated. Data are for all randomly assigned women who did not withdraw consent to use their data, and who did not have a miscarriage or termination of
pregnancy before 20 weeks’ gestation, or stillbirth. Adjusted analyses included stratification variables (centre, parity, BMI category), maternal smoking status, age at consent,
and socioeconomic status quintile as covariates. *Insufficient events for analysis or imputation; p value from Fisher’s exact test on un-imputed data. †Poisson model with
robust variance estimation used for adjusted analysis because binomial model did not converge. ‡Includes 30 women in the metformin group and 44 women in the placebo
group who had an elective repeat caesrean section.

Table 5: Maternal labour and birth outcomes

The planned health economic cost analysis was not
done because the intervention had no significant impact
on clinical outcomes in the overall study population.
In a post-hoc meta-analysis incorporating the findings
of the GRoW trial into the previously reported Cochrane
systematic review,26 metformin was identified to have
only a modest impact on gestational weight gain among
pregnant women who were overweight or obese (mean
difference –2·27 kg, 95% CI –4·45 to –0·08 [ four studies,
1278 women]). There was no evidence of an impact on
birthweight (mean difference 11·22 g, –52·87 to 75·31
[three studies; 1348 infants]) or the risk of pre-eclampsia
(risk ratio 0·82, 95% CI 0·25 to 2·68 [three studies;
1355 women]).
Discussion
In the GRoW randomised trial, use of metformin in
addition to dietary and lifestyle advice did not affect the
proportion of infants with a birthweight greater than
4000 g compared with placebo and dietary and lifestyle
advice. Although there were no significant differences in
total gestational weight gain, women who received
metformin were more likely to have weight gain below
IoM recommendations, and had lower average weekly
gestational weight gain. However, these differences in
gestational weight gain were not accompanied by
significant effects on maternal and infant pregnancy or
birth outcomes.
Our trial has several strengths. The trial is the first of
its kind to include both overweight and obese women,
which is important in view of the potential for benefit
from interventions at different levels of BMI above the
normal range. We used robust methods, including
prospectively measured height, weight, and BMI in all
participants, central randomisation, and appropriate
masking of participants, clinicians, and outcome asses­
sors. Furthermore, we pre­specified outcomes of clinical
relevance, followed a prespecified analysis plan, and had
complete follow-up data for the primary outcome.
GRoW is the first trial to assess the effect of metformin
given in addition to an antenatal dietary and lifestyle
intervention. Following dietary intervention over the
course of pregnancy, women across both treatment
groups were successful in modifying their dietary intake,
specifically reducing their overall energy intake and
improving their healthy eating index score as an
indicator of diet quality. These findings are consistent
with those reported previously from the LIMIT trial,12,27
sub­stantiating the reproducibility of the intervention
among overweight and obese pregnant women in
producing dietary change. Together, these findings also
suggest that many of the complex determinants of
gestational weight gain might not be readily modifiable
by changes to dietary intake and physical activity.
Our trial population was predominantly white and
from areas with high levels of socioeconomic dis­
advantage. Additionally, 85% of eligible women declined
to participate—among the most common reasons cited
were time constraints and lack of willingness to take
medication during pregnancy. These factors might limit
the generalisability of our findings to some extent.
However, such rates of uptake of trial participation (15%)
are within the range described by similar trials in the
scientific literature, which have varied from 13% to 47%.9,10
Our measure of compliance suggests that 84% of
respondents took the maximum of four tablets per day,
with no differences identified between the treatment
groups. These figures are difficult to directly compare

8 www.thelancet.com/diabetes-endocrinology Published online December 4, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30310-3


