Review Article
Review Article
Review Article
Review Article
Effect of Metformin Intervention during Pregnancy on
the Gestational Diabetes Mellitus in Women with Polycystic
Ovary Syndrome: A Systematic Review and Meta-Analysis
Zhihong Zhuo,1,2 Aiming Wang,3 and Huimin Yu2
1
1. Introduction
Polycystic ovarian syndrome (PCOS), which is one of the
common endocrine disorders, is one of the main causes of
ovulatory infertility, affecting 510% of women of reproductive age [1, 2]. PCOS is characterized by the presence of typical
ultrasound features of polycystic ovaries, oligomenorrhea,
and clinical and/or biochemical hyperandrogenism and,
commonly, by insulin resistance, hyperinsulinemia, morbid
obesity, and infertility [39]. Insulin resistance appears in
both obese and nonobese women with PCOS [10]. Among
these women, insulin promotes intraovarian steroidogenesis
by interacting with luteinizing hormone (LH) leading to
inappropriate advancement of granulose cell differentiation
and arrest of follicle growth. The outcomes with hyperinsulinemia may directly enhance ovarian secretion and abnormal follicular development, which ultimately lead to ovarian
dysfunction [11, 12]. Moreover, hyperinsulinemia has been
3. Results
3.1. Flowchart of Study Selection. The flowchart of the study
selection according to the inclusion and exclusion criteria
above is shown in Figure 1. A total of 13 trials potentially
resulted for inclusion in the meta-analysis [22, 2536]. In
particular, we excluded the trials as follows: the data on the
occurrence of GDM were not available from papers and could
not be obtained from the investigators by e-mail contact; it
was not possible to contact the corresponding investigators
and the occurrence rate of gestational diabetes has not been
evaluated.
3.2. Characteristics of Studies. Table 1 summarizes the quality
of the trials included in the analysis. The main characteristics of the populations, the interventions received, and the
outcomes obtained in the trials are summarized in Tables 2
and 4, respectively. A total of five RCTs were also included in
the final analysis as Table 3. However, three RCTs including
Fougner et al. [30], Vanky et al. [32], and Salvesen et al. [35]
are duplicate, and Vanky et al. [22] reported an epianalysis
of two randomized controlled trials as Vanky et al. [32] and
Salvesen et al. [35]. Finally, we reviewed two RCTs [32, 35] in
our meta-analysis. No research included in the system review
and meta-analysis had occurrence of gestational diabetes
as a primary end point, and none was powered to detect
differences in GDM incidence. In addition, other potential
gestational complications, such as miscarriage, preeclampsia, and preterm delivery, including the infants characteristics, were investigated in these studies. The populations
4. Discussion
In our mind, this is the first systematic review and metaanalysis of trials including RCTs performed to establish the
Data
collection
22
25
CO
26
27
CC
No description.
28
CO
29
CC
No description.
No stillbirths, perinatal deaths, or major
birth defects. One baby in group A had
polydactyl.
30
No description.
No maternal lactic acidosis and no
maternal or neonatal hypoglycemia. Of
the 180 live births to
the 142 nondiabetic women with PCOS,
there was one major birth defect
(sacrococcygeal teratoma), as determined
by pediatricians without knowledge of
metformin dose or duration.
Number
Malformation described
No description.
No miscarriages or neonatal loss
occurred in either group.
One baby girl born with major birth
defect (tracheoesophageal fistula).
Metformin group: one postpartum
pulmonary embolism, one postpartum
circulatory shock, one peripartum
cardiomyopathy, and one sudden infant
death.
Placebo group: three spontaneous
abortions, ileus in one patient with
former gastric bypass operation, and one
perinatal infant death caused by serious
asphyxia.
31
CO (self as control)
32
33
CO (self as control)
34
CO
P and R
35
No description.
36
CO
No description.
No maternal lactic acidosis or maternal
hypoglycemia; no major birth defects;
there have been no congenital defects or
evidence of intrauterine growth. Seventy
of the 84 fetuses have had a favourable
outcome; no cases of neonatal
hypoglycemia.
None developed lactic acidosis.
Intermittent diarrhea or gastritis was
common in the first 3 weeks of
metformin therapy but resolved
spontaneously and was not limiting
factors. No major fetal malformations or
fetal hypoglycemia occurred.
Intervention
Comparison
Relevant outcomes
22
160 PCOS.
Age 29.1 4.3,
BMI 28.6 7.3.
Second-trimester
miscarriage, preterm
delivery, preeclampsia, and
gestational diabetes.
25
160 women
discontinued
metformin use at the
time of conception.
