CAOG Papers ajog.

org

The effects of metformin on weight loss in

women with gestational diabetes: a pilot
randomized, placebo-controlled trial
Jerrie S. Refuerzo, MD; Oscar A. Viteri, MD; Maria Hutchinson, MS; Claudia Pedroza, PhD;
Sean C. Blackwell, MD; Jon E. Tyson, MD, MPH; Susan M. Ramin, MD

OBJECTIVE: We sought to compare weight loss in the first 6 weeks
postpartum among women with gestational diabetes mellitus (GDM)
treated with metformin or placebo, a promising therapy to reduce later
risk of progression to diabetes mellitus.
STUDY DESIGN: We conducted a pilot, randomized trial of metformin
vs placebo in postpartum women with GDM. Women with pre-
GDM, unable to tolerate metformin, resumed on insulin or oral hy-
poglycemic agent, delivered <34 weeks’ gestation, or with a body
mass index <20 kg/m2 were excluded. Women were randomized to
either metformin 850 mg daily for 7 days, then metformin 850 mg
twice a day for the next 5 weeks or placebo prescribed in a similar
frequency. The subject, health care provider, and research staff were
blinded to the treatment. The primary outcome was weight change
from delivery to 6 weeks postpartum. Secondary outcomes included
the percentage of women achieving their self-reported prepregnancy
weight, reported medication adherence, adverse effects, and satis-
faction. Differences in weight change between groups were deter-
mined by Wilcoxon rank sum test and in achieving prepregnancy
weight by c2 test.
RESULTS: Of 114 women randomized, 79 (69.3%) completed the
6 weeks; 36 (45.6%) were randomized to metformin and 43 (54.4%)
to placebo. Metformin and placebo groups were similar in median
weight loss (6.3 kg [range, e0.3 to 19.8] vs 6.5 kg [range, e0.3 to
12.1], P ¼ .988) and percentage of women achieving reported
prepregnancy weight (41.7 vs 37.2%, P ¼ .69). Self-reported
adherence in taking >50% of medication was 75% at 3 weeks
and 97% at 6 weeks. Nausea, diarrhea, and hypoglycemia were
reported in approximately 11-17% of women and 56-63% reported
dissatisfaction with the medication.
CONCLUSION: Women with GDM lost approximately 6 kg by 6 weeks’
postpartum. This was similar in both groups and resulted in <50% of
women achieving their prepregnancy weight. Although the reported
adherence and satisfaction with the medication was high, adverse
effects were reported with nearly 1 in 5 women including nausea,
diarrhea, and hypoglycemia. Contrary to expectation, we found
no evidence of benefit from metformin. However, longer treatment
periods and larger studies with minimal attrition may be warranted.
Key words: gestational diabetes, metformin, weight loss

Cite this article as: Refuerzo JS, Viteri OA, Hutchinson M, et al. The effects of metformin on weight loss in women with gestational diabetes: a pilot randomized, placebo-
controlled trial. Am J Obstet Gynecol 2015;212:389.e1-9.

G estational diabetes mellitus (GDM)

is carbohydrate intolerance first
recognized in pregnancy.1 After deli-
very, carbohydrate intolerance is expect-
ed to resolve gradually. Once a woman
develops GDM, she remains at risk of
recurrence in future pregnancies, and
has a 7-fold risk of developing type 2
diabetes mellitus (DM) later in life.2-4
Additionally, GDM develops in 14% of
obese women.5 Excessive gestational
weight gain (EGWG) occurs in approxi-
mately 45% of obese pregnant women,

From the Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences (Drs Refuerzo, Viteri, and Blackwell and
Ms Hutchinson), and Center for Clinical Research and Evidence-Based Medicine, Division of Neonatology, Department of Pediatrics (Drs Pedroza and
Tyson), University of Texas Health Science Center at Houston, and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Baylor
College of Medicine (Dr Ramin), Houston, TX.
Received Aug. 15, 2014; accepted Dec. 15, 2014.
This research was supported by the Center for Clinical and Translational Sciences, which is funded by National Institutes of Health Clinical and
Translational Award number UL1 000371 from the National Center for Advancing Translational Research, and by the Larry C. Gilstrap, MD, Center for
Perinatal and Women’s Health Research, University of Texas Health Science Center at Houston (both to J.S.R.).
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing
Translational Research or the National Institutes of Health.
The authors report no conflict of interest.
Presented in oral format at the 81st annual meeting of the Central Association of Obstetricians and Gynecologists, Albuquerque, NM, Oct. 8-11, 2014.
Corresponding author: Jerrie S. Refuerzo, MD. Jerrie.S.Refuerzo@uth.tmc.edu
0002-9378/free  ª 2015 Elsevier Inc. All rights reserved.  http://dx.doi.org/10.1016/j.ajog.2014.12.019

