Keywords
obesity - gestation - gestational diabetes mellitus - metformin
Palavras-chave
obesidade - gestação - diabetes mellitus gestacional - metformina
Introduction
Obesity is one of the major epidemics of this millennium and is considered a public
health problem by the World Health Organization (WHO).[1] In Brazil, cases of obesity have grown over the last decades; specifically among
women, 1.9 million cases were registered in 1975 compared with 18 million in 2014.[2] This public health problem affects a great number of women, particularly those in
reproductive age.[3]
Maternal obesity during pregnancy is associated with the development of gestational
diabetes mellitus (GDM).[4] Gestational diabetes mellitus is the most common metabolic disorder during gestation,
affecting 3–25% of all pregnancies, depending on the diagnostic criteria applied and
on the population and ethnic groups studied. Between 24–28 weeks of gestation, all
pregnant women without a previous diagnosis of diabetes undergo screening for GDM
with the oral glucose tolerance test (OGTT) after 8 hours of fasting. The Brazilian
Society of Diabetes (Sociedade Brasileira de Diabetes [SBD, in the Portuguese acronym])
recommends that pregnant women should be classified as having GDM when presenting
a blood glucose level between 92 and 125 mg/dL at fasting, ≥ 180 mg/dL at 1 hour,
or 153–199 mg/dL at 2 hours; an abnormal result at one of the time points of the test
characterizes GDM.[5]
Prevention of hyperglycemia during pregnancy may reduce immediate adverse pregnancy
outcomes, childbirth risks, and, consequently, costs to the public health care system
directed to GDM treatment.[6] Strategies for GDM prevention among women at risk of developing the disease may
include changes in lifestyle, reduction of obesity, nutritional intervention, physical
activity, and pharmacological measures.[7]
Women who develop GDM during one of the gestational trimesters require attention during
prenatal care to stabilize blood glucose levels to values similar to those of pregnant
women without GDM.[6]
[8] Nutritional therapy is the first step in GDM management, but when it fails to achieve
glycemic control, it is associated with drug therapy.[8] The standard pharmacological treatment of GDM is insulin therapy; however, oral
hypoglycemic agents, like metformin, have also been used for glycemic control of overweight
and obese women with GDM.[9]
In obese pregnant women, nutritional intervention and lifestyle changes may reduce
many of the problems caused by GDM, achieving reduced blood glucose levels and BMI,
as well as controlled blood pressure; however, low adherence by the patients fails
to lead to a significant decrease in GDM incidence.[10]
[11]
The use of drugs like metformin has a preventive effect, especially in the control
of obesity, which is one of the major causes of GDM. In the past, the use of hypoglycemic
agents was contraindicated during pregnancy due to a risk of teratogenicity; however,
this concept has changed over the past years. Metformin is no longer considered teratogenic;
it is now considered a safe drug during pregnancy, with a low incidence of side effects,
in addition to being helpful in controlling blood glucose levels and reducing BMI
and levels of total cholesterol and fractions.[12]
[13] When associated with lifestyle changes, metformin is also a potentially effective
and safe approach to obesity and GDM control.[13]
[14]
[15]
Based on these considerations, this study aimed at evaluating the effectiveness of
metformin in the incidence of GDM in obese pregnant women attending a public maternity
hospital in Joinville (Santa Catarina, Brazil).
Methods
The present study was a randomized clinical trial analyzing the use of metformin in
obese pregnant women, who were randomized into two groups (control group and metformin
group). Both groups received counseling regarding diet and physical activity. All
pregnant women received care by a multidisciplinary team comprising a nutritionist,
nurse, physical therapist, and an obstetrician in a reference maternity hospital in
the city of Joinville (Santa Catarina, Brazil).