Age 31.5 2.4,
BMI 29.6 1.6.
Gestational diabetes,
preeclampsia, and
caesarean section rate.
26
Placebo in pregnant
PCOS women (n =
138).
Age 29.2 4.4,
BMI 28.5 7.2.
Preeclampsia, preterm
delivery, GDM
weight, blood pressure,
heart rate, and mode and
length of delivery.
In 78 cases, metformin
was stopped in first
trimester or they
conceived without
metformin.
21 conceived without
medication, 13
conceived on
metformin, and 44
required induction of
ovulation and
metformin.
Age 26 5.3,
BMI 33.2 5.2.
27
28
29 continued metformin
throughout pregnancy.
1500 mg daily for BMI 29,
2000 mg daily for BMI 3032 and
2500 mg daily for BMI >32.
Age 28.14 2.92, BMI 28.21
2.37.
32 conceived without
metformin
Age 30 2.9,
BMI 31.2 4.6.
PIH/preeclampsia; GDM;
IUGR; miscarriage;
preterm delivery; live birth;
mean birth weight.
18 with placebo.
Age 28.9 2.5,
BMI 32.1 3.1.
29
30
Table 2: Continued.
Number Population
31
32
33
34
35
Intervention
Comparison
Relevant outcomes
22 were placebo.
Age 28.3 3.7,
BMI 39.3 8.0.
Conceived on metformin,
1.52.55 g/day.
BMI 33 5.8.
Self as control
Gestational diabetes,
number of first trimester
SAB, live births, normal
ongoing pregnancies 13
weeks, nature of
intrauterine fetal
development by
sonography, congenital
defects, infant birth weight
and height, and height,
weight, and motor and
social development during
the first 6 months of life.
39 nondiabetic women
with PCOS who had
live birth pregnancies
without metformin
therapy.
Pretreatment height,
weight, body mass index
(BMI), glucose, insulin,
insulin resistance and
insulin secretion, and
gestational diabetes.
Identical placebo
capsules.
Age 28.3 3.7,
BMI 29.3 8.0.
Minor complications
included mild
preeclampsia, hypertension
and/or insulin-treated
GDM. Severe
complications included
preterm deliveries before 32
gestational weeks, severe
preeclampsia, or serious
postpartum problems (e.g.,
endometritis and Group A
streptococcal sepsis, adult
acute respiratory distress
syndrome (ARDS),
thrombosis, or lung
embolism).
7
Table 2: Continued.
Number Population
36
Intervention
Comparison
Relevant outcomes
Got pregnant
spontaneously or by
use of ovulation
inducing agents but did
not use metformin
before or after
pregnancy.
Age 28.12 4.35, BMI
28.35 1.97
Country
A: adequate
B: unclear
C: inadequate
22
Norway
(2 RCTs)
26
Norway
(multicenter
study)
30
Norway
32
Norway
35
Norway
Blinding
A: investigators ITT
B: patients
C: outcome
assessors
A: Yes
B: Yes
Yes
C: No
A: Yes
B: Yes
No
C: Yes
A: Yes
B: Yes
No
C: Not reported
A: Yes
B: Yes
No
C: Not reported
A: Yes
B: Yes
No
C: Not reported
ITT: intention-to-treat.
researchers have already demonstrated that the administration of metformin throughout pregnancy may decrease
miscarriage and improve pregnancy outcomes including
GDM, preeclampsia, and preterm delivery [34, 3944].
Although a population-based cohort research, a system
review, and meta-analysis recently identified that the patients
with PCOS are at higher risk for pregnancy complications
[45, 46], moreover, unless metformin was recommended
for treatment in pregnancy complications especially DM
because of its characteristics of safety, effectiveness, and
nonteratogenicity, they could not reach an agreement on
its use in prevention or treatment of GDM, hyperinsulinemia, and hyperandrogenemia throughout the pregnancy in
women with PCOS. In our knowledge, during the past several
decades, the retrospective and nonrandomized studies have
confirmed beneficial effects of metformin on pregnancy miscarriage and pregnancy complications, in particular GDM in
women with PCOS, whereas the potential effect of metformin
to pregnancy complications in women with PCOS has been
explored in five randomized, placebo-controlled trials so far
[26, 32]. The studies suggested no statistical difference in the
prevalence of gestational diabetes, preeclampsia, and preterm
delivery between the metformin- and the placebo-treated
groups. As a result, meta-analytical summaries of existing
studies therefore are of importance to GDM in PCOS.
