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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 24.54
· DOI :10.1016/S2213-8587(19)30002-6
Tone Shetelig Løvvik2
Estimated H-index: 2
(NTNU: Norwegian University of Science and Technology),
Sven M. Carlsen23
Estimated H-index: 23
(NTNU: Norwegian University of Science and Technology)
+ 16 AuthorsEszter Vanky19
Estimated H-index: 19
(NTNU: Norwegian University of Science and Technology)
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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 (32)
  • Citations (2)
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References32
Newest
Published on Jan 1, 2019in The Lancet Diabetes & Endocrinology 24.54
Jodie M Dodd34
Estimated H-index: 34
(University of Adelaide),
Jennie Louise5
Estimated H-index: 5
(University of Adelaide)
+ 4 AuthorsWilliam M. Hague25
Estimated H-index: 25
(University of Adelaide)
Summary Background Maternal overweight and obesity are associated with well recognised pregnancy complications. Antenatal dietary and lifestyle interventions have a modest effect on gestational weight gain without affecting pregnancy outcomes. We aimed to assess the effects on maternal and infant outcomes of antenatal metformin given in addition to dietary and lifestyle advice among overweight and obese pregnant women. Methods GRoW was a multicentre, randomised, double-blind, placebo-controlled ...
4 Citations Source Cite
Published on Apr 1, 2018in The Journal of Clinical Endocrinology and Metabolism 5.61
Liv Guro Engen Hanem3
Estimated H-index: 3
(NTNU: Norwegian University of Science and Technology),
Solhild Stridsklev4
Estimated H-index: 4
(NTNU: Norwegian University of Science and Technology)
+ 5 AuthorsEszter Vanky19
Estimated H-index: 19
(NTNU: Norwegian University of Science and Technology)
36 Citations Source Cite
Published on Feb 1, 2018in Regulatory Toxicology and Pharmacology 3.00
Tuğba Adak1
Estimated H-index: 1
(Hacettepe University),
Afshin Samadi2
Estimated H-index: 2
(Hacettepe University)
+ 1 AuthorsSuna Sabuncuoğlu7
Estimated H-index: 7
(Hacettepe University)
Abstract This review investigates the different biological effect of Metformin (MET) in different conditions. MET is an oral antidiabetic drug used for the treatment of type 2 diabetes mellitus (T2DM) particularly in overweight people. The main mechanism of action of the MET is inhibition of hepatic glucose production and reduction of insulin resistance. In addition to its antidiabetic effects, MET is also found to be related with the risk for development of several human solid cancers types suc...
13 Citations Source Cite
Published on Jan 2, 2018in Critical Reviews in Analytical Chemistry 4.33
Mariana Teixeira da Trindade2
Estimated H-index: 2
(UNESP: Sao Paulo State University),
Ana Carolina Kogawa6
Estimated H-index: 6
(UNESP: Sao Paulo State University),
Hérida Regina Nunes Salgado19
Estimated H-index: 19
(UNESP: Sao Paulo State University)
ABSTRACTDiabetes mellitus (DM) is considered a public health problem. The initial treatment consists of improving the lifestyle and making changes in the diet. When these changes are not enough, the use of medication becomes necessary. The metformin aims to reduce the hepatic production of glucose and is the preferred treatment for type 2. The objective is to survey the characteristics and properties of metformin, as well as hold a discussion on the existing analytical methods to green chemistry...
5 Citations Source Cite
Published on Jan 1, 2018in Journal of Obstetrics and Gynaecology Research 1.12
E. Valdes5
Estimated H-index: 5
(University of Chile),
Alvaro Sepúlveda-Martínez5
Estimated H-index: 5
(University of Chile)
+ 4 AuthorsEduardo Cuellar1
Estimated H-index: 1
Aim We aimed to assess the use of metformin (MTF) in the prevention of gestational diabetes mellitus (GDM) in patients with pregestational insulin resistance (PIR). Methods A double blind, multicenter, randomized trial was carried out in patients with a history of PIR and pregestational MTF treatment. Groups were allocated either to MTF 1700 mg/day or placebo. Patients were recruited between 12+0 and 15+6 gestational weeks, and treatment was extended until week 36. A multiple logistic regression...
5 Citations Source Cite
Published on Nov 17, 2017in The Journal of Clinical Endocrinology and Metabolism 5.61
Anna Hjorth-Hansen1
Estimated H-index: 1
(Levanger Hospital),
Øyvind Salvesen22
Estimated H-index: 22
(NTNU: Norwegian University of Science and Technology)
+ 4 AuthorsRønnaug Ødegård10
Estimated H-index: 10
(NTNU: Norwegian University of Science and Technology)
10 Citations Source Cite
Published on Dec 1, 2016in Medicine 1.87
Hai-Feng Yu1
Estimated H-index: 1
,
Hong-Su Chen1
Estimated H-index: 1
+ 1 AuthorsJian Gong1
Estimated H-index: 1
Background: Polycystic ovary syndrome (PCOS) is inconsistently associated with increased risk of adverse pregnancy outcomes. The purpose of this meta-analysis was to summarize the evidence regarding the strength of the association between pregnancy in women with PCOS and pregnancy complications.
31 Citations Source Cite
Published on Aug 19, 2016in Circulation Research 15.86
Amy R. Cameron6
Estimated H-index: 6
(Dund.: University of Dundee),
Vicky L. Morrison10
Estimated H-index: 10
(Glas.: University of Glasgow)
+ 13 AuthorsAaron Wong8
Estimated H-index: 8
(Princess of Wales Hospital)
Rationale:The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood. Objective:Here, we have studied anti-inflammatory effects of the drug and their relationship to antihyperglycemic properties. Methods and Results:In primary hepatocytes from healthy animals, metformin and the IKKβ (inhibitor of kappa B kinase) inhibitor BI605906 both inhibited tumor necrosis factor-α–dependent IκB degrad...
78 Citations Source Cite
Published on Aug 1, 2016in Journal of Clinical Investigation 12.28
Wenbo Deng5
Estimated H-index: 5
,
Jeeyeon Cha13
Estimated H-index: 13
+ 7 AuthorsSudhansu K. Dey62
Estimated H-index: 62
Abstract Inflammation and oxidative stress are known risk factors for preterm birth (PTB); however, the mechanisms and pathways that influence this condition are not fully described. Previously, we showed that mTORC1 signaling is increased in mice harboring a uterine-specific deletion of transformation-related protein 53 (p53d/d mice), which exhibit premature decidual senescence that triggers spontaneous and inflammation-induced PTB. Treatment with the mTORC1 inhibitor rapamycin reduced the inci...
22 Citations Source Cite
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Published on Jun 1, 2019in European Journal of Endocrinology 5.11
Maria Othelie Underdal2
Estimated H-index: 2
,
Øyvind Salvesen22
Estimated H-index: 22
+ 2 AuthorsEszter Vanky19
Estimated H-index: 19
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Published on Apr 1, 2019in The Lancet Diabetes & Endocrinology 24.54
Lourdes Ibáñez56
Estimated H-index: 56
(University of Barcelona),
Francis de Zegher65
Estimated H-index: 65
(Katholieke Universiteit Leuven)
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