Considering that GDM has a 2-fold higher risk in obese women and an incidence of 18%
in the general population, and with the objective of obtaining a 50% decreased incidence
with the drug, with a confidence level of 80%, we found that a sample size of 94 subjects
in each group would be adequate. Considering a 10% rate of loss to follow-up, we selected
208 pregnant women to participate in the study, 104 of whom were allocated to the
control group and 104 to the metformin group.[5]
The data were collected at Maternidade Darcy Vargas (MDV, in the Portuguese acronym)
from October 31, 2014 to October 1, 2016. The study was initiated after approval by
the Research Ethics Committee at Universidade da Região de Joinville (Univille), with
the Certificate of Presentation for Appreciation (CAAE, in the Portuguese acronym)
approval number 34863514.1.0000.5366, and was made possible by the Research Ethics
Committee of Hospital Regional Hans Dieter Schmidt/Sesc/SC, with the CAAE approval
number 34863514.1.3001.5363. This study is registered with the Brazilian Registry
of Clinical Trials with the code RBR-9rpqdn and identification number U1111–1162–6908.
This report follows the recommendations of the Consolidated Standards Reporting Trial
(CONSORT).[16]
Pregnant women with gestational age (GA) ≤ 20 weeks and obesity (body mass index [BMI] ≥ 30
kg/m2) were referred by primary health care units to the gestational obesity outpatient
clinic at the MDV. The patients were invited to participate during lectures held at
the MDV auditorium about gestational obesity and the effectiveness of metformin in
the prevention of GDM, during which the study objectives, as well as its risks and
benefits, were explained. The women who agreed to participate in the study signed
two copies of a free and informed consent form, one of which was given to the participant
and the other was maintained by the principal investigator. The lectures took place
on Thursdays at 7:30 am in the MDV auditorium during the period of the study.
The study included pregnant women with a diagnosis of obesity according to the WHO
criteria (BMI ≥ 30 kg/m2); age ≥ 18 years; negative GDM screening in early pregnancy (GA ≤ 20 weeks); no history
of diabetes before pregnancy; no allergy to metformin; no history or presence of liver,
renal, or gastrointestinal disease, or other condition that could interfere with the
absorption, distribution, excretion, or metabolism of the drug. We excluded women
who interrupted the follow-up, had intolerance or allergic reaction to the drug, or
refused to continue participating in the study.
The participants received prenatal care according to the primary protocol recommended
by the Brazilian Ministry of Health. Screening for GDM was performed between 24–28
weeks with the OGTT (75 g of glucose diluted at 25%). According to the SBD, a diagnosis
of GDM should be established in pregnant women presenting a glucose level between
92 and 125 mg/dL at fasting, ≥ 180 mg/dL at 1 hour, or 153 to 199 mg/dL at 2 hours;
an abnormal result at one of the time points of the test characterizes GDM.[5]
All participants were referred for nutritional care, in which they received dietary
guidance with small reductions in their caloric intake of 24 kcal/kg/day, a fractionated
diet with five to six daily meals, a daily caloric composition comprising 40–50% of
fiber-rich complex carbohydrates, 20% of protein, and 30–40% of unsaturated fats.
Daily calories were distributed as 10–20% at breakfast, 20–30% at lunch, 20–30% at
dinner, and up to 30% as snacks, including a snack before bedtime to avoid nocturnal
hypoglycemia. The participants were referred to physical therapy and received recommendations
for physical activity, with a regular walking program of 20 minutes per day.[17]
Participants in the metformin group received a metformin dose of 1,000 mg twice daily
(500 mg at breakfast and 500 mg at dinnertime), as prescribed by the obstetrician.
If a diagnosis of GDM was established, metformin was not discontinued, since it was
offered free of charge by the Brazilian Unified Health System (SUS, in the Portuguese
acronym). Laboratory tests were performed at Laboratório Gimenez Ltda., which is located
adjacent to the MDV. All tests performed in the study are part of the clinical and
laboratory routine of obese pregnant women seen at MDV.
During the first visit to the gestational obesity outpatient clinic, the participants
were randomized with a computerized algorithm using the software Microsoft Excel (Microsoft,
Redmond, WA, USA), which generated a random allocation order list in a non-fixed proportion,
divided into two groups: a study group, which was treated with metformin and received
guidance on diet and physical activity, and a control group, which received only diet
and physical activity counseling. The participants received a coded seal on their
prenatal follow-up record, which identified them as participants of the multidisciplinary
research team during outpatient visits throughout the study.
