Pharmacological and non-pharmacological strategies for obese women with subfertility.

Clinicians primarily recommend weight loss for obese women seeking pregnancy. The effectiveness of interventions aimed at weight loss in obese women with subfertility is unclear.

To assess the effectiveness and safety of pharmacological and non-pharmacological strategies compared with each other, placebo, or no treatment for achieving weight loss in obese women with subfertility. Search methods We searched the CGF Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and AMED from inception to 18 August 2020. We also checked reference lists and contacted experts in the field for additional relevant papers. Selection criteria We included published and unpublished randomised controlled trials in which weight loss was the main goal of the intervention. Our primary effectiveness outcomes were live birth or ongoing pregnancy and primary safety outcomes were miscarriage and adverse events. Secondary outcomes included clinical pregnancy, weight change, quality of life, and mental health outcome. Data collection and analysis Review authors followed standard Cochrane methodology. Main results This review includes 10 trials. Evidence was of very low to low quality: the main limitations were due to lack of studies and poor reporting of study methods. The main reasons for downgrading evidence were lack of details by which to judge risk of bias (randomisation and allocation concealment), lack of blinding, and imprecision. Non-pharmacological intervention versus no intervention or placebo Evidence is insufficient to determine whether a diet or lifestyle intervention compared to no intervention affects live birth (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.65 to 1.11; 918 women, 3 studies; I/two.sups = 78%; low-quality evidence). This suggests that if the chance of live birth following no intervention is assumed to be 43%, the chance following diet or lifestyle changes would be 33% to 46%. We are Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews uncertain if lifestyle change compared with no intervention affects miscarriage rate (OR 1.54, 95% CI 0.99 to 2.39; 917 women, 3 studies; I/two.sups = 0%; very low-quality evidence). Evidence is insufficient to determine whether lifestyle change compared with no intervention affects clinical pregnancy (OR 1.06, 95% CI 0.81 to 1.40; 917 women, 3 studies; I/two.sups = 73%; low-quality evidence). Lifestyle intervention resulted in a decrease in body mass index (BMI), but data were not pooled due to heterogeneity in effect (mean difference (MD) -3.70, 95% CI -4.10 to -3.30; 305 women, 1 study; low-quality evidence; and MD -1.80, 95% CI -2.67 to -0.93; 43 women, 1 study; very low-quality evidence). Non-pharmacological versus non-pharmacological intervention We are uncertain whether intensive weight loss interventions compared to standard care nutrition counselling affects live birth (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low-quality evidence), clinical pregnancy (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low-quality evidence), BMI (MD -3.00, 95% CI -5.37 to -0.63; 11 women, 1 study; very low-quality evidence), weight change (MD -9.00, 95% CI -15.50 to -2.50; 11 women, 1 study; very low-quality evidence), quality of life (MD 0.06, 95% CI -0.03 to 0.15; 11 women, 1 study; very low-quality evidence), or mental health (MD -7.00, 95% CI -13.92 to -0.08; 11 women, 1 study; very low-quality evidence). No study reported on adverse events . Pharmacological versus pharmacological intervention For metformin plus liraglutide compared to metformin we are uncertain of an effect on the adverse events nausea (OR 7.22, 95% CI 0.72 to 72.7; 28 women, 1 study; very low-quality evidence), diarrhoea (OR 0.31, 95% CI 0.01 to 8.3; 28 women, 1 study; very low-quality evidence), and headache (OR 5.80, 95% CI 0.25 to 133; 28 women, 1 study; very low-quality evidence). We are uncertain if a combination of metformin plus liraglutide vs metformin affects BMI (MD 2.1, 95% CI -0.42 to 2.62; 28 women, 1 study; very low-quality evidence) and total body fat (MD -0.50, 95% CI -4.65 to 3.65; 28 women, 1 study; very low-quality evidence). For metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo, we are uncertain of an effect on miscarriage (OR 3.58, 95% CI 0.73 to 17.55; 274 women, 1 study; very low-quality evidence), clinical pregnancy (OR 5.56, 95% CI 2.57 to 12.02; 274 women, 1 study; very low-quality evidence) or BMI (MD -0.3, 95% CI 1.17 to 0.57, 274 women, 1 study, very low-quality evidence). We are uncertain if dexfenfluramine versus placebo affects weight loss in kilograms (MD -0.10, 95% CI -2.77 to 2.57; 21 women, 1 study; very low-quality evidence). No study reported on live birth, quality of life, or mental health outcomes. Pharmacological intervention versus no intervention or placebo We are uncertain if metformin compared with placebo affects live birth (OR 1.57, 95% CI 0.44 to 5.57; 65 women, 1 study; very low-quality evidence). This suggests that if the chance of live birth following placebo is assumed to be 15%, the chance following metformin would be 7% to 50%. We are uncertain if metformin compared with placebo affects gastrointestinal adverse events (OR 0.91, 95% CI 0.32 to 2.57; 65 women, 1 study; very low-quality evidence) or miscarriage (OR 0.50, 95% CI 0.04 to 5.80; 65 women, 1 study; very low-quality evidence) or clinical pregnancy (OR 2.67, 95% CI 0.90 to 7.93; 96 women, 2 studies; I/two.sups = 48%; very low-quality evidence). We are also uncertain if diet combined with metformin versus diet and placebo affects BMI (MD -0.30, 95% CI -2.16 to 1.56; 143 women, 1 study; very low-quality evidence) or waist-to-hip ratio (WHR) (MD 2.00, 95% CI -2.21 to 6.21; 143 women, 1 study; very low-quality evidence). Pharmacological versus non-pharmacological intervention No study undertook this comparison. Authors' conclusions Evidence is insufficient to support the use of pharmacological and non-pharmacological strategies for obese women with subfertility. No data are available for the comparison of pharmacological versus non-pharmacological strategies. We are uncertain whether pharmacological or non-pharmacological strategies effect live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life, or mental health outcomes. However, for obese women with subfertility, a lifestyle intervention may reduce BMI. Future studies should compare a combination of pharmacological and lifestyle interventions for obese women with subfertility. P L A I N /uni00A0 L A N G U A G E /uni00A0 S U M M A R Y Do pharmacological and non-pharmacological strategies reduce weight in obese women with subfertility? To assess the effectiveness and safety of pharmacological and non-pharmacological strategies compared with each other, placebo, or no treatment for weight reduction in obese women with subfertility.

To prevent the adverse effects of obesity, weight loss is recommended as the first line of treatment for obese women seeking pregnancy. The effectiveness of pharmacological and non-pharmacological interventions for obese women with subfertility is unclear. Study characteristics Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews We found 10 randomised trials comparing pharmacological and non-pharmacological strategies in 1490 obese women with subfertility. Key results Lