Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial

Published on Apr 1, 2019in The Lancet Diabetes & Endocrinology 19.31
· DOI :10.1016/S2213-8587(19)30002-6
Tone Shetelig Løvvik2
Estimated H-index: 2
(Norwegian University of Science and Technology),
Sven M. Carlsen24
Estimated H-index: 24
(Norwegian University of Science and Technology)
+ 16 AuthorsEszter Vanky18
Estimated H-index: 18
(Norwegian University of Science and Technology)
Abstract
Summary Background Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy complications. Epi-analysis of two previous randomised controlled trials that compared metformin with placebo during pregnancy in women with PCOS showed a significant reduction in late miscarriages and preterm births in the metformin group. The aim of this third randomised trial (PregMet2) was to test the hypothesis that metformin prevents late miscarriage and preterm birth in women with PCOS. Methods PregMet2 was a randomised, placebo-controlled, double-blind, multicentre trial done at 14 hospitals in Norway, Sweden, and Iceland. Singleton pregnant women with PCOS aged 18–45 years were eligible for inclusion. After receiving information about the study at their first antenatal visit or from the internet, women signed up individually to participate in the study. Participants were randomly assigned (1:1) to receive metformin or placebo by computer-generated random numbers. Randomisation was in blocks of ten for each country and centre; the first block had a random size between one and ten to assure masking. Participants were assigned to receive oral metformin 500 mg twice daily or placebo during the first week of treatment, which increased to 1000 mg twice daily or placebo from week 2 until delivery. Placebo tablets and metformin tablets were identical and participants and study personnel were masked to treatment allocation. The primary outcome was the composite incidence of late miscarriage (between week 13 and week 22 and 6 days) and preterm birth (between week 23 and week 36 and 6 days), analysed in the intention-to-treat population. Secondary endpoints included the incidence of gestational diabetes, preeclampsia, pregnancy-induced hypertension, and admission of the neonate to the neonatal intensive care unit. We also did a post-hoc individual participant data analysis of pregnancy outcomes, pooling data from the two previous trials with the present study. The study was registered with ClinicalTrials.gov , number NCT01587378 , and EudraCT, number 2011-002203-15. Findings The study took place between Oct 19, 2012, and Sept 1, 2017. We randomly assigned 487 women to metformin (n=244) or placebo (n=243). In the intention-to-treat analysis, our composite primary outcome of late miscarriage and preterm birth occurred in 12 (5%) of 238 women in the metformin group and 23 (10%) of 240 women in the placebo group (odds ratio [OR] 0·50, 95% CI 0·22–1·08; p=0·08). We found no significant differences for our secondary endpoints, including incidence of gestational diabetes (60 [25%] of 238 women in the metformin group vs 57 [24%] of 240 women in the placebo group; OR 1·09, 95% CI 0·69–1·66; p=0·75). We noted no substantial between-group differences in serious adverse events in either mothers or offspring, and no serious adverse events were considered drug-related by principal investigators. In the post-hoc pooled analysis of individual participant data from the present trial and two previous trials, 18 (5%) of 397 women had late miscarriage or preterm delivery in the metformin group compared with 40 (10%) of 399 women in the placebo group (OR 0·43, 95% CI 0·23–0·79; p=0·004). Interpretation In pregnant women with PCOS, metformin treatment from the late first trimester until delivery might reduce the risk of late miscarriage and preterm birth, but does not prevent gestational diabetes. Funding Research Council of Norway, Novo Nordisk Foundation, St Olav's University Hospital, and Norwegian University of Science and Technology.
  • References (31)
  • Citations (1)
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References31
Tb Eilertsen1
Estimated H-index: 1
(Namsos Hospital),
Eszter Vanky18
Estimated H-index: 18
,
Sven M. Carlsen24
Estimated H-index: 24
(Norwegian University of Science and Technology)
Results Twenty-nine of 114 women (25.4%) met the PCOS criteria among women with preterm birth, compared with 18 of 127 (14.2%) among controls (P = 0.03). Eight (7.1%) women with preterm birth were diagnosed with diabetes compared with none in the control group (P < 0.01). Hirsutism was present in 34 (29.8%) women with preterm birth versus 12 (9.4%) in the control group (P < 0.01). Conclusions The prevalences of PCOS, diabetes and hirsutism are increased among women with a history of preterm birt...
12 Citations Source Cite
Published on Sep 1, 2015in Human Reproduction Update 11.85
Negar Naderpoor7
Estimated H-index: 7
(Monash University),
Soulmaz Shorakae6
Estimated H-index: 6
(Monash University)
+ 3 AuthorsHelena Teede47
Estimated H-index: 47
(University of Adelaide)
Abstract Polycystic ovary syndrome (PCOS) is a common endocrine disorder with diverse reproductive and metabolic features. It is underpinned by insulin resistance that is exacerbated by obesity. Lifestyle modification is the first line treatment in PCOS, but it is associated with low adherence and sustainability. In small studies, metformin improves outcomes such as hyperinsulinaemia, ovulation and menstrual cyclicity. We conducted a systematic review and meta-analysis to compare the effect of l...
