Metformin versus placebo in obese pregnant women without diabetes mellitus
Abstract
BACKGROUND: Obesity is associated with an increased risk of adverse pregnancy outcomes. Lifestyle-intervention studies have not shown improved outcomes. Metformin improves insulin sensitivity and in pregnant patients with gestational diabetes it leads to less weight gain than occurs in those who do not take metformin. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned pregnant women without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of more than 35 to receive metformin, at a dose of 3.0 g per day, or placebo (225 women in each group) from 12 to 18 weeks of gestation until delivery. The BMI was calculated at the time of study entry (12 to 18 weeks of gestation). The primary outcome was a reduction in the median neonatal birth-weight z score by 0.3 SD (equivalent to a 50% reduction, from 20% to 10%, in the incidence of large-for-gestational-age neonates). Secondary outcomes included maternal gestational weight gain and the incidence of gestational diabetes and of preeclampsia, as well as the incidence of adverse neonatal outcomes. Randomization was performed with the use of computer-generated random numbers. The analysis was performed according to the intention-to-treat principle. RESULTS: A total of 50 women withdrew consent during the trial, which left 202 women in the metformin group and 198 in the placebo group. There was no significant between-group difference in the median neonatal birth-weight z score (0.05 in the metformin group [interquartile range, -0.71 to 0.92] and 0.17 in the placebo group [interquartile range, -0.62 to 0.89], P=0.66). The median maternal gestational weight gain was lower in the metformin group than in the placebo group (4.6 kg [interquartile range, 1.3 to 7.2] vs. 6.3 kg [interquartile range, 2.9 to 9.2], P<0.001), as was the incidence of preeclampsia (3.0% vs. 11.3%; odds ratio, 0.24; 95% confidence interval, 0.10 to 0.61; P=0.001). The incidence of side effects was higher in the metformin group than in the placebo group. There were no significant between-group differences in the incidence of gestational diabetes, large-for-gestational-age neonates, or adverse neonatal outcomes. CONCLUSIONS: Among women without diabetes who had a BMI of more than 35, the antenatal administration of metformin reduced maternal weight gain but not neonatal birth weight. (Funded by the Fetal Medicine Foundation; ClinicalTrials.gov number, NCT01273584; EudraCT number, 2008-005892-83.).
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In the Fetal Medicine Foundation trial, almost 80% of women took at least 50% of the total number of tablets prescribed.
“In the Fetal Medicine Foundation trial, almost 80% of women took at least 50% of the total number of tablets prescribed, and 91% of those prescribed more than 2.5 g/day did so(96).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [96]
In the Fetal Medicine Foundation trial, women were treated with a higher starting and maximum dose of metformin than in the EMPOWaR trial.
“In the Fetal Medicine Foundation trial, women had a higher BMI (>35 kg/m2 vs. >30 kg/m2), were treated with a higher starting and maximum dose of metformin, and were more compliant than women in the EMPOWaR trial(95, 96).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [96]
In the Fetal Medicine Foundation trial, metformin significantly reduced the frequency of preeclampsia.
“Although metformin did not reduce the frequency of LGA neonates, it significantly reduced the frequency of preeclampsia and maternal weight gain, although not the rate of gestational diabetes(96).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [96]
47% (400/844) of eligible women were recruited to the Fetal Medicine Foundation study.
“It is also noteworthy that only 13% (443/3329) of eligible patients consented to participate in the EMPOWaR study, whereas 47% (400/844) of eligible women were recruited to the Fetal Medicine Foundation study, making the latter group more representative of women who meet the study’s eligibility criteria and to whom the study’s results apply.”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [96]
In the Fetal Medicine Foundation trial, 91% of those prescribed more than 2.5 g/day took at least 50% of the total number of tablets prescribed.
“In the Fetal Medicine Foundation trial, almost 80% of women took at least 50% of the total number of tablets prescribed, and 91% of those prescribed more than 2.5 g/day did so(96).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [96]
In the Fetal Medicine Foundation trial, metformin did not reduce the rate of gestational diabetes.
“Although metformin did not reduce the frequency of LGA neonates, it significantly reduced the frequency of preeclampsia and maternal weight gain, although not the rate of gestational diabetes(96).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [96]
In the Fetal Medicine Foundation trial, metformin did not reduce the frequency of LGA neonates.
“Although metformin did not reduce the frequency of LGA neonates, it significantly reduced the frequency of preeclampsia and maternal weight gain, although not the rate of gestational diabetes(96).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [96]
In the Fetal Medicine Foundation trial, women had a higher BMI (>35 kg/m2 vs. >30 kg/m2) than in the EMPOWaR trial.
“In the Fetal Medicine Foundation trial, women had a higher BMI (>35 kg/m2 vs. >30 kg/m2), were treated with a higher starting and maximum dose of metformin, and were more compliant than women in the EMPOWaR trial(95, 96).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [96]
In the Fetal Medicine Foundation trial, metformin significantly reduced maternal weight gain.
“Although metformin did not reduce the frequency of LGA neonates, it significantly reduced the frequency of preeclampsia and maternal weight gain, although not the rate of gestational diabetes(96).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [96]
In the Fetal Medicine Foundation trial, women were more compliant than women in the EMPOWaR trial.
“In the Fetal Medicine Foundation trial, women had a higher BMI (>35 kg/m2 vs. >30 kg/m2), were treated with a higher starting and maximum dose of metformin, and were more compliant than women in the EMPOWaR trial(95, 96).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [96]
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- Authors
- Syngelaki, A., Nicolaides, K. H., Balani, J., Hyer, S., Akolekar, R., Kotecha, R., Pastides, A., & Shehata, H.
- Affiliations
- Epsom and St Helier University Hospitals NHS Trust (GB)
- Harris Birthright Research Centre for Fetal Medicine (GB)
- St Helier Hospital (GB)
- Medway Maritime Hospital (GB)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-02-04
- Volume
- 374
- Issue
- 5
- Pages
- 434-443
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2253351763
- Cited by
- 394
- References
- 33
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 31 · 2023: 25 · 2022: 31 · 2021: 27 · 2020: 39 · 2019: 35 · 2018: 51 · 2017: 90 · 2016: 21
- FWCI
- 84.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Keywords
- metformin, maternal obesity, pregnancy, gestational weight gain, birth weight, large-for-gestational-age neonates, preeclampsia, gestational diabetes mellitus, insulin sensitivity, adverse pregnancy outcomes, placental growth factor, placental protein 13
- MeSH terms
- Adult, Birth Weight, Double-Blind Method, Female, Fetal Macrosomia, Humans, Hypoglycemic Agents, Infant, Newborn, Metformin, Obesity, Pregnancy, Pregnancy Complications, Weight Gain, Body Mass Index, Medication Adherence
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