All patients were identified using a specific research form containing the participant's
name; date of birth; age; marital status; occupation; educational level; ethnicity;
BMI; GA; allergy to metformin; number of pregnancies; age at birth of first child;
interval between deliveries; abortion; type of delivery; use of medication during
pregnancy; diagnosis of liver, renal, or gastrointestinal disease; diagnosis of GDM
in previous pregnancies; and diagnosis of polycystic ovary disease. The results of
the laboratory tests, fasting blood glucose levels, and OGTT throughout the prenatal
period were recorded during appointments at the obesity outpatient clinic. The tests
were ordered at baseline (GA ≤ 20 weeks) and at 24–28 gestational weeks.
For the statistical analysis, the collected data were entered into a Microsoft Excel
version 2016 spreadsheet and were later analyzed using the statistical software IBM
SPSS Statistics version 22.0 (IBM Corp., Armonk, NY, USA). The quantitative variables
are presented as mean and standard deviation, while the qualitative variables are
represented as absolute and relative frequencies. Once the normal distribution of
the studied characteristics was confirmed, the Student t-test was applied to analyze
quantitative variables and the chi-square test for qualitative ones. To verify the
distribution of fasting blood glucose values before and after treatment, box-plot
graphs were built, and the Friedman test was used to compare the distribution of the
data. For all analytical models, p values below 0.05 were considered significant, and the absolute risk reduction was
estimated.
Results
Obese pregnant women with a BMI ≥ 30 kg/m2, classified as having high-risk pregnancies, were referred by the primary health
care units to the gestational obesity outpatient clinic at the MDV maternity, as shown
in [Fig. 1].
Fig. 1 Flowchart of the participants at each stage of the study.
Among the pregnant women referred to the clinic, 116 failed to meet the study's inclusion
criteria. Out of 253 eligible obese pregnant women, 89 declined to participate in
the study, yielding 164 participants for randomization, of whom 82 were enrolled in
the metformin group and 82 in the control group. The main demographic characteristics
analyzed in the study were maternal age, marital status, occupation, education level,
ethnicity, number of pregnancies, and GA at the first visit. Assessments included
the anthropometric characteristic BMI and the metabolic parameter fasting blood glucose
level (in mg/dL) [Table 1].
Table 1
Characteristics of obese pregnant women at ≤ 20 weeks of gestation
|
Metformin
(n = 82)
|
Control
(n = 82)
|
p value
|
|
Age (years)
|
|
Mean (SD)
|
28.8 (6.0)
|
29.7 (6.3)
|
0.36[†]
|
|
Range
|
18.0–40.0
|
19.0–44.0
|
|
Marital status
|
|
Married
|
63 (76.8)
|
66 (80.5)
|
0.56[‡]
|
|
Single
|
19 (23.2)
|
16 (19.5)
|
|
Occupation
|
|
Working
|
82 (100)
|
82 (100)
|
–
|
|
Not working
|
0 (0.0)
|
0 (0.0)
|
|
Education level
|
|
Elementary school
|
27 (32.9)
|
25 (30.5)
|
0.89[‡]
|
|
High school
|
42 (51.2)
|
45 (54.9)
|
|
Higher education
|
13 (15.9)
|
12 (14.6)
|
|
Ethnicity
|
|
White
|
67 (81.7)
|
65 (79.3)
|
0.86[‡]
|
|
Black
|
8 (9.8)
|
8 (9.8)
|
|
Others
|
7 (8.5)
|
9 (11.0)
|
|
Number of pregnancies
|
|
Mean (SD)
|
2.3 (1.3)
|
2.6 (1.5)
|
0.09[†]
|
|
Range
|
1.0–6.0
|
1.0–8.0
|
|
GA (first visit)
|
|
Mean (SD)
|
15.1 (4.2)
|
17.1 (4.6)
|
< 0.01[†]
|
|
Range
|
5.0–24.0
|
6.0–26.0
|
|
Fasting glucose (mg/dL)
|
|
Mean (SD)
|
79.3 (9.5)
|
80.4 (10.2)
|
0.47[†]
|
|
Range
|
52.0–99.0
|
63.0–120.0
|
|
BMI (kg/m2)
|
|
Mean (SD)
|
37.5 (4.7)
|
37.5 (5.0)
|
0.99[†]
|
|
Range
|
25.3–50.8
|
25.3–49.5
|
Abbreviations: BMI, body mass index; GA, gestational age; SD, standard deviation.