72 Citations Source Cite
Published on Jun 1, 2011in American Journal of Obstetrics and Gynecology 5.73
Lucinda E. Kjerulff1
Estimated H-index: 1
(University of Florida),
Luis Sanchez-Ramos31
Estimated H-index: 31
(University of Florida),
Daniel Duffy1
Estimated H-index: 1
(University of Florida)
Objective The purpose of this study was to examine which maternal and neonatal complications are associated with polycystic ovary syndrome (PCOS) in pregnant women. Study Design The studies that were included compared pregnancy outcomes between women with PCOS and those without diagnosed PCOS. Our primary outcomes included gestational diabetes mellitus, pregnancy-induced hypertension, and preeclampsia. Secondary outcomes included cesarean delivery rates, operative vaginal delivery rates, preterm...
110 Citations Source Cite
Kristian J. Fougner15
Estimated H-index: 15
,
Eszter Vanky18
Estimated H-index: 18
(Norwegian University of Science and Technology),
Sven M. Carlsen24
Estimated H-index: 24
(Norwegian University of Science and Technology)
Objective. Previous non‐randomized and uncontrolled studies indicate major metformin effects on glucose homeostasis in pregnant women with polycystic ovary syndrome (PCOS). We investigated metformin effects on glucose homeostasis in a prospective controlled study. Material and methods. Forty pregnant women with PCOS and without known diabetes mellitus were included in the first trimester and randomized to either metformin 850 mg twice daily or placebo. Outcome measures were fasting glucose and i...
24 Citations Source Cite
Eszter Vanky18
Estimated H-index: 18
,
Solhild Stridsklev4
Estimated H-index: 4
+ 16 AuthorsKarin Flo2
Estimated H-index: 2
(University of Tromsø)
Context: Metformin is widely prescribed to pregnant women with polycystic ovary syndrome (PCOS) in an attempt to reduce pregnancy complications. Metformin is not approved for this indication, and evidence for this practice is lacking. Objectives: Our objective was to test the hypothesis that metformin, from first trimester to delivery, reduces pregnancy complications in women with PCOS. Design and Setting: We conducted a randomized, placebo-controlled, double-blind, multicenter study at 11 secon...
163 Citations Source Cite
Jennifer Zeitlin40
Estimated H-index: 40
(Pierre-and-Marie-Curie University),
Katarzyna Szamotulska7
Estimated H-index: 7
+ 7 AuthorsBéatrice Blondel40
Estimated H-index: 40
(Pierre-and-Marie-Curie University)
Objective To investigate time trends in preterm birth in Europe by multiplicity, gestational age, and onset of delivery. Design Analysis of aggregate data from routine sources. Setting Nineteen European countries. Population Live births in 1996, 2000, 2004, and 2008. Methods Annual risk ratios of preterm birth in each country were estimated with year as a continuous variable for all births and by subgroup using log-binomial regression models. Main outcome measures Overall preterm birth rate and ...
112 Citations Source Cite
Published on Mar 1, 2004in Fertility and Sterility 4.80
Paul Claman23
Estimated H-index: 23
(University of Ottawa)
Abstract There is accumulating evidence that workplace exposure to toxic substances contributes to male infertility. Men suffering from infertility problems may do well to look at their occupations, where exposure to certain substances may be a contributory factor, if not a direct cause, of infertility. Most of the studies to date are either case reports or epidemiological studies (population-based, case-control, or cohort studies). Additional, controlled studies need to be done to ascertain the...
1,921 Citations Source Cite
Published on Jan 1, 2008in Seminars in Reproductive Medicine 2.67
Carolien M. Boomsma13
Estimated H-index: 13
,
Bart C.J.M. Fauser76
Estimated H-index: 76
,
Nick S. Macklon51
Estimated H-index: 51
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. There is an increasing body of evidence indicating that PCOS may have significant implications for pregnancy outcomes and long-term health of a woman and her offspring. Whether or not PCOS itself or the symptoms that coincide with PCOS, like obesity and fertility treatment, are responsible for these increased risks is a continuing matter of debate. Miscarriage rates among women with PCOS are beli...
109 Citations Source Cite
Yasushi Hirota28
Estimated H-index: 28
,
Jeeyeon Cha13
Estimated H-index: 13
+ 2 AuthorsSudhansu K. Dey65
Estimated H-index: 65
Although preterm delivery is a major global health issue, its causes and underlying mechanism remain elusive. Using mutant mice, mimicking aspects of human preterm birth, we show here that uterine decidual senescence early in pregnancy via heightened mammalian target of rapamycin complex 1 (mTORC1) signaling is a significant contributor of preterm birth and fetal death, and that these adverse phenotypes are rescued by a low dose of rapamycin, an inhibitor of mTORC1 signaling. This role of mTORC1...
63 Citations Source Cite
Published on Sep 1, 2010in Annals of the New York Academy of Sciences 4.28
Evanthia Diamanti-Kandarakis47
Estimated H-index: 47
(National and Kapodistrian University of Athens),
Frangiskos Economou6
Estimated H-index: 6
(National and Kapodistrian University of Athens)
+ 1 AuthorsCharikleia Christakou10
Estimated H-index: 10
(National and Kapodistrian University of Athens)
Polycystic ovary syndrome (PCOS) affects 6.6–6.8% of women in reproductive age. Insulin resistance and hyperinsulinemia play a critical role in the pathogenesis of PCOS and are associated with a high risk for type 2 diabetes mellitus and cardiometabolic abnormalities. Metformin has been introduced as a therapeutic option in PCOS, targeting of cardiometabolic and reproductive abnormalities on the basis of its action on the reduction of glucose levels and the attenuation of insulin resistance. The...
57 Citations Source Cite