Nitert et al.

BMC Pregnancy and Childbirth 2013, 13:50

http://www.biomedcentral.com/1471-2393/13/50

STUDY PROTOCOL

Open Access

SPRING: an RCT study of probiotics in the

prevention of gestational diabetes mellitus in
overweight and obese women
Marloes Dekker Nitert1,2*, Helen L Barrett1,2, Katie Foxcroft3, Anne Tremellen4, Shelley Wilkinson4,5,
Barbara Lingwood1, Jacinta M Tobin6, Chris McSweeney7, Peter ORourke8, H David McIntyre9 and
Leonie K Callaway2,3

Abstract
Background: Obesity is increasing in the child-bearing population as are the rates of gestational diabetes.
Gestational diabetes is associated with higher rates of Cesarean Section for the mother and increased risks of
macrosomia, higher body fat mass, respiratory distress and hypoglycemia for the infant. Prevention of gestational
diabetes through life style intervention has proven to be difficult. A Finnish study showed that ingestion of specific
probiotics altered the composition of the gut microbiome and thereby metabolism from early gestation and
decreased rates of gestational diabetes in normal weight women. In SPRING (the Study of Probiotics IN the
prevention of Gestational diabetes), the effectiveness of probiotics ingestion for the prevention of gestational
diabetes will be assessed in overweight and obese women.
Methods/design: SPRING is a multi-center, prospective, double-blind randomized controlled trial run at two tertiary
maternity hospitals in Brisbane, Australia. Five hundred and forty (540) women with a BMI > 25.0 kg/m2 will be
recruited over 2 years and receive either probiotics or placebo capsules from 16 weeks gestation until delivery. The
probiotics capsules contain > 1x109 cfu each of Lactobacillus rhamnosus GG and Bifidobacterium lactis BB-12 per
capsule. The primary outcome is diagnosis of gestational diabetes at 28 weeks gestation. Secondary outcomes
include rates of other pregnancy complications, gestational weight gain, mode of delivery, change in gut
microbiome, preterm birth, macrosomia, and infant body composition. The trial has 80% power at a 5% 2-sided
significance level to detect a >50% change in the rates of gestational diabetes in this high-risk group of pregnant
women.
Discussion: SPRING will show if probiotics can be used as an easily implementable method of preventing
gestational diabetes in the high-risk group of overweight and obese pregnant women.

Background
The incidence of gestational diabetes mellitus (GDM),
diabetes mellitus first diagnosed during pregnancy, is
on the rise in concordance with the rise in overweight
and obesity in the obstetric population [1]. GDM is
associated with short term and long term morbidity for
mother and baby. In the short term, women with GDM
have an increased risk of developing preeclampsia and
* Correspondence: m.dekker@uq.edu.au
1
The UQ Centre for Clinical Research, The University of Queensland, RBWH
campus, Butterfield street, Herston QLD 4029, Australia
2
School of Medicine, The University of Queensland, Herston, Australia
Full list of author information is available at the end of the article

delivery by Cesarean section [2,3]. For the infant, maternal GDM increases the risk of excessive adiposity,
macrosomia (a birth weight of >4000 g), shoulder dystocia, admittance to the neonatal intensive care unit and
neonatal hypoglycemia [4,5]. In the long term, maternal
GDM is associated with increased risk of obesity as well
as metabolic (type 2 diabetes) and cardiovascular disease
in both mother and baby [6-8]. While current therapy,
which is focused on normalizing blood glucose levels, is
variably successful in reducing the short term
complications of GDM, this may not be true for the
longer term complications [9]. Therefore, prevention of
GDM would be preferable.

2013 Nitert et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Nitert et al. BMC Pregnancy and Childbirth 2013, 13:50

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The incidence of GDM is higher in women who are

overweight or obese prior to falling pregnant [10]. Strategies for the prevention of GDM have until now been
restricted to diet and exercise interventions, which
have had mixed results [11,12]. Many of these trials
have had small sample sizes and their methodological
heterogeneity complicates comparability. Additionally,
there are substantial barriers to pregnant women engaging in intensive lifestyle intervention programs
[13,14].
The role of the gut microbiome as a modulator of
metabolic and inflammatory process is currently being
investigated. The gut microbiome is the composite of
bacterial species present in the gut. Many factors influence the exact gut microbiome species composition in
adult life including antibiotic therapy in early life [15],
growth and inhibitory factors determined by diet, host
and microbial factors as well as luminal pH, osmolarity
and organism replication rates [16]. Gut microbiome
species have discrete capabilities in generating energy
for take-up by the host. The gut microbiome composition is altered in obese humans and animals, although
weight loss causes changes in species composition to
that resembling the gut microbiome of normal-weight
individuals [17,18].
Ingestion of probiotics microorganisms . . . able to
confer defined health benefits on the host [19] is an
alternative pathway to alter gut microbiome species
composition. The exact effects on metabolic and inflammatory processes in the host exerted by probiotics treatment are dependent on the genus and strain supplied in
the probiotics. In the food chain, probiotic cultures are
commonly present in variable amounts in dairy products
such as yoghurts, fermented foods and some cheeses. It
is not known to what extent these food sources alter the
gut microbiome and thereby have biological effects outside research settings. Probiotic supplements are available from many outlets but effectiveness is dependent
on especially temperature and anaerobic storage
conditions, initial dose strain and quality. Probiotic supplementation in pregnancy is considered safe based on
the limited safety data available [20].
A recent randomized controlled trial of probiotic
intervention in normal weight women in pregnancy
reported a decline in the rate of GDM from 34% to 13%
with a combined dietary/probiotic supplementation approach [21]. To our knowledge, this trial has not been
repeated and in particular, there has been no examination of whether probiotics might offer a useful therapeutic approach for overweight and obese women [22].
If probiotic supplementation were to offer substantial
clinical benefit, it would provide a pragmatic approach
to the prevention of GDM. This trial aims to provide an
answer to these questions.

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Methods/design
Study design

This is a prospective double blind randomized controlled trial, designed according to the CONSORT
guidelines [23]. Our study will investigate the treatment
of overweight and obese women with an oral probiotic
combination using Lactobacillus rhamnosus GG and
Bifidobacterium animalis subsp. lactis BB-12 (Chr.
Hansen A/S, Horsholm, Denmark) at a dose of >1 x 109
colony-forming units each per day or placebo (microcrystalline cellulose and dextrose anhydrate capsules
Chr. Hansen). Capsules will be taken once daily from enrolment prior to 16 weeks gestation until birth
(Figure 1).
Outcomes

The primary outcome of the study is the frequency of

diagnosis of GDM at 28 weeks gestation by a 75 g oral
glucose tolerance test (OGTT) using the criteria of the
International Association of the Diabetes and Pregnancy
Study Group (IADPSG) [24].
A number of secondary outcomes will be assessed,
which are listed in Table 1 [25].
Sample size justification/power calculation

At least one third of pregnant women cared for in Brisbane are overweight and obese, in line with the overweight and obesity rates for the general obstetric
population in Australia [26]. In one year, across the
Mater Mothers Hospital and the Royal Brisbane and
Womens Hospital, over 3300 overweight and obese
pregnant women receive pregnancy care. We anticipate
to recruit around 40 women per month across both
centers with the recruitment strategy tested in a previous study [27]. Based on the Brisbane cohort within
the Hyperglycemia and Adverse Pregnancy Outcome
(HAPO) data [28], the rate of GDM amongst women
who are overweight and obese is 19.3%. We expect that
our screening strategy including a random venous
plasma glucose and subsequent OGTT to confirm or exclude the diagnosis of overt diabetes, or early GDM will
result in the exclusion of around 5% of women who
were included in the HAPO study. This will reduce our
expected prevalence of GDM to around 18% (5% of
19.3% is ~ 1%). The previous trial reported a 67% risk
reduction [21]. However, even a risk reduction of 50%
would be clinically meaningful, and we have based our
power calculation on a 50% reduction. To detect a
change in the incidence of GDM from 18% to 9%, with a
power of 0.8, of 0.05, and a two-tailed test, the
estimated sample size is 226 per group. Allowing for
20% attrition of participants, we will recruit 270 women
into each group. We anticipate that it will take 15
months to recruit this sample size.

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Figure 1 Recruitment at 1416 wks gestation.

Inclusion criteria

The inclusion criteria for this study are: pregnant

women at less than 16 weeks gestation; singleton pregnancy; body mass index (BMI) of >25.0 kg/m2; >18.0
years of age; able to read and understand English and
provide informed consent.
Exclusion criteria

The exclusion criteria for this study are: pregnancy at

>16 weeks gestation at recruitment; multiple pregnancy;
known pre-existing diabetes, impaired fasting glucose
(IFG) or impaired glucose tolerance (IGT); GDM prior
to recruitment as diagnosed by early pregnancy glucose
testing described below; taking medications likely to

influence glucose metabolism (in particular metformin, glucocorticoids and immunosuppressants); medical
conditions associated with altered glucose metabolism
(in particular Cushings syndrome/disease and hepatic
cirrhosis); known major fetal abnormality noted on 12
week ultrasound examination; and known ingestion of
probiotics via capsules or sachets.
The early pregnancy glucose testing follows a strategy
supported by the guidelines of the IADPSG [29]. All
women will have their random venous plasma glucose
measured. Women with a random venous plasma glucose level of >11.0 mmol/L will be considered as having
likely overt diabetes and will undergo appropriate further evaluation with fasting glucose, proceeding to an 75

Table 1 Maternal, neonatal and process/intervention secondary outcomes assessed in SPRING

Maternal

Neonatal

Process/intervention

Gestational weight gain

Body composition, anthropometry

Visit attendance

Preeclampsia*

Preterm delivery

Adherence to probiotic/placebo
regimen

Induction of labor

Shoulder dystocia

Cesarean delivery

Hypoglycemia

Elective
Emergency

Treatment with supplementary

fluids/feeds

Change in prevalence of L. rhamnosus and B. lactis in gut microbiome

Nerve palsy

Change in lipids and inflammatory profile

Admission to neonatal intensive

care unit

Change in dietary indices and physical activity levels between baseline and
28 weeks gestation

Jaundice requiring phototherapy

Bone fracture
Death: stillbirth or neonatal death

* Preeclampsia as diagnosed as per the criteria of the international society for the study of hypertension in pregnancy (ISSHP) [25].

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g OGTT if required. Women with overt diabetes or early

GDM will be excluded from this study.
In order to ensure participant safety, we do not
want to enrol women with serious early pregnancy
disturbances in glucose metabolism. Therefore, to err on
the side of caution, we will refer any woman with a random venous plasma glucose between 8.0 and 11.0
mmol/L for a 75 g OGTT. Women who are diagnosed
with early GDM on this OGTT will be referred for treatment, and excluded from this study. Conversely, those
women with an initial elevated random venous plasma
glucose but normal OGTT results will remain eligible
for randomization.
Recruitment facility

This study will be conducted at the Royal Brisbane and

Womens Hospital and the Mater Mothers Hospital in
Brisbane, Australia. Both hospitals are major tertiary referral obstetric hospitals. Combined, they care for 10,000
public and 5,000 private births annually.
Enrollment process

Our recruitment strategy is based on the successful

strategy used in a previous pilot study [27]. All women
enrolling for pregnancy care at the two centers will be
sent a letter inviting them to participate in this study.
Those who respond will be screened for inclusion and
exclusion criteria during an initial phone call, and if eligible, will be invited to attend a baseline assessment.
Baseline assessment

At the baseline assessment at <16 weeks gestation after

review of the inclusion/exclusion criteria and the initial
random venous plasma glucose test, data will be
obtained on clinical history and anthropometrics and
clinical measurements will be taken (Figure 2).
Dietary intake will be assessed using the Cancer Council
Victorias Dietary Questionnaire for Epidemiological Studies
(Version 2) [30]. The validated food frequency questionnaire (FFQ) [31] comprises a food list of 74 items with 10
frequency response options ranging from Never to 3 or
more times per day. The FFQ also contains three
photographs of scaled portions for four foods (used to calculate a portion size calibrator), questions on the overall
frequency of fruit and vegetable consumption, and
questions on consumption of foods that do not fit easily
into the frequency format (such as breads). The 74 food
items are grouped into 4 categories: cereal foods, sweets
and snacks; dairy products; meats and fish; fruit, and
vegetables. A separate set of questions covers intake of alcoholic beverages. The food composition data used to calculate nutrients are from NUTTAB95, supplemented by
other data where necessary. The output includes: kilojoules,
detailed macronutrient and micronutrient profiles, as well