MARCH 2015 American Journal of Obstetrics & Gynecology 389.e1

CAOG Papers
many of whom have GDM, and has been
linked to postpartum weight retention.6
This fuels the progression of obesity even
after pregnancy ends and, as a result, pla-
ces these women at further risk of devel-
oping type 2 DM.7
Weight loss is a key element associated
with preventing the onset of diabetes.8-10
Every 1 kg lost is associated with a
16% reduction in diabetes risk.8 Life-
style modifications focused on nutrition
and exercise are first-line therapies
for prevention and control of type 2
DM in obese, nonpregnant women.11,12
Though weight loss is recommended af-
ter delivery, behavioral alterations
are difficult postpartum when mothers
have the onset of responsibilities to a
newborn. Though good intentions are
present, realistic circumstances may
fall short of expectations and many
cease these behavioral modifications over
time. With the failure to reduce post-
partum weight gain in multiple random-
ized trials, the evaluation of new strategies,
including medications, is needed.11
Metformin is an insulin-sensitizing
medication. It functions to improve in-
sulin sensitivity by reducing fasting
plasma glucose and insulin concentra-
tions. Importantly, it has been shown to
be beneficial in reducing weight.13,14
However, the true mechanism by which
this insulin sensitizer results in weight
loss is not fully known. Weight loss is a
natural physiologic occurrence in the
postpartum period including water
loss and adipose tissue. Enhancement of
this natural weight loss represents an
opportunity for obstetricians to inter-
vene and halt the progression towards
persistent obesity. We considered that
metformin could act in conjunction with
the physiologic weight loss unique to
the postpartum period to accentuate the
inherent descending slope of weight.
Moreover, postpartum women accus-
tomed to taking oral medications, such
as prenatal vitamins, would find the
concept of an oral daily medication for
the purpose of weight loss appealing and
be compliant with this medical treat-
ment. If weight loss were enhanced,
this could blunt the progression of
obesity and potentially avoid the devel-
opment of type 2 DM later in life in
389.e2 American Journal of Obstetrics & Gynecology MARCH 2015
this high-risk group. Our objective was
to conduct a pilot study to assess
whether metformin increased post-
partum weight loss compared to placebo
among women with GDM.
M ATERIALS AND M ETHODS
Study design
We conducted a pilot randomized,
placebo-controlled trial of metformin
vs placebo from January 2011 through
January 2014, at the Memorial Hermann
Hospital-Texas Medical Center and
Lyndon B. Johnson Hospital in Houston,
TX. On the postpartum ward, women
with GDM were invited to participate
within 24 hours of delivery and prior to
discharge. Women were excluded if they
had pre-GDM (either type 1 or 2 DM),
reported inability to tolerate metformin,
discharged home on insulin or oral hy-
poglycemic agent, delivered <34 weeks
of pregnancy, were <18 or >49 years
old, or had a body mass index (BMI)
<20 kg/m2. The diagnosis of GDM
(treated with insulin, oral hypoglycemic
agent, or diet control) was made >24
weeks based on a documented 1-hour
glucola screen >200 mg/dL or by a
confirmatory 3-hour glucola test (based
on either the Carpenter and Coustan or
the Diabetes Task Force criteria).1
Informed consent and randomization
This study was approved by the institu-
tional review board at University of Texas
Health, Houston, TX (no. HSC-MS-10-
0426, approved October 2010). After
reviewing the potential benefits, risks,
and adverse effects of the medication and
placebo, written informed consent was
obtained. Subjects were randomized to
either metformin or placebo via central
randomization conducted by the Inves-
tigational Drug Service (IDS) pharmacy
at Memorial Hermann Hospital-Texas
Medical Center and stratified by site.
Permuted block randomization with a
random fashion was used to prevent
imbalances between groups. The subject,
health care provider, research staff, and
statistician were blinded to the treatment
group. Only the IDS pharmacy knew the
treatment group. The randomization
scheme was unmasked after completion
of the analysis.
ajog.org
Study procedures
Prior to discharge, the subject was star-
ted on either metformin or placebo. The
metformin dose was 850 mg daily for
7 days, then 850 mg twice a day for the
next 5 weeks. The placebo was similar in
size, color, and taste, and prescribed in a
similar frequency: once daily for 7 days,
then twice daily for the next 5 weeks for a
total of 6 weeks. The metformin and
placebo were compounded by a licensed
compounding pharmacy and monitored
on a routine schedule for quality assur-
ance and potency of the drugs by
the IDS. The subject received the medi-
cation or placebo in prefilled push cards
designating the regimen for subject
convenience. There were no drop-in,
drop-out, or crossover of subjects.
Within 24 hours of delivery, maternal
weight was measured using a single
specified digital weight scale (did not
require calibration) on a hard surface
at each site. A research nurse counseled
all participants regarding their diet
and provided a simple exercise plan
of walking a minimum of 30 minutes,
