Match!

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 & Endocrinology24.54
· DOI :10.1016/S2213-8587(19)30002-6
Tone Shetelig Løvvik3
Estimated H-index: 3
(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)
Sources
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 (3)
📖 Papers frequently viewed together
8 Citations
5 Citations
103 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References32
Newest
#1Jodie M. Dodd (University of Adelaide)H-Index: 36
#2Jennie Louise (University of Adelaide)H-Index: 6
Last. William M. Hague (University of Adelaide)H-Index: 28
view all 7 authors...
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 ...
5 CitationsSource
#1Joanne Given (Ulster University)H-Index: 6
#2Maria Loane (Ulster University)H-Index: 32
Last. Helen Dolk (Ulster University)H-Index: 52
view all 14 authors...
Abstract Objective To investigate whether exposure to metformin during the first trimester of pregnancy, for diabetes or other indications, increases the risk of all or specific congenital anomalies. Design Population based exploratory case-control study using malformed controls. Cases of 29 specific subgroups of non-genetic anomalies, and all non-genetic anomalies combined, were compared with controls (all other non-genetic anomalies or genetic syndromes). Setting 11 EUROmediCAT European congen...
12 CitationsSource
#1Liv Guro Engen Hanem (NTNU: Norwegian University of Science and Technology)H-Index: 3
#2Solhild Stridsklev (NTNU: Norwegian University of Science and Technology)H-Index: 4
Last. Eszter Vanky (NTNU: Norwegian University of Science and Technology)H-Index: 19
view all 8 authors...
40 CitationsSource
#1Tuğba Adak (Hacettepe University)H-Index: 1
#2Afshin Samadi (Hacettepe University)H-Index: 2
Last. Suna Sabuncuoğlu (Hacettepe University)H-Index: 7
view all 4 authors...
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...
15 CitationsSource
#1Mariana Teixeira da Trindade (UNESP: Sao Paulo State University)H-Index: 2
#2Ana Carolina Kogawa (UNESP: Sao Paulo State University)H-Index: 7
Last. Hérida Regina Nunes Salgado (UNESP: Sao Paulo State University)H-Index: 20
view all 3 authors...
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...
6 CitationsSource
#1E. Valdes (University of Chile)H-Index: 5
#2Alvaro Sepúlveda-Martínez (University of Chile)H-Index: 5
Last. Eduardo CuellarH-Index: 1
view all 7 authors...
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 CitationsSource
#1Anna Hjorth-Hansen (Levanger Hospital)H-Index: 1
#2Øyvind Salvesen (NTNU: Norwegian University of Science and Technology)H-Index: 23
Last. Rønnaug Ødegård (NTNU: Norwegian University of Science and Technology)H-Index: 11
view all 7 authors...
11 CitationsSource
#1Jiao WangH-Index: 2
#2Lingyan ZhuH-Index: 4
Last. Ji-Xiong XuH-Index: 4
view all 7 authors...
1 CitationsSource
#1Hai-Feng YuH-Index: 1
#2Hong-Su ChenH-Index: 1
Last. Jian GongH-Index: 1
view all 4 authors...
AbstractBackground: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 complicatio
38 CitationsSource
#1Amy R. Cameron (Dund.: University of Dundee)H-Index: 6
#2Vicky L. Morrison (Glas.: University of Glasgow)H-Index: 11
Last. Graham Rena (Dund.: University of Dundee)H-Index: 21
view all 16 authors...
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...
91 CitationsSource
Cited By3
Newest
#1Eszter Vanky (NTNU: Norwegian University of Science and Technology)H-Index: 19
#2Tone Shetelig Løvvik (NTNU: Norwegian University of Science and Technology)H-Index: 3
Abstract For decades, infertility and metabolic health challenges have been the main concerns for women diagnosed with polycystic ovary syndrome (PCOS). Poorer pregnancy outcomes and obstetric complications have only recently been recognized as concerns for women with PCOS. Women diagnosed with PCOS are more often overweight and obese, and the prevalence of pregnancy complications in PCOS is influenced by several co-factors such as BMI, co-morbidities, and ethnicity. The most frequently reported...