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as glycemic index, and glycemic load. The DQESv2 analysis

will be performed by the Cancer Council Victoria following
the instructions in the User Information Guide.
Self-reported physical activity will be assessed using the
Active Australia Survey (AAS) [32]. The AAS assesses the
frequency and duration of participation in walking, moderate, and vigorous physical activity in the past week.
Physical activity data will be summed to determine total
minutes of weekly physical activity, as per the AAS manual [32]. This captured time spent in activities of walking,
vigorous exercise, and vigorous yardwork/gardening. It
does not record household chores, occupational or incidental activity [32]. In calculation of minutes of physical
activity, minutes of vigorous activity will not be weighted
by two as suggested in the AAS manual [32], as we are
interested in absolute minutes active, rather than the association between physical activity dose and health benefits
that may be dependent on total energy expenditure. This
allows the creation of the parametric variable minutes of
physical activity. This will be capped at 840 minutes,
according to the AAS manual [32].
Weight will be measured to the nearest 0.1 kg using a
spring balance scale. Height will be measured with a wall
mounted stadiometer to the nearest 0.5cm. Waist
measurements will be taken with a flexible, inelastic tape
measure with measures taken on the skin where the circumference is the smallest with the measure positioned
horizontally, parallel to the floor with the patient
standing up straight at the end of normal expiration.
Hip measurements will be taken at the point where the
hip circumference is greatest.
Intervention

After the baseline assessment, women will be randomly

allocated to probiotic or matching placebo trial capsules.
Participants will be advised to take their capsule with a
cold drink, excluding carbonated and sugared beverages,
to maximize survival and potential benefit of the
probiotics. All women will be provided with dietary advice that follows current Australian nutrition guidelines
for pregnancy [33], including simple advice regarding
recommended weight gain in pregnancy [34]. Further
dietary advice will be provided as clinically indicated as
part of standard clinical care.
Randomization procedure

Participant randomization will occur based on computergenerated random number codes sealed in opaque
envelopes. Participants will be stratified by center and by
BMI category (BMI >25-30; BMI >30-40; BMI>40 kg/m2).
Allocation concealment and blinding

Placebo and Probiotic supplements will be identically

packaged and refrigerated. All medical staff, research

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Figure 2 Baseline assessment at 16 weeks gestation including clinical history of the mother as well as anthropometric and
clinical measurements.

assistants, nursing staff and participants will be masked

to the randomized allocation.
Clinical assessments
Comprehensive assessment at 28 weeks gestation

At 28 weeks gestation, all baseline clinical assessments,

blood tests, stool samples, questionnaires and an updated
medical history will be repeated. At this time point, a 75 g
OGTT will be performed to identify women who have
developed GDM (primary endpoint of the study).

Retention optimization

All women independent of treatment allocation will be seen

on at baseline, 28 and 36 weeks gestation, but will also receive a telephone consult monthly or more frequently as
required. This is for monitoring of weight, blood pressure,
pill count and early detection of adverse events. Women
will also be offered further supply of capsules when needed.
The additional monthly phone review is also expected to
assist with adherence and retention.
Confirmation of probiotic colonization

Assessment at 36 weeks gestation

At 36 weeks gestation, weight, waist to hip ratio, blood

pressure and medication compliance will be assessed by
interview.
Post delivery assessment

At delivery, cord blood will be sampled, and umbilical

cord and placenta will be collected in a subset of
women. Neonatal anthropometry will be collected and
fetal body composition will be measured by air displacement plethysmography in a PEAPOD Infant Body Composition System (Cosmed, Rome, Italy) [35] within 3
days after birth.
Compliance

Compliance with probiotic ingestion will be assessed by:

(1) participant interview; (2) monthly telephone followup; and (3) change in fecal microbiome at 28 weeks
gestation.

Maternal stool carriage of probiotic species will be

documented to confirm colonization and quantify the
number of L. rhamnosus and B. lactis species using stool
samples. This will be done using a stool sample prior to
the first dose of probiotic or placebo and repeated at 28
weeks gestation. DNA will be extracted from the stool
sample using previously developed techniques [36,37].
Briefly, microbial DNA extraction involves an enzymatic
lysis step followed by bead beating in the presence of
high concentrations of sodium dodecyl sulfate salt and
EDTA, with final DNA purification by a commercial
clean-up kit (Qiagen). Extracted DNA will be tested by
quantitative real-time PCR for Lactobacillus rhamnosus
GG and Bifidobacterium lactis BB12 using strain specific
primers and probes [38].
Ethical considerations

The study has been approved by the human research

ethics committees of the Royal Brisbane and Womens

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Hospital, Mater Health Services and The University of

Queensland. Any adverse events will be reported to the
clinical trial management committee and the human research ethics committees involved.
Trial Governance

An independent data monitoring committee, consisting

of the Director of Pharmacy at the Royal Brisbane and
Womens Hospital, an ethicist and an independent clinician with clinical trials experience is appointed to assess
the progress of the trial after completion of the data for
each 100 participants enrolled. Any adverse events that
might be due to the probiotics will be reported to the
clinical trial management committee and the human research ethics committees of the Royal Brisbane and
Womens Hospital and Mater Health Services.
Analysis
Analysis methods

Data will be analysed using the intention-to- treat

principle and no intermediate analyses are scheduled.
The primary outcome of the study is diagnosis of GDM
at 28 weeks gestation. This will be assessed by a 75 g
OGTT. The frequency of GDM will be compared between the groups with binary logistic regression
accounting for the initial stratification by site and BMI
catrgory. The secondary outcomes will be analyzed with
general linear models for continuous outcomes and logistic regression for binary outcomes. All data will be
summarized by mean and standard deviation for continuous variables and frequencies for categories.