3-5 times a week.15,16 Maternal de-
mographics, clinical characteristics, and
neonatal outcomes were collected. At 3
weeks postpartum (range, 2e4 weeks), a
research nurse contacted the subject via
telephone to inquire about adverse ef-
fects and ability to take the prescribed
medication (metformin or placebo). At 6
weeks postpartum (range, 5e8 weeks),
maternal weight was measured with the
same digital weight scale used for the
initial maternal postpartum weight.
The research nurse again inquired
about adverse effects and conducted a
satisfaction survey.
Study outcomes
The primary outcome was weight change
in kilograms defined as: weight change ¼
Weightpostpartum(PP)-Weight6wk.17 Sec-
ondary outcomes included the rate of
retained gestational weight represented
as the percentage of women achieving
their self-reported prepregnancy weight
and percentage of women achieving their
ideal body weight. Demographic, preg-
nancy characteristics, self-reported
medication adherence, and adverse
ajog.org
effects of medications were collected.
A satisfaction survey was performed
assessing difficulty and satisfaction with
diet, exercise, and medication according
to a 5-point Likert scale.
Analysis
We conducted an intent-to-treat analysis
of patients as randomized. We also
analyzed patients as treated in exploring
the potential impact on subject adher-
ence to treatment on weight change.
Differences in weight change (primary
outcome) between groups were deter-
mined by Wilcoxon rank sum (Mann-
Whitney) test. Differences between
groups in achieving prepregnancy
weight and achieving ideal body weight
were compared using c2 and relative
risks (RR) with 95% confidence intervals
(CI) were reported. A P value < .05 was
considered statistically significant. Sta-
tistical analysis was conducted using
STATA version 21 (StataCorp, College
Station, TX).
Sample size calculation was deter-
mined based on data from Scholl et al,17
who demonstrated that maternal weight
showed little change between 4-6 weeks
and 6 months’ postpartum. Because the
majority of women with GDM have
EGWG, we used weight change data in
this population to calculate a sample
size. Based on a maternal weight change
of 10.4  6.1 kg, effect size of 50%, alpha
of 0.05, power of 0.8, and attrition rate
of 10%, a sample size was calculated to
be 40 subjects per group.
R ESULTS
Population
Of 239 women screened for eligibility,
114 (47.7%) women were randomized as
described in Figure 1 following Consol-
idated Standards of Reporting Trials
(CONSORT) guidelines. In all, 35 ran-
domized women did not complete the
primary outcome assessment at 6 weeks.
At the 3-week telephone call, the met-
formin group had 3 subjects choose to
stop the study, 1 subject was instructed
to discontinue the study by her physi-
cian, and 9 subjects were lost to follow-
up and did not answer their telephone.
In the placebo group, 4 subjects chose to
stop the study, 1 subject was instructed
CAOG Papers
FIGURE 1
Enrollment according to CONSORT flowchart
Assessed for
Enrollment
Eligibility
N=239
Excluded (N=126)
-Not meeting study criteria
(n=44)
-Declined (N=75)
-Medication unavailable
(N=7)
Randomized
N=114
Allocated to Metformin (N=55) Allocated to Placebo (N=59)
-Received allocated metformin Allocation -Received allocated placebo
(N=59)
(N=55)
From 3 week phone call From 3 week phone call
- Discontinued, subject chose to - Discontinued, subject chose to
stop study (N=3) stop study (N=4)
- Discontinued, physician - Discontinued, physician
instructed subject to stop study instructed subject to stop study
(N=1) Follow (N=1)
- Lost to follow up, did not answer - Lost to follow up, did not answer
phone call (N=9) phone call (N=3)
From 6 week visit From 6 week visit
- Lost to follow-up, did not -Lost to follow-up, did not
complete visit (N=6) complete visit (N=8)
Analyzed (N=36) Analyzed (N=43)
Analysis
CONSORT, Consolidated Standards of Reporting Trials.
Refuerzo. Metformin vs placebo for weight loss in women with GDM. Am J Obstet Gynecol 2015.
to discontinue the study by her physi- higher rate of prior preterm birth and
cian, and 3 subjects were lost to follow- delivered at an earlier gestational age
up and did not answer their telephone. compared to placebo (Table 2). They also
At the 6-week visit, 6 subjects were lost to had a higher BMI at enrollment
follow-up in the metformin group, and compared to other groups. Thus, the
8 subjects in the placebo group. subjects with the highest BMI (potentially
A total of 79 (69%) of the randomized the highest risk group) did not complete
subjects completed the assessment of the study and were not part of the final
primary outcome; 36 (45.6%) received analysis of weight loss.
metformin and 43 (54.4%) received pla-
cebo. Maternal characteristics, pregnancy Weight outcomes
outcomes, and neonatal outcomes of Contrary to our hypothesis, median
those who completed the primary eval- weight loss among all for whom the
uation are described in Table 1. Women data were obtained was similar between
randomized to metformin but who did groups (metformin, 6.3 kg [range, e0.3
not complete the primary outcome had a to 19.8] vs placebo, 6.5 kg [range, e0.3
MARCH 2015 American Journal of Obstetrics & Gynecology 389.e3
CAOG Papers ajog.org