Source
#1Hanne Klæboe Greger (NTNU: Norwegian University of Science and Technology)H-Index: 4
Last. Eszter Vanky (NTNU: Norwegian University of Science and Technology)H-Index: 19
view all 4 authors...
BACKGROUND: Metformin is widely used in pregnancy to treat gestational diabetes mellitus and polycystic ovary syndrome (PCOS). Association between PCOS and developmental delay in offspring, and larger head circumference of metformin-exposed newborns has been reported. The objective of this study was to explore whether metformin exposure in utero had any effect on offspring cognitive function. METHOD: The current study is a follow-up of two randomized, placebo-controlled studies which were conduc...
Source
#1Suhail A. R. Doi (Qatar University)H-Index: 31
#2Luis Furuya-Kanamori (Qatar University)H-Index: 13
Last. Lukman Thalib (College of Health Sciences, Bahrain)H-Index: 31
view all 7 authors...
Previous randomized and observational studies on the efficacy of metformin in pregnancy to reduce incident gestational diabetes mellitus (GDM) in women at high risk (obesity, polycystic ovary syndrome [PCOS], or pregestational insulin resistance) have been conflicting and several groups are planning further randomized controlled trials (RCTs) to answer this question conclusively. This work assesses the efficacy of metformin in pregnancy to avert one outcome—incident GDM in women at high risk. We...
1 CitationsSource
#1Rachel Blair (Harvard University)H-Index: 1
#2Emily A. Rosenberg (Harvard University)
Last. Nadine E. Palermo (Harvard University)H-Index: 3
view all 3 authors...
Purpose of Review To assess evidence to date for use of non-insulin agents in treatment of gestational diabetes mellitus.
Source
#1Carolyn E. Cesta (KI: Karolinska Institutet)H-Index: 4
#2Jacqueline M. Cohen (FHI: Norwegian Institute of Public Health)H-Index: 15
Last. Ingvild Odsbu (KI: Karolinska Institutet)H-Index: 9
view all 20 authors...
Objective Diabetes in pregnancy and consequently the need for treatment with antidiabetic medication (ADM) has become increasingly prevalent. The prevalence and patterns of use of ADM in pregnancy from 2006 onward in seven different countries was assessed. Research design and methods Data sources included individually linked data from the nationwide health registers in Denmark (2006–2016), Finland (2006–2016), Iceland (2006–2012), Norway (2006–2015), Sweden (2006–2015), state-wide administrative...
Source
#1Beata Banaszewska (Poznan University of Medical Sciences)H-Index: 10
#2Leszek Pawelczyk (Poznan University of Medical Sciences)H-Index: 12
Last. Robert Z. Spaczynski (Poznan University of Medical Sciences)H-Index: 19
view all 3 authors...
Abstract Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age. PCOS is characterized by hyperandrogenism, menstrual disorders, and polycystic ovarian morphology. PCOS patients have an increased risk of type 2 diabetes, cardiovascular disease, and infertility. The mechanism of PCOS is not yet fully understood, but insulin resistance and genetic factors may play distinct roles in the pathomechanism. There is ongoing research on new therapeutic modalities for wom...
1 CitationsSource
Source
#1Lourdes Ibáñez (University of Barcelona)H-Index: 57
#2Francis de Zegher (Katholieke Universiteit Leuven)H-Index: 67
Source
#1John A. Barry (UCL: University College London)H-Index: 11
It is popularly thought that stress can have a negative impact on fertility, but what is the evidence for this? In this chapter, the ways in which psychology and biology can interact to impact fertility are described. This chapter also assesses the impact of PCOS on sexual functioning and satisfaction, and explores evidence for how oral contraceptives—often prescribed in PCOS—might impact psychological functioning.
Source