with other studies, which have used varying measures to
assess treatment compliance,9,10 although our measure is
similar to the overall compliance of 80% reported by
Syngelaki and colleagues10 and 66% reported by Chiswick
and colleagues.9
Although metformin is increasingly used in pregnancy
for the treatment of gestational diabetes, and there is
evidence to support its safety,8 longer-term childhood
follow-up of the offspring of women who participated in
this trial will be important. The primary findings from
the MIG trial did not identify any differences in infant
birthweights for women with gestational diabetes treated
with insulin or metformin.8 However, follow-up of child
participants at age 7–9 years suggested that children ex­
posed in utero to metformin, as compared with insulin,
had higher body­weight and BMI, with some suggestion
of increased adipose tissue deposition as measured by
dual-energy x-ray absorptiometry.28
During the course of the GRoW trial there was a
change in the diagnostic criteria for gestational diabetes
across South Australia.15 However, the criteria were
applied equally across the two treatment groups, and we
demonstrated no significant differences in diagnosis or
requirements for metformin or insulin between the two
treatment groups. The change in criteria might have
resulted in an increase in the number of women being
diagnosed with gestational diabetes; however, discussion
of the relative merits and evidence base to support a
range of different testing approaches and criteria is
beyond the scope of this report.
Our findings do not suggest that metformin impacts
clinical pregnancy and birth outcomes—this conclusion
is broadly consistent with the existing scientific
literature.9,10,29 Syngelaki and colleagues reported a signi­
fi­cant reduction in the risk of pre-eclampsia with met­
formin use.10 However, this effect was not evident when
the current trial data were incorporated into the available
published meta-analysis,26 raising the possibility that this
was a spurious finding from a secondary outcome in
Syngelaki and colleagues’ trial.
We did not identify a significant reduction in total
gestational weight gain, although there was some
evidence of effect modification, with a possible benefit
from metformin in reducing the risk of infant birth­
weight greater than 4000 g and reducing total gestational
weight gain among overweight women, but not among
obese women. Although this secondary analysis was
prespecified, these findings should be interpreted with
caution, and warrant confirmation by others.
Our overall findings in relation to gestational weight
gain are consistent with those of Chiswick and colleagues
(EMPOWaR trial),9 but not with those of Syngelaki and
colleagues (MOP trial)10 and Abd El Fattah.29
Incorporation of our data into the Cochrane systematic
review and meta-analysis26 suggests that, overall,
metformin has a very modest effect on gestational
weight gain (mean difference –2·27 kg, 95% CI
www.thelancet.com/diabetes-endocrinology Published online December 4, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30310-3 9
Articles
–4·45 to –0·08 [ four studies; 1278 women]). Although
there are inherent variations in the design of the
randomised trials done to date,9,10,29 including the BMI of
women recruited (overweight and obese in the current
trial vs obese only9,10,29), the dose of metformin assessed
(1000 mg29 up to 3000 mg10 per day), and the inclusion of
a dietary and lifestyle intervention for all women in the
current trial, these differences seem insufficient to
explain the overall observations of a limited reduction in
gestational weight gain and lack of effect on clinical
outcomes.
Such a limited effect of metformin is, however,
consistent more broadly with the evidence relating to
prenatal dietary and lifestyle interventions2 for women
who are overweight or obese, and raises important
questions concerning their modest at best reduction in
gestational weight gain, and little evidence of effect on
clinical outcomes. Importantly, the IoM recom­ men­
dations16 for gestational weight gain are based on
extensive observational evidence identifying associations
between gestational weight gain and pregnancy out­
comes, with an underlying assumption that the observed
associations are causal in nature. Furthermore, it has
been assumed that gestational weight gain can be
modified either through use of metformin, or via
changes to diet and lifestyle during pregnancy, and that
weight gain within the recommended range leads to
optimal maternal and infant outcomes.
These prevailing assumptions need to be questioned
in view of the mounting available clinical evidence from
randomised trials. For pregnant women who are
over­­weight or obese, intervention during pregnancy
(whether through metformin, dietary or lifestyle
modification, or a combination of the two) might be too
little, too late, emphasising the need to target women,
particularly those who are overweight or obese, before
conception to improve their diet and lifestyle and to
encourage weight loss.30 Notwithstanding the logistical
implications of inter­vention before conception, there is
currently little evidence to support improved pregnancy
outcomes following preconception weight loss, and
robust evalu­ ation of such an approach is urgently
needed.
In conclusion, our findings suggest that the use of
metformin in addition to a dietary and lifestyle inter­
vention among pregnant women who are overweight or
obese was associated with some evidence of reduced
gestational weight gain measures, but did not affect
clinical pregnancy and birth outcomes. Use of metformin
in this clinical setting should not be advocated on the
basis of these data.
Contributors
All authors were involved in the development and design of the trial, the
conduct of the trial, drafting of the report, and revision for intellectual
content. JL and JMD did the statistical analyses.
Declaration of interests
We declare no competing interests.
 Articles
Data sharing statement
Additional trial-related documents and requests for de-identified data
(aggregate or individual participant level) may be requested by written
application to the corresponding author and will be considered on an
individual basis by the trial steering committee.
Acknowledgments
This study was funded by an Australian National Health and Medical
Research Council (NHMRC) project grant (ID 1043181). JMD is funded
by an NHMRC practitioner fellowship (ID 1078980). We thank the
women and their infants who participated in the trial. We also thank
John Svigos and Michael Stark (both at Women’s & Children’s Hospital,
North Adelaide, SA, Australia and University of Adelaide, Adelaide, SA,
Australia) for their role in the trial adverse events committee. Additional
acknowledgments are in appendix.
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