Metformin during ovulation induction with gonadotrophins followed by timed intercourse or intrauterine insemination for subfertility associated with polycystic ovary syndrome

Esmée M Bordewijk; Marleen Nahuis; Michael F Costello; Fulco Van der Veen; Leopoldo O Tso; Ben Willem J Mol; Madelon van Wely

doi:10.1002/14651858.CD009090.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 4

Forest plot of comparison: 1 dichotomous outcome, outcome: 1.1 live birth rate (per woman).

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Figure 5

Forest plot of comparison: 1 Metformin versus placebo co‐treatment for assisted reproduction, outcome: 1.2 Multiple pregnancy rate (per woman).

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Figure 6

Forest plot of comparison: 1 Metformin versus placebo co‐treatment for assisted reproduction, outcome: 1.3 Ongoing pregnancy rate (per woman).

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Figure 7

Forest plot of comparison: 1 Metformin versus placebo co‐treatment for assisted reproduction, outcome: 1.4 Clinical pregnancy rate.

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Analysis 1.1

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 1 Live birth rate (per woman).

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Analysis 1.2

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 2 Multiple pregnancy rate (per woman).

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Analysis 1.3

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 3 Ongoing pregnancy rate (per woman).

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Analysis 1.4

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 4 Clinical pregnancy rate.

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Analysis 1.5

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 5 Miscarriage rate (per clinical pregnancy).

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Analysis 1.6

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 6 Ovulation rate (per started cycle).

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Analysis 1.7

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 7 OHSS rate (per woman).

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Analysis 1.8

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 8 Cycle cancellation rate (per started cycle).

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Analysis 1.9

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 9 Adverse effects.

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Analysis 1.10

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 10 FSH dose per cycle.

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Analysis 1.11

Comparison 1 Metformin versus placebo co‐treatment for assisted reproduction, Outcome 11 Duration of stimulation days per cycle.

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Summary of findings for the main comparison. Metformin versus placebo co‐treatment for assisted reproduction for subfertility associated with polycystic ovary syndrome

Metformin versus placebo co‐treatment for assisted reproduction for subfertility associated with polycystic ovary syndrome
Patient or population: patients with subfertility associated with polycystic ovary syndrome Settings: outpatient Intervention: metformin vs placebo co‐treatment for assisted reproduction
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo co‐treatment	Metformin co‐treatment
Live birth rate (per woman) Follow‐up: 3‐6 months	267 per 1000	457 per 1000 190 more per 1000 (42 to 345)	OR 2.31 (1.24 to 4.33)	180 (2 studies)	⊕⊕⊝⊝ Low^a
Multiple pregnancy rate (per woman)	52 per 1000	26 per 1000 23 fewer per 1000 (44 fewer to 25 more)	OR 0.55 (0.15 to 1.95)	232 (4 studies)	⊕⊕⊝⊝ Low^a,b
Ongoing pregnancy rate (per woman)	217 per 1000	393 per 1000 189 more per 1000 (57 to 336)	OR 2.46 (1.36 to 4.46)	232 (4 studies)	⊕⊕⊝⊝ Low^a
Clinical pregnancy rate (per woman)	252 per 1000	444 per 1000 206 more per 1000 (78 to 340)	OR 2.51 (1.46 to 4.31)	264 (5 studies)	⊕⊕⊝⊝ Low^a
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aLimited sample size, limited precision, lack of blinding of participants and of outcome assessors. ^bMultiple pregnancy had a very low incidence.

Summary of findings for the main comparison. Metformin versus placebo co‐treatment for assisted reproduction for subfertility associated with polycystic ovary syndrome

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Comparison 1. Metformin versus placebo co‐treatment for assisted reproduction

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth rate (per woman) Show forest plot	2	180	Odds Ratio (M‐H, Random, 95% CI)	2.31 [1.23, 4.34]

2 Multiple pregnancy rate (per woman) Show forest plot	4	232	Odds Ratio (M‐H, Fixed, 95% CI)	0.55 [0.15, 1.95]

3 Ongoing pregnancy rate (per woman) Show forest plot	4	232	Odds Ratio (M‐H, Fixed, 95% CI)	2.46 [1.36, 4.46]

4 Clinical pregnancy rate Show forest plot	5	264	Odds Ratio (M‐H, Fixed, 95% CI)	2.51 [1.46, 4.31]

5 Miscarriage rate (per clinical pregnancy) Show forest plot	3	84	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.19, 2.01]

6 Ovulation rate (per started cycle) Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7 OHSS rate (per woman) Show forest plot	2	180	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 8.23]

8 Cycle cancellation rate (per started cycle) Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Adverse effects Show forest plot	2	90	Odds Ratio (M‐H, Fixed, 95% CI)	1.78 [0.39, 8.09]

10 FSH dose per cycle Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Totals not selected

11 Duration of stimulation days per cycle Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 1. Metformin versus placebo co‐treatment for assisted reproduction

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