Although it yields a reassuring trend, this analysis exemplifies the need for more research on metformin to DM
during pregnancy. It was our initial aim to identify all possible
adverse pregnancy outcomes including miscarriage, minor
anomalies, major malformations, intrauterine growth retardation, GDM, preterm delivery, live birth, caesarean section
rate, or the characteristics of infants in particular the birthheight, birth-weight, APGAR in 1 or 5 or 10 minutes, and
head circumference. However, we were limited to focusing
mainly on the pregnancy complications on GDM because of
the paucity of data and the paradoxical effect of metformin
on GDM in PCOS.
Notwithstanding our data, metformin administered
alone throughout the pregnancy, or at least during first
trimester, or in combination with other infertility treatments
for inducing ovulation in patients with PCOS seems to have
significant effect on GDM prevention. In fact, our non-RCTs
22
25
26
Outcome
Second-trimester
miscarriage and delivery
<gestational week 37 + 0
Preeclampsia
New gestational diabetes
Controls
5/153
18/159
P = 0.008
12/153
27/142
7/157
26/141
GDM
8/200
32/160
Gestational hypertension
and/or preeclampsia
6/200
13/160
106/200
96/160
Preeclampsia
10/135
5/135
Preterm delivery
5/135
11/135
GDM
22/125
21/124
P = 0.24
P = 0.90
P < 0.001, OR = 0.17, 95%
CI = 0.070.37
P = 0.03, OR = 0.35, 95% CI
= 0.130.94
P = 0.18, OR = 0.75, 95% CI
= 0.491.15
P = 0.18, RD = 3.7%, 95%
CI = 1.79.2
P = 0.12, RD = 4.4%, 95%
CI = 10.11.2
P = 0.87, RD = 0.8%, 95%
CI = 8.610.2
RD (risk difference)
2500 g
8/135
25014500 g 125/135
>4500 g
2/135
50.3 4.4
9/119
2500 g
8/135
25014500 g 120/135
>4500 g
7/135
50.0 2.5
23/78
P = 0.32
P = 0.44
P < 0.002
Weight
27
28
29
Length of delivery
Miscarriage rate
EPL with recurrent
miscarriage
Gestational diabetes
PIH
IUGR
Live birth rate
2/16
5/11
P < 0.001
12/119
20/119
20/119
109/119
34/78
35/78
30/78
55/78
GDM
1/29
9/30
0.0021
<0.002
<0.001
<0.001
OR = 12, 95% CI =
6.2018.08
Abortion
Macrosomia
LBW (low birth weight)
Birth asphyxia
Neonatal death
Preterm labor
Birth weight
APGAR (5 min)
1/29
0/29
0/29
0/29
0/29
2/29
2.79 0.143
10 00
Group A Group B Group C
14/32
6/18
6/45
15/32
10/18
13/45
7/32
3/18
1/45
8/40
2/20
0/45
8/32
5/18
2/41
32/40
18/20
45/45
2.67 0.91 2.71 0.89 2.88 0.95
1/30
4/30
0/30
5/30
1/30
3/30
3 0.499
9.03 0.326
P = 0.016
P = 0.006
8/26
12/26
5/26
6/32
5/26
26/32
2.9 1.1
P = 0.002
P = 0.968
P = 0.026
P = 0.006
P = 0.035
P = 0.016
P = 0.81
PIH/preeclampsia
GDM
IUGR
Miscarriage
Preterm delivery
Live birth
Mean birth weight
9
Table 4: Continued.
Number
Outcome
Controls
30
31
GDM
GDM
Preterm deliveries
Preeclampsia/hypertension
GDM
CS (caesarean section)
Head circumference
Birth weight
Birth length
Apgar (5 min)
Apgar (10 min)
SAB (first-trimester
spontaneous abortion)
GDM
GDM
GDM
Overall pregnancy
complications
Severe pregnancy
complications
Miscarriage
Preterm birth
Fatal macrosomia
IUGR
5 min Apgar score (7)
Fatal anomalies
Neonatal mortality
GDM
6/22
6/50
0/18
3/18
1/18
3/18
36 1
3595 420
50 2
9.3 1.0
9.8 0.7
3/18
19/64
5/22
2/22
3/22
4/22
34 5
3215 1048
48 8
9.5 0.6
9.9 0.2
12/46
62/100
3/68
1/33
2/18
9/34
10/37
6/22
P = 0.07
P = 0.1
P = 0.2
P = 0.3
P = 0.3
McNemars = 32, df = 1, P <
0.0001
McNemars = 5, P = 0.025
P = 0.0074 (Fisher test)
P = 0.3
3/18
10/22
P = 0.09
0/18
7/22
P = 0.01
1/31
1/31
1/31
0/31
1/31
0/31
0/31
1/31
7/26
2/26
1/26
1/26
3/26
1/26
1/26
6/26
P = 0.01
P = 0.58
P = 1.0
P = 0.45
P = 0.32
P = 0.45
P = 0.45
32
33
34
35
36
Study or subgroup
Fougner 2008
Selvesen 2007
Vanky 2004
Vanky 2010
Vanky 2012
Total (95% CI)
Treatment
Control
Events Total Events Total Weight
6
2
8
22
27
22
18
18
125
142
143
3
6
9
21
26
18
22
22
124
141
Odds ratio
M-H, fixed, 95% CI
20.6%
79.4%
0.0%
Not estimable
Not estimable
1.16 [0.33, 4.07]
1.05 [0.54, 2.02]
1.04 [0.57, 1.89]
146 100.0%
Total events
30
30
Heterogeneity: 2 = 0.02, df = 1 (P = 0.89); I2 = 0%
Test for overall effect: Z = 0.23 (P = 0.82)
Odds ratio
M-H, fixed, 95% CI
0.01
0.1
1
10
100
Favours (experimental) Favours (control)
Figure 2: The meta-analysis of the odds ratio for gestational diabetes in RCTs.