weight (metformin, 2.8% vs placebo,

TABLE 1 2.3%; RR, 0.80; 95% CI, 0.7e19.9;
Demographics and pregnancy characteristics of women assessed P ¼ .899).
at 6 wks for primary outcome
Variable Metformin, n [ 36 Placebo, n [ 43 Other outcomes
Maternal age, y 31.6  5.3 28.8  6.4 Within the limits of the data collected,
no major differences between groups
Gravidity 2 (1e7) 3 (1e12)
were identified for either treatment
Parity 2 (0e5) 3 (0e10) adherence of hazards as described in
Race Table 4. At 3 weeks, 89.5% (n ¼ 102) of
African American 4 (11.1%) 12 (27.9%) all women randomized completed the
telephone call, 83.6% metformin and
Caucasian 1 (2.8%) 5 (11.6%)
93% placebo (P ¼ .95). Among those
Hispanic 30 (83.3%) 25 (58.1%) queried, 72% of women in the metfor-
Asian 1 (2.8%) 1 (2.3%) min group and 71% in the placebo group
reported taking >50% of medications.
Insurance
Approximately 97% in both groups seen
Public 30 (83.3%) 41 (95.4%) at the 6-week clinic visit reported taking
Private 5 (13.9%) 2 (4.6%) >50% of medications.
Self-pay 1 (2.8%) 0 (0%) There were similar rates of reported
adverse effects with no differences be-
Prior preterm birth 2 (5.6%) 3 (7%) tween groups at each time point of
Prior cesarean delivery 15 (41.7%) 12 (27.9%) inquiry. Diarrhea, nausea, and hypogly-
Smoking 0 (0%) 1 (2.3%) cemia were the most common adverse
effects reported in the metformin group
Gestational age at delivery, wk 37.8  1.0 38.1  1.3
with frequencies as high as 17%, 15%,
GDM, 50-g glucola >200 mg/dL 7 (19.4%) 10 (23.8%) and 11%, respectively.
Prepregnancy weight, kg 76.1 (54.1e131.8) 77.3 (45.4e131.8) Based on the satisfaction survey,
Postpartum weight at enrollment, kg 79.8 (59.4e165.6) 88.2 (59.6e143.6) approximately 8-23% of women found
it was difficult (reported as quite or
Gestational weight gain, kg 8.1 (e12.9 to 65.6) 9.6 (e11.0 to 37.1)
extremely difficult) to adhere with the
Excessive gestational weight gain 11 (33.3%) 20 (48.8%) recommended diet, 17-23% of women
BMI at enrollment, kg/m2 31.3 (21.1e42.8) 31.9 (17.2e46.3) with the recommended exercise, and
Obese at enrollment 26 (72.2%) 35 (81.4%) 25-37% with the medication as shown
in Figure 2. Higher rates of dissatisfac-
Class III obese at enrollment 7 (19.4%) 13 (30.2%) tion (not at all or slightly satisfied)
Rate of preterm birth <37 wk 3 (8.3%) 4 (9.3%) were reported including 42-63% with
Preeclampsia 5 (3.1%) 5 (18.4%) the recommended diet, 28-40% with
the recommended exercise, and 56-63%
Cesarean delivery rate 4 (50%) 0 (42.1%)
with the medication as described in
Male sex 6 (53.1%) 4 (42.1%) Figure 3.
Birthweight, g 3372 (2370e4745) 3315 (2409e4260)
Birth length, cm 50.3 (46.5e54.7) 50.0 (45.4e55.0) C OMMENT
This is the first randomized controlled
Birth head circumference, cm 34.5 (31.0e36.0) 33.5 (33.6e37.0)
trial to assess medical therapy for weight
Macrosomia rate (>4000 g) 5 (13.9%) 1 (2.3%) loss during the 6-week postpartum
Breast-feeding immediately 29 (84.3%) 31 (79.0%) period in populations at high risk for
postpartum developing overt diabetes. Contrary to
Obese is BMI >30 kg/m2. Class III obese is BMI >40 kg/m2. Data are N (%), mean  SD, median (range). P values are not expectation, we found no evidence of
provided for groups as randomized as all differences at baseline necessarily resulted by chance during randomization.
benefit from metformin. Weight loss in
BMI, body mass index; GDM; gestational diabetes mellitus.
these women with GDM was approxi-
Refuerzo. Metformin vs placebo for weight loss in women with GDM. Am J Obstet Gynecol 2015.
mately 6 kg and similar in both groups.
Less than 50% of women were able to
to 12.1], P ¼ .99) (Table 3). The groups weight (metformin, 41.7% vs placebo, achieve their prepregnancy weight.
were also similar in the percent of 37.2%; RR, 0.80; 95% CI, 0.5e2.9; P ¼ Although adherence with medication
women achieving their prepregnancy .686) and achieving their ideal body was 97% at 6 weeks’ postpartum, nearly

