Evidence map›Metformin × pregnancy & neonatal›PMID 22592687›Full record

SynthesisThe Cochrane database of systematic reviews2012

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.

Thomas Tang, Jonathan M Lord, Robert J Norman, Ephia Yasmin, Adam H Balen

Registry-linked trialOpen access · greenAbstract readMeta-AnalysisSystematic Review
PubMed Publisher
In one paragraph

Synthesis in The Cochrane database of systematic reviews, 2012. The graph read 7 numbers from its abstract, feeding 2 cells of the map: it supports the treatment in 1, finds no clear difference in 1. It is linked to trial NCT04881851 (Effects of Inositol Alone or Associated With Alpha-lipoic Acid in Polycystic Ovary Syndrome Treatment), which is not on this map. Cited by 114 papers, 18 of them syntheses that pooled it.

7numbers the graph read from it
2cells of the map it votes in
114citing papers in PubMed, 18 pooled it
76.1field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

← favours the treatmentfavours the comparator →
0.250.524101 · no effect
Clinical pregnancy ratesmetformin and clomiphene vs clomiphene alonefavours the comparator · gdm, t2dfeeds one cell of the map
OR 1.511.17 to 1.96
However, clinical pregnancy rates were improved for metformin versus placebo (pooled OR 2.31, 95% CI 1.52 to 3.51, 8 trials, 707 women) and for metformin and clomiphene versus clomiphene alone (pooled OR 1.51, 95% CI 1.17 to 1.96, 11 trials, 1208 women).
FeedsMetformin×pregnancy & neonatal
Incidence of gastrointestinal disturbancesmetformin vs placebofavours the comparator · gdm, t2dfeeds one cell of the map
OR 4.272.40 to 7.59
In the studies that compared metformin and clomiphene alone, there was evidence of an improved live birth rate (pooled OR 0.3, 95% CI 0.17 to 0.52, 2 trials, 500 women) and clinical pregnancy rate (pooled OR 0.34, 95% 0.21 to 0.55, 2 trials, 500 women) in the group of obese women who took clomiphene.Metformin was also associated with a significantly higher incidence of gastrointestinal disturbances than placebo (pooled OR 4.27, 95% CI 2.4 to 7.59, 5 trials, 318 women) but no serious adverse effects were reported.
FeedsMetformin×adverse events & safety
Clinical pregnancy rateclomiphene alone vs metformin and clomiphene, in obese womenfavours the treatment · gdm, t2dfeeds one cell of the map
OR 0.340.21 to 0.55
In the studies that compared metformin and clomiphene alone, there was evidence of an improved live birth rate (pooled OR 0.3, 95% CI 0.17 to 0.52, 2 trials, 500 women) and clinical pregnancy rate (pooled OR 0.34, 95% 0.21 to 0.55, 2 trials, 500 women) in the group of obese women who took clomiphene.Metformin was also associated with a significantly higher incidence of gastrointestinal disturbances than placebo (pooled OR 4.27, 95% CI 2.4 to 7.59, 5 trials, 318 women) but no serious adverse effects were reported.
FeedsMetformin×pregnancy & neonatal
Live birth rateclomiphene alone vs metformin and clomiphene, in obese womenfavours the treatment · gdm, t2dfeeds one cell of the map
OR 0.300.17 to 0.52
In the studies that compared metformin and clomiphene alone, there was evidence of an improved live birth rate (pooled OR 0.3, 95% CI 0.17 to 0.52, 2 trials, 500 women) and clinical pregnancy rate (pooled OR 0.34, 95% 0.21 to 0.55, 2 trials, 500 women) in the group of obese women who took clomiphene.Metformin was also associated with a significantly higher incidence of gastrointestinal disturbances than placebo (pooled OR 4.27, 95% CI 2.4 to 7.59, 5 trials, 318 women) but no serious adverse effects were reported.
FeedsMetformin×pregnancy & neonatal
Clinical pregnancy ratesmetformin vs placebofavours the comparator · gdm, t2dfeeds one cell of the map
OR 2.311.52 to 3.51
However, clinical pregnancy rates were improved for metformin versus placebo (pooled OR 2.31, 95% CI 1.52 to 3.51, 8 trials, 707 women) and for metformin and clomiphene versus clomiphene alone (pooled OR 1.51, 95% CI 1.17 to 1.96, 11 trials, 1208 women).
FeedsMetformin×pregnancy & neonatal
Live birth ratesmetformin in combination with clomiphene vs clomiphene alone (implied by context)no clear difference · gdm, t2dfeeds one cell of the map
OR 1.160.85 to 1.56
MAIN RESULTS: Forty-four trials (3992 women) were included for analysis, 38 of them using metformin and involving 3495 women.There was no evidence that metformin improved live birth rates, whether it was used alone (pooled OR 1.80, 95% CI 0.52 to 6.16, 3 trials, 115 women) or in combination with clomiphene (pooled OR 1.16, 95% CI 0.85 to 1.56, 7 trials, 907 women).