10
Study or subgroup
Begum 2009
Glueck 2002
Glueck 2004
Glueck 2008
Hameed 2011
Odds ratio
M-H, fixed, 95% CI
0.08 [0.01, 0.71]
0.08 [0.01, 0.70]
0.13 [0.03, 0.51]
0.32 [0.12, 0.88]
Khattab 2011
200
32
160
27.2%
Newaz 2008
Newaz 2010
13
12
45
119
12
34
26
78
8.6%
29.4%
455 100.0%
575
Total events
45
Odds ratio
M-H, fixed, 95% CI
131
1
0.01
0.1
Favours (experimental)
10
100
Favours (control)
Figure 3: The meta-analysis of the odds ratio for gestational diabetes in the studies with disease-matched controls or patients selves as control.
Study or subgroup
Begum 2009
Glueck 2002
Hameed 2011
Khattab 2011
Newaz 2008
Newaz 2010
Treatment
Control
Events Total Events Total Weight
1
1
1
8
13
12
29
33
31
200
45
119
9
10
6
32
12
34
457
36
30
37
26
160
26
78
Odds ratio
M-H, fixed, 95% CI
8.1%
8.6%
6.0%
32.2%
10.2%
34.9%
357 100.0%
Odds ratio
M-H, fixed, 95% CI
103
0.01
0.1
1
10
100
Favours (experimental) Favours (control)
Figure 4: The meta-analysis of the odds ratio for gestational diabetes in the studies with PCOS as control.
Study or subgroup
Glueck 2004
Glueck 2008
11
Treatment
Control
Events Total Events Total Weight
68
34 43.9%
3
9
50
64 56.1%
6
19
Total events
118
98 100.0%
Odds ratio
M-H, fixed, 95% CI
0.13 [0.03, 0.51]
0.32 [0.12, 0.88]
Odds ratio
M-H, fixed, 95% CI
28
0.01
0.1
1
10
100
Favours (experimental) Favours (control)
Figure 5: The meta-analysis of the odds ratio for gestational diabetes in the studies with patients selves as control.
5. Conclusion
Metformin is an effective insulin sensitizer treating type 2
diabetes mellitus. However, the functional consequences of
metformin administration throughout pregnancy on gestational diabetes mellitus (GDM) have not been assessed.
Metformin has been increasingly regarded to be effective and
safe medicine for the metabolic and endocrine abnormalities
in PCOS. In our knowledge, this is the first systematic review
and meta-analysis of trials including RCTs performed to
establish the potential effect of metformin intervention during the gestational period on gestational diabetes occurrence
risk in patients with polycystic ovary syndrome. We therefore
performed a meta-analysis and system review to determine
the effect of metformin on GDM in patients with PCOS.
A meta-analysis was performed on the published studies
before December, 2013. Meta-analysis examined whether
metformin could reduce GDM occurrence in PCOS with a
fixed effect model. The odds ratio (OR) with 95% confidence
interval (95% CI) was calculated to estimate the strength
of association. A total of 13 studies including five RCTs
and eight non-RCTs were enrolled. Ultimately, effectiveness
analysis demonstrated that, in total, there was no significant
availability of metformin on GDM in PCOS in contrast
to placebo (OR = 1.07, 95% CI 0.601.92) in RCTs and
significant availability of metformin on GDM (OR = 0.19,
95% CI 0.130.27) was indicated in non-RCTs. Subanalysis
was conducted to separate studies into those with PCOS and
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
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