Discussion
Anticipated limitations

In this randomized control trial, the capacity of two specific probiotic substrains to prevent GDM will be tested.
A number of limitations can be envisioned: First, the
number of organisms in the probiotic capsules given
may be too low to prevent GDM. The dosage of the
probiotics is based on the previous study performed in
normal weight women [21], however overweight and
obese women may require a higher dose. Second, the effect size of the probiotics may be lower than expected.
Our power calculations are based on a reduction of the
incidence of GDM by 50%. A 30% reduction would not
reach statistical significance but would be clinically important. Third, there is a risk that women in both the
probiotics and placebo group will perceive a potential
advantage from probiotic ingestion and increase the intake of probiotics-containing foods such as yoghurts,
even while they are requested not to, thereby blurring
the results. The dietary questionnaire obtained at 28
weeks gestation is designed to identify this, should it
occur. In all RCTs, there is the risk of non-compliance

Page 6 of 7

with the treatment. Regular encouraging mobile phone

text messages, phone interviews and review visits will be
conducted to improve compliance. At the review visits,
capsule counting will be performed to assess compliance. Additionally, comparison of the stool samples
provided at baseline and at 28 weeks gestation for the
species provided by the probiotics will give an objective
biological measure of compliance [39].
Clinical significance of the study

This trial will evaluate the efficacy of probiotic ingestion

from early pregnancy to prevent GDM in a high-risk
group of women who are overweight and obese. If successful, probiotics would offer a therapeutic option for
the prevention of GDM that is simple, cheap and easy to
incorporate into standard clinical care.
Trial status

This RCT started enrolling in November 2012. Currently

eight participants have been enrolled.
Competing interests
The probiotics and placebo capsules have been donated by Chr. Hansen A/
S. None of the authors has any competing interests.
Authors contributions
MDN, HLB, HDM and LKC conceived and designed the study. MDN wrote
the manuscript. HLB, HDM and LKC helped draft the manuscript. SW advised
on diet, physical activity, and anthropometric assessment, measurement, and
analysis. KF, BL, JMT, CM assisted with study design and manuscript revision.
POR contributed to study design, sample size calculations and the statistical
analysis plan. All authors read and approved the final manuscript.
Acknowledgments
This study has been funded by the National Health Medical Research Council
(NHMRC) of Australia (APP1028575). MDN is funded by Patricia Dukes
fellowship from the RBWH Foundation. HLB is a recipient of a NHMRC PhD
scholarship. SW is a NHMRC TRIP Research Fellow. The authors thank
Professor Graham Giles of the Cancer Epidemiology Centre of The Cancer
Council Victoria, for permission to use the Dietary Questionnaire for
Epidemiological Studies (Version 2), Melbourne: The Cancer Council Victoria,
1996.
Author details
1
The UQ Centre for Clinical Research, The University of Queensland, RBWH
campus, Butterfield street, Herston QLD 4029, Australia. 2School of Medicine,
The University of Queensland, Herston, Australia. 3The Royal Brisbane and
Womens Hospital, Herston, Australia. 4Mater Medical Research Institute,
Mothers & Babies Theme, South Brisbane, Australia. 5Department of Nutrition
& Dietetics, Mater Mothers Hospital, Brisbane, Australia. 6Western Clinical
School, The University of Melbourne, Melbourne, Australia. 7CSIRO, St Lucia,
Australia. 8Statistics Unit, Queensland Institute of Medical Research, Herston,
Australia. 9Mater Clinical School, The University of Queensland, South
Brisbane, Australia.
Received: 16 February 2013 Accepted: 22 February 2013
Published: 25 February 2013
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doi:10.1186/1471-2393-13-50
Cite this article as: Nitert et al.: SPRING: an RCT study of probiotics in
the prevention of gestational diabetes mellitus in overweight and
obese women. BMC Pregnancy and Childbirth 2013 13:50.