The authors add: There was no evidence that metformin improved live birth rates

FeedsMetformin×pregnancy & neonatal
Live birth ratesmetformin alone vs placebo or no treatment (implied by context of 'used alone' vs control)no clear difference · gdm, t2dfeeds one cell of the map
OR 1.800.52 to 6.16
MAIN RESULTS: Forty-four trials (3992 women) were included for analysis, 38 of them using metformin and involving 3495 women.There was no evidence that metformin improved live birth rates, whether it was used alone (pooled OR 1.80, 95% CI 0.52 to 6.16, 3 trials, 115 women) or in combination with clomiphene (pooled OR 1.16, 95% CI 0.85 to 1.56, 7 trials, 907 women).

The authors add: There was no evidence that metformin improved live birth rates

FeedsMetformin×pregnancy & neonatal

clause the extractor read what became the number

2 · Its place on the map

Where it lands on the map

Rows are treatments, columns are outcomes. The coloured squares are the cells this paper feeds, coloured by the vote it casts there. Click one to jump to what this paper adds to it.

supports the treatmentfavours the comparatorno clear differenceread, but no usable result
3 · What it changes

What it adds to each cell

For every cell the paper feeds: the belief in the claim with and without this paper, and this paper's estimate drawn against every other readable study in the cell. The ringed dot is this paper.

Metformin×pregnancy & neonatal

InconclusiveOpen on the map →What to test next →

3 readable studies in this cell: 0 favour the treatment, 3 find no difference, 0 favour the comparator.

Belief with this paper
0.00contested · 0 families support, 1 contradict · against placebo
Without itNot a counted family in this claim, so removing it changes nothing.
← favours the treatmentfavours the comparator →
1 · no effect
NCT02932475831 enrolled · 2017
OR 0.860.63 to 1.19
Association Between Metformin Use in Early Gestational or Type 2 Diabe…PMID 39236318 · 2024
OR 1.040.70 to 1.56

This paper's own estimate is on a different scale from the rest of the cell, so it is not drawn here.

Metformin×adverse events & safety

SupportsOpen on the map →What to test next →

22 readable studies in this cell: 8 favour the treatment, 8 find no difference, 6 favour the comparator.

Belief with this paper
0.27contested · 4 families support, 11 contradict · against placebo
Without itNot a counted family in this claim, so removing it changes nothing.
← favours the treatmentfavours the comparator →
0 · no effect
NCT017190031,413 enrolled · 2012
Adjusted mean -0.72-0.95 to -0.48
NCT018093271,186 enrolled · 2013
Δ -0.40-0.59 to -0.21
NCT022730501,136 enrolled · 2014
Δ -8.90-13.3 to -4.50
NCT01126580807 enrolled · 2010
Δ -0.22-0.36 to -0.08
NCT01023581784 enrolled · 2009
Δ -0.67-0.96 to -0.37
NCT00386100688 enrolled · 2006
Δ 1.47-14.8 to 20.8
NCT01217073685 enrolled · 2010
Δ 1.00-9.80 to 13.1
NCT01890122647 enrolled · 2013
Δ -0.68-0.89 to -0.47
NCT00727857600 enrolled · 2007
Δ 0.860.51 to 1.22
NCT01958671461 enrolled · 2013
Δ -2.60-13.1 to 8.10
NCT00328172302 enrolled · 2006
Δ -0.85-1.10 to -0.59
NCT01485614200 enrolled · 2012
Δ 2.40-10.0 to 14.9

This paper's own estimate is on a different scale from the rest of the cell, so it is not drawn here.