389.e4 American Journal of Obstetrics & Gynecology MARCH 2015

ajog.org CAOG Papers
1 in 20 women reported adverse effects
including diarrhea, nausea, and hypo- TABLE 2
glycemia. Moreover, 56-63% of women Maternal demographics and pregnancy outcomes of women who did not
reported dissatisfaction with the complete 6-wk assessment
medication. Women who did not complete 6-wk
The premise of this study was based assessment, n [ 35
on prior studies examining metformin’s Demographic Metformin, n [ 20 Placebo, n [ 15
effects in high-risk groups for weight Maternal age, y 30.7  6.7 31.1  7.2
loss and prevention of overt diabetes.
Gravidity 4 (1e9) 3.5 (1e7)
Again, the true mechanism of metfor-
min resulting in weight loss is not Parity 3 (0e9) 2.5 (0e6)
known. Retention of EGWG postpartum Race
in obese women with GDM is a risk African American 5 (25%) 4 (26.7%)
factor for type 2 DM.6,7 Reduction of
this retained EGWG is beneficial to Caucasian 0 (0%) 1 (6.7%)
reduce type 2 DM. A metaanalysis of Hispanic 14 (70%) 8 (53.3%)
31 trials involving 4570 high-risk par- Asian 1 (5%) 1 (6.7%)
ticipants showed that metformin use of
Insurance
at least 8 weeks reduced BMI (e5.3%;
95% CI, e6.7 to e4.0).18 However, a Public 18 (90%) 13 (86.7%)
randomized trial conducted by the Dia- Private 2 (10%) 2 (13.3%)
betes Prevention Program showed only Self-pay 0 (0%) 0 (0%)
modest reduction in glucose intolerance
a
with metformin compared to placebo Prior preterm birth 9 (45%) 1 (6.7%)
in adults with prediabetes.9 Prior cesarean delivery 8 (40%) 7 (46.7%)
For the purposes of obstetrics, the Smoking 0 (0%) 4 (26.7%)
effects of metformin on reducing the
Gestational age at delivery, wk 36.8  1.8 a
38.3  0.9
onset of type 2 DM in women with prior
GDM have also been studied. A ran- GDM, 50-g glucola >200 mg/dL 2 (10%) 3 (20%)
domized, controlled study of 2190 Prepregnancy weight, kg 72.7 (51.4e131.4) 76.2 (49.1e111.5)
women conducted by the Diabetes Pre- Postpartum weight at enrollment, kg 87.4 (63.0e122.5) 89.9 (63.7e132.9)
vention Program demonstrated that
those with a history of GDM had a crude Gestational weight gain, kg 11.5 (e26.6 to 24.1) 8.0 (e2.1 to 19.5)
incidence rate of diabetes 71% higher Excessive gestational weight gain 12 (60%) 6 (40%)
than that of women without a history of BMI at enrollment, kg/m 2
36.4 (25.4e45.2) a
35.1 (25.5e51.8)
GDM.10 Women who were treated with
Obese at enrollment 14 (70%) 10 (66.7%)
metformin therapy reduced the inci-
dence of diabetes by approximately 50% Morbidly obese at enrollment 4 (20%) 5 (33.3%)
compared to placebo during the 3-year Rate of preterm birth <37 wk 9 (45%) a
0 (0%)
study period. Such findings suggest that Preeclampsia 5 (25%) 0 (0%)
extended treatment with metformin
Cesarean delivery rate 10 (50%) 7 (46.7%)
may be effective in women with prior
GDM to reduce the onset of diabetes Male sex 8 (40%) 7 (46.7%)
later in life. However, we found no evi- Birthweight, g 3060 (2245e4050) 3239 (2631e5135)
dence of benefit from a brief period of Birth length, cm 50.0 (44.0e56.0) 49.5 (47.0e53.5)
postpartum treatment of women with
Birth head circumference, cm 34.0 (32.0e36.2) 34.0 (30.5e38.5)
GDM.
Self-reported adverse effects described Macrosomia rate (>4000 g) 1 (5%) 3 (20%)
in our study were similar to those pre- Breast-feeding immediately 16 (80%) 10 (66.7%)
viously reported. Symptomatic hypo- postpartum
glycemia related to metformin occurs in Obese is BMI >30 kg/m2. Morbidly obese is BMI >40 kg/m2. Data are n (%), mean  SD, median (range).
0-21% of women.19 In addition, gastro- BMI, body mass index; GDM; gestational diabetes mellitus.
intestinal upset (eg, diarrhea, flatulence, a
P < .05.
nausea, and vomiting) occur at a rate of Refuerzo. Metformin vs placebo for weight loss in women with GDM. Am J Obstet Gynecol 2015.
5-15%.19,20 These adverse effects can be
minimized by gradually increasing