† Student t test.
‡ Chi-square test.
When comparing BMI values in the control and metformin groups prior to metformin treatment,
at GA ≤ 20 weeks, and after treatment, at 24–28 gestational weeks, no influence of
the drug was observed on BMI increase in the control and metformin groups (0.9 ± 1.2
versus 1.0 ± 0.9, respectively, p = 0.63) [Table 2]).
Table 2
Body mass index at ≤ 20 weeks and 24–28 weeks of gestation in obese pregnant women
in the control and metformin groups
|
Control Group (n = 82)
|
Metformin Group (n = 82)
|
Δ Metformin versus
Δ Control (p)
|
|
≤ 20
|
24–28
|
Δ
|
≤ 20
|
24–28
|
Δ
|
|
BMI kg/m2
(mean ± SD)
|
37.5 ± 4.7*
|
38.4 ± 4.9*
|
0.9 ± 1.2
|
37.5 ± 5.0*
|
38.5 ± 5.1*
|
1.0 ± 0.9
|
0.63**
|
Abbreviations: Δ, Variation; BMI, body mass index, SD, standard deviation. *Student
t-test. **Chi-square test.
Blood glucose levels during the OGTT were comparable among participants allocated
to the metformin and control groups: fasting 77.5 (9.0) mg/dL and 78.9 (12.1) mg/dL,
respectively (p = 0.66), 1 hour 129.3 (27.5) mg/dL and 134.0 (33.9) mg/dL, respectively (p = 0.50), 2 hours 110.6 (28.1) mg/dL and 111.7 (30.6) mg/dL, respectively (p = 0.99) [Fig. 2].
Fig. 2 Oral glucose tolerance test (OGTT) at 24–28 gestational weeks in obese pregnant women
allocated to the metformin and control groups
The diagnosis of GDM was established in 13 (15.9%) patients in the metformin group
and 16 (19.5%) of those in the control group (p = 0.683). The absolute risk reduction in the metformin group was 3.6 (95% confidence
interval -8.0 to 15.32), which was not significant. The magnitude of the risk of GDM
development in the metformin group was equivalent to 80% of that in the control group,
that is, the metformin group had a 20% reduction in the risk of GDM development compared
with the control group, as shown in [Table 3].
Table 3
Absolute risk reduction in the incidence of gestational diabetes mellitus with metformin
in obese pregnant women
|
Group
|
N (%)
|
P value
|
|
Gestational diabetes mellitus
|
Metformin
|
13 (15.9)
|
0.683
|
|
Control
|
16 (19.5)
|
|
Absolute risk reduction (95%CI)
|
NNT
|
|
3.6% (-0.08–0.15)
|
25
|
Abbreviation: NNT, number needed to treat; 95%CI, 95% confidence interval.
Discussion
The present study demonstrated that none of the groups (control or metformin) influenced
the BMI increase between gestational weeks ≤ 20 and 24–28, and that the efficacy of
metformin in preventing the development of GDM in obese pregnant women was not significant.
The general characteristics of the participants in each group showed no significant
differences, except for GA at the first visit. Similar findings have been observed
regarding maternal characteristics and obstetric history in a clinical trial with
202 obese pregnant women treated with metformin.[11] Another study with 43 pregnant women, which assessed the glycemic control with metformin
during pregnancy in GDM, also found no significant differences in demographic characteristics
among the groups.[18]
The relationship between the pharmacodynamics and pharmacokinetic mechanisms of metformin
has not been well elucidated in the scientific literature yet, especially concerning
the effect of these mechanisms on obese pregnant women. However, studies have demonstrated
the ability of metformin to activate the AMP-activated protein kinase (AMPK), a protein
involved in the control of body energy and a metabolic substrate, helping to reduce
the BMI.[13]
[14]
[15]
[16]
[17]
[18]
[19] Several studies have shown fewer BMI changes among obese women with GDM treated
with this drug.[20]
[21]
[22]
The results of the present study identified that participants in both control and
metformin groups showed no significant increase in BMI between gestational weeks ≤ 20
and 24–28. The combination of metformin with lifestyle changes represents a potentially
effective and safe approach to obesity control.[14] According to Fattah et al,[15] metformin limits the weight gain throughout pregnancy. A similar finding has been
reported in a clinical trial by Syngelaki et al,[11] in which obese women without GDM taking prophylactic metformin for 12–18 weeks until
delivery achieved lower weight gain during pregnancy, in contrast to the findings
of the present study.