4 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT04881851 naterminatednot on this mapstarted 2015, after this paper: background citation

Effects of Inositol Alone or Associated With Alpha-lipoic Acid in Polycystic Ovary Syndrome Treatment

TypeinterventionalSponsorUniversita di VeronaRan2015 to 2025Enrolled76ConditionsPolycystic Ovary SyndromeArmsInositol + alpha lipoic acid, Inositol, Folic acid (placebo comparator)
5 · Its place in the literature

Who cites it

114 citing papers in PubMed, 18 syntheses or guidelines pooled it, 695 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Pooled it
  5. Pooled it
  6. Acupuncture for polycystic ovarian syndrome.The Cochrane database of systematic reviews · 2019
    Pooled it
  7. Pooled it
  8. Pooled it
  9. Pooled it
  10. Ovarian surgery for symptom relief in women with polycystic ovary syndrome.The Cochrane database of systematic reviews · 2017
    Pooled it
  11. Pooled it
  12. Pooled it
  13. Pooled it
  14. Pooled it
  15. Pooled it
  16. Pooled it
  17. Pooled it
  18. Pooled it
  19. Trial
  20. Feasibility and Acceptability of Metformin to Augment Low Milk Supply: A Pilot Randomized Controlled Trial.Journal of human lactation : official journal of International Lactation Consultant Association · 2019
    Trial

54 more citing papers are in PubMed but not listed here.

6 · The record

Corrections and comments

7 · Who and what money

Authors and funding

5 authors at 5 institutions in 2 countries.

Thomas TangObstetrics and Gynaecology, Bradford Teaching Hospitals NHS Trust, Bradford, UK.
Jonathan M Lord
Robert J Norman
Ephia Yasmin
Adam H Balen
Bradford Teaching Hospitals NHS Foundation Trust · GBLeeds General Infirmary · GBLeeds Teaching Hospitals NHS Trust · GBRoyal Cornwall Hospital · GBUniversity of Adelaide · AU

Funding

No grant is acknowledged in the PubMed record.

8 · The paper itself

Abstract

The marked sentences are the ones the graph read a number from.

backgroundPolycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation (anovulation), high levels of male hormones (hyperandrogenaemia) and high levels of insulin (hyperinsulinaemia secondary to increased insulin resistance). Hyperinsulinaemia is associated with an increase in cardiovascular risk and the development of diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating the features of PCOS, including anovulation.

objectivesTo assess the effectiveness of insulin-sensitising drugs in improving reproductive outcomes and metabolic parameters for women with PCOS. SEARCH

methodsWe searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 3rd Quarter 2011), CINAHL (October 2011), MEDLINE (January 1966 to October 2011), and EMBASE (January 1985 to October 2011). SELECTION CRITERIA: Randomised controlled trials of insulin sensitising drugs compared with either placebo, no treatment, or an ovulation induction agent for women with PCOS, menstrual disturbance and subfertility. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and trial quality, and extracted data. MAIN

resultsForty-four trials (3992 women) were included for analysis, 38 of them using metformin and involving 3495 women.There was no evidence that metformin improved live birth rates, whether it was used alone (pooled OR 1.80, 95% CI 0.52 to 6.16, 3 trials, 115 women) or in combination with clomiphene (pooled OR 1.16, 95% CI 0.85 to 1.56, 7 trials, 907 women). However, clinical pregnancy rates were improved for metformin versus placebo (pooled OR 2.31, 95% CI 1.52 to 3.51, 8 trials, 707 women) and for metformin and clomiphene versus clomiphene alone (pooled OR 1.51, 95% CI 1.17 to 1.96, 11 trials, 1208 women). In the studies that compared metformin and clomiphene alone, there was evidence of an improved live birth rate (pooled OR 0.3, 95% CI 0.17 to 0.52, 2 trials, 500 women) and clinical pregnancy rate (pooled OR 0.34, 95% 0.21 to 0.55, 2 trials, 500 women) in the group of obese women who took clomiphene.Metformin was also associated with a significantly higher incidence of gastrointestinal disturbances than placebo (pooled OR 4.27, 95% CI 2.4 to 7.59, 5 trials, 318 women) but no serious adverse effects were reported. AUTHORS'

conclusionsIn agreement with the previous review, metformin was associated with improved clinical pregnancy but there was no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the role of metformin in improving reproductive outcomes in women with PCOS appears to be limited.

Indexed as

Insulin ResistanceAnovulationClomipheneFemaleHumansHypoglycemic AgentsInfertility, FemaleInositolLive BirthMetforminOvulation InductionPolycystic Ovary SyndromePregnancyPregnancy RateRandomized Controlled Trials as TopicThiazolidinedionesClomipheneHypoglycemic AgentsInositolMetforminThiazolidinediones

Identifiers

PMID22592687
OpenAlexW2149842750

What OpenQuestion holds

Texttitle and abstract
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.