MARCH 2015 American Journal of Obstetrics & Gynecology 389.e5

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we observed are influenced by attrition,

TABLE 3
Weight change in women who received metformin compared to placebo
Variable Metformin, n [ 36 Placebo, n [ 43
Postpartum weight at enrollment, kg 79.8 (59.4e165.6) 88.2 (59.6e143.6)
Postpartum visit, wk 6.06  1.0 6.26  0.87
Postpartum weight at 6-wk visit, kg 75.5 (52.4e145.8) 82.8 (52.3e141.1)
Change in postpartum weight, kg 6.3 (e0.3 to 19.8) 6.5 (e0.3 to 12.1) .988
Achieving prepregnancy weight 15 (41.7%) 16 (37.2%)
Achieving ideal body weight 1 (2.8%) 1 (2.3%)
Data are n (%), mean  SD, median (range). Achieving prepregnancy weight: relative risk, 0.80 (0.5e2.9), P ¼ .686.
Achieving ideal body weight: relative risk, 0.80 (0.07e19.9), P ¼ .899.
Refuerzo. Metformin vs placebo for weight loss in women with GDM. Am J Obstet Gynecol 2015.
metformin over several days. In our Interestingly, similar rates of reported
study, metformin was prescribed as adverse effects were seen in both groups
850 mg once a day for 1 week then 850 although attrition rates were relatively
mg twice a day for another 5 weeks. high. It is unclear to what extent the rates
placebo effects associated with informed
consent, or true adverse events.21 In
P value addition, it is unclear whether the
.104 adverse effects were related to weight
loss. The survey used in this study only
.218
addressed opinion on diet, exercise, and
.151 medication satisfaction. Inquiry on the
rate of compliance was obtained, but
.657 unfortunately, further detail on impact
of medication adverse effects were
.551
not collected. Gathering this infor-
mation in future studies may be helpful
in determining the effect of adverse
effects on compliance of medication.
Another consideration for future
studies is to potentially count pill packs
as a relative objective measure of
compliance. Future studies could also
consider a gradual increase in dosing