Of note, both groups received diet and physical activity counseling in the present
study. According to the literature, adherence to these preventive practices by women
before, during, and after pregnancy is effective in controlling BMI and blood glucose,
and reducing the incidence of GDM.[23]
[24] Promising results in GDM prevention have been observed among obese women adhering
to nutritional counseling recommendations.[25]
[26]
Physical activity performed early in pregnancy has a beneficial effect in reducing
the risk of GDM in obese women.[27]
[28] Among the participants performing physical activity in the present study, GDM developed
in 15.9% of those in the metformin group and 19.5% of those in the control group.
Depending on the diagnostic criteria applied, GDM has an incidence between 3 and 25%,
according to the Brazilian Society of Diabetes.[5] A multicenter, prospective study performed in nine European countries compared different
approaches to prevent GDM among obese women; the study found that 14% of the women
developed GDM between 24 and 28 weeks of gestation, regardless of the interventions
used.[29] These findings are similar to those in the present study.
Women presenting with increased BMI, elevated fasting blood glucose level, and glucose
intolerance have an increased short- and long-term risk of developing diabetes mellitus.
However, according to the results of a study assessing the impact of lifestyle and
metformin interventions over 10 years in women with a history of GDM in 27 clinical
centers,[30] this risk can be substantially reduced with lifestyle changes and use of metformin.
In the present study, 15.9% of the participants treated with metformin along with
diet and physical activity developed GDM. Of note, lifestyle changes must take place
during pregnancy to reduce the risk of GDM occurring before the 15th week of gestation in women with obesity.[27]
[31]
The differences in the results of the OGTT, performed in both control and metformin
groups, were not significant. However, other studies with GDM women support the treatment
of GDM with metformin, without an increased risk of maternal hypoglycemia.[13]
[32]
[33]
[34]
[35] In the present study, metformin was administered at a dosage of 1,000 mg twice daily.
This dose of 1,000 mg is different from the one used in another study with 104 pregnant
women treated with 500 to 2,500 mg of metformin, in which the drug was effective in
controlling blood glucose levels during pregnancy.[18] A clinical trial with 132 pregnant women also treated with metformin 500–2,500 mg
also obtained blood glucose control at 28 weeks of gestation.[6] In contrast, a clinical trial with 100 pregnant women treated with metformin 500–1,500 mg
found no significant difference in glycemic control.[15]
Studies performed with pregnant women with polycystic ovary syndrome (PCOS) who underwent
lifestyle changes combined with treatment with metformin have shown a relationship
between lower BMI increase and improvements in metabolic rate and glycemic control.
Of note, metformin has been used for some time in patients with PCOS with promising
results when treatment is initiated before pregnancy.[35]
This study offers a new perspective in GDM prevention in obese women and is aligned
with recommendations by other authors describing that prevention, detection, control,
and early access to therapy are fundamental and necessary interventions to reduce
the occurrence of GDM.[36]
Conclusion
Limitations of this study include the reduced number of pregnant women randomized
to each group and the effectiveness of dietary intervention and physical activity.
The study lacks high-quality evidence to offer significant conclusions regarding the
benefits of the use of metformin in relation to diet and physical activity since a
group without intervention was not used. Further studies are suggested to confirm
the efficacy of metformin in a larger number of obese pregnant women in several centers
throughout the country and with a metformin dose similar to that used in international
clinical trials.