TABLE 4
Reported adherence and adverse effects from medication at 3-wk telephone call and at 6-wk visit
Frequency of reported compliance with medications at 3-wk telephone call
Variable Metformin, n ¼ 46 returned telephone call/55 Placebo, n ¼ 55 returned telephone call/59 randomized
randomized (84%) (93%)
Unknown <50% >50% 100% Unknown <50% >50% 100%
Reported compliance 2% n ¼ 1 26% n ¼ 12 41% n ¼ 19 30% n ¼ 14 9% n ¼ 4 18% n ¼ 10 36% n ¼ 20 35% n ¼ 19
Frequency of adverse effects with medications at 3-wk telephone call
3-wk telephone call Metformin, n ¼ 46 (100%) Placebo, n ¼ 56 (95%)
Nausea 15% (n ¼ 7) 13% (n ¼ 7)
Vomit 0% (n ¼ 0) 5% (n ¼ 3)
Diarrhea 17% (n ¼ 8) 11% (n ¼ 6)
Hypoglycemia 9% (n ¼ 4) 5% (n ¼ 3)
Medication intolerance 4% (n ¼ 2) 9% (n ¼ 5)
Frequency of reported compliance with medications at 6-wk postpartum visit
Metformin, n ¼ 36 completed study/55 Placebo, n ¼ 43 completed study/59
randomized (65%) randomized (73%)
Unknown <50% >50% 100% Unknown <50% >50% 100%
6-wk visit 0% n ¼ 0 2.8% n ¼ 1 50% n ¼ 18 47.2% n ¼ 17 0% n ¼ 0 2.3% n ¼ 1 32.6% n ¼ 14 65.1% n ¼ 28
Frequency of adverse effects with medications at 6-wk postpartum visit
6-wk visit Metformin, n ¼ 36 (46%) Placebo, n ¼ 43 (73%)
Nausea 11% (n ¼ 4) 7% (n ¼ 3)
Vomit 3% (n ¼ 1) 2% (n ¼ 1)
Diarrhea 17% (n ¼ 6) 7% (n ¼ 3)
Hypoglycemia 11% (n ¼ 4) 14% (n ¼ 6)
Medication intolerance 3% (n ¼ 1) 9% (n ¼ 4)

Refuerzo. Metformin vs placebo for weight loss in women with GDM. Am J Obstet Gynecol 2015.

389.e6 American Journal of Obstetrics & Gynecology MARCH 2015

ajog.org CAOG Papers
regimens to reduce adverse effects and
improve compliance. FIGURE 2
There were limitations to our study. Reported difficulty with recommended diet, exercise, and medication
Due to time constraints, cost, and diffi-
culty following up our population, we
were only able to assess these women up
to 6 weeks’ postpartum (range, 5e8
weeks). As a result, our lack of difference
in weight change between groups could
be due to a short treatment period. Most
weight loss studies involved treatment
ranging from 8 weeks up to 2-3 years.
Consideration to include a second
postpartum visit at 8-12 weeks could
have identified whether length of medi-
cation treatment is an important factor
affecting weight loss and could have
resulted in a significant change. Sus-
tained weight may be a factor leading to
diabetes later in life. Another limitation
is our sample size. Our sample size was
small and our findings did not exclude
the possibility of clinically important
treatment effects. Our sample was also
based on women with GDM with
EGWG. However, in our study, EGWG
only occurred in 33.3% of women in the
metformin group and 48.8% in placebo
group. Rather than include women with
a spectrum of weight gain, perhaps our
enrollment criteria should have been
restricted to only women with EGWG to
target the highest risk population.
Importantly, women randomized to
metformin who did not complete the
study had significantly higher BMI and
higher rate of preterm birth compared to
all groups. These women are the highest
risk group for weight gain, weight
retention, and developing type 2 DM
later in life. However, given the attrition
we observed, metformin may not benefit
this group in the absence of successful
strategies to increase their adherence.
Also, our sample size was based on an
attrition rate of 10% and effect size of
50%, but our true attrition rate was
approximately 30%. Understanding
attrition rates, effect sizes that are usually
30%, and sample calculations during
this pilot study provided us information
to improve the design of future studies. GDM, gestational diabetes mellitus.
Refuerzo. Metformin vs placebo for weight loss in women with GDM. Am J Obstet Gynecol 2015.
Our attrition rate could be the result of a
type II error. But this is unlikely given
our similar results in both groups with
similar CI. Another limitation was that

MARCH 2015 American Journal of Obstetrics & Gynecology 389.e7

CAOG Papers ajog.org

we did not conduct a dietary history or

FIGURE 3 food frequency questionnaire in this
Reported satisfaction with recommended diet, exercise, and medication study, which could have provided more
information regarding weight loss. We
also did not collect information on other
medications used by the subjects, which
could be included in future studies.
In summary, this pilot randomized
controlled trial demonstrated similar
weight loss in women with GDM who
received metformin and placebo and
inability to reduce retained gestational
weight postpartum. However, longer
treatment periods with metformin, a
focus on the higher risk mothers, and/or
much larger studies with minimal attri-
tion may be warranted. -

REFERENCES
1. American College of Obstetricians and
Gynecologists Committee on Practice Bulletins,
Obstetrics. Gestational diabetes mellitus. Prac-
tice bulletin no. 137. Obstet Gynecol 2013;122:
406-16.
2. Reece EA, Leguizamon G, Wiznitzer A.
Gestational diabetes: the need for a common
ground. Lancet 2009;373:1789-97.
3. England LJ, Dietz PM, Njoroge T, et al.
Preventing type 2 diabetes: public health im-
plications for women with a history of gesta-
tional diabetes mellitus. Am J Obstet Gynecol
2009;200:365.e1-8.
4. Bellamy L, Casas JP, Hingorani AD,
Williams D. Type 2 diabetes mellitus after
gestational diabetes: a systematic review and
meta-analysis. Lancet 2009;373:1773-9.
5. Torloni MR, Betran AP, Horta BL, et al. Pre-
pregnancy BMI and the risk of gestational dia-
betes: a systematic review of the literature with
meta-analysis. Obes Rev 2009;10:194-203.
6. Chu SY, Callaghan WM, Bish CL, D’Angelo D.
Gestational weight gain by body mass index
among US women delivering live births, 2004-
2005: fueling future obesity. Am J Obstet
Gynecol 2009;200:271.e1-7.
7. Nohr EA, Bech BH, Vaeth M, Rasmussen KM,
Henriksen TB, Olsen J. Obesity, gestational
weight gain and preterm birth: a study within the
Danish National Birth Cohort. Paediatr Perinat
Epidemiol 2007;21:5-14.
8. Hamman RF, Wing RR, Edelstein SL, et al.
Effect of weight loss with lifestyle intervention on
risk of diabetes. Diabetes Care 2006;29:
2102-7.
9. Perreault L, Kahn SE, Christophi CA,
Knowler WC, Hamman RF; Diabetes Prevention
Program Research Group. Regression from pre-
diabetes to normal glucose regulation in the
diabetes prevention program. Diabetes Care
GDM, gestational diabetes mellitus. 2009;32:1583-8.
Refuerzo. Metformin vs placebo for weight loss in women with GDM. Am J Obstet Gynecol 2015. 10. Ratner RE, Christophi CA, Metzger BE, et al.
Prevention of diabetes in women with a history of

389.e8 American Journal of Obstetrics & Gynecology MARCH 2015

ajog.org
gestational diabetes: effects of metformin and
lifestyle interventions. J Clin Endocrinol Metab
2008;93:4774-9.
11. Powell LH, Calvin JE III, Calvin JE Jr. Effec-
tive obesity treatments. Am Psychol 2007;62:
234-46.
12. Tuomilehto J, Lindstrom J, Eriksson JG,
et al. Prevention of type 2 diabetes mellitus by
changes in lifestyle among subjects with
impaired glucose tolerance. N Engl J Med
2001;344:1343-50.
13. Desilets AR, Dhakal-Karki S, Dunican KC.
Role of metformin for weight management in
patients without type 2 diabetes. Ann Phar-
macother 2008;42:817-26.
14. Nieuwenhuis-Ruifrok AE, Kuchenbecker WK,
Hoek A, Middleton P, Norman RJ. Insulin
sensitizing drugs for weight loss in women of
reproductive age who are overweight or obese:
systematic review and meta-analysis. Hum
Reprod Update 2009;15:57-68.
15. American College of Obstetricians and
Gynecologists Committee Obstetric Prac-
tice. Exercise during pregnancy and the
postpartum period. ACOG Committee
opinion no. 267. Obstet Gynecol 2002;99:
171-3.
16. MyPyramid tracker. United States Depart-
ment of Agriculture. Center for Nutrition Policy and
Promotion. Available at: http://www.cnpp.usda.
gov/mypyramidtracker.htm. Accessed Aug.
15, 2013.
17. Scholl TO, Hediger ML, Schall JI, Ances IG,
Smith WK. Gestational weight gain, pregnancy
MARCH 2015 American Journal of Obstetrics & Gynecology
CAOG Papers
outcome, and postpartum weight retention.
Obstet Gynecol 1995;86:423-7.
18. Salpeter SR, Buckley NS, Kahn JA,
Salpeter EE. Meta-analysis: metformin treat-
ment in persons at risk for diabetes mellitus. Am
J Med 2008;121:149-57.e2.
19. Bolen S, Feldman L, Vassy J, et al. Sys-
tematic review: comparative effectiveness and
safety of oral medications for type 2 diabetes
mellitus. Ann Intern Med 2007;147:386-99.
20. Asche CV, McAdam-Marx C, Shane-
McWhorter L, Sheng X, Plauschinat CA. Associ-
ation between oral antidiabetic use, adverse
events and outcomes in patients with type 2 dia-
betes. Diabetes Obes Metab 2008;10:638-45.
21. Cohen S. The placebo effect of informed
consent. Bioethics 2014;28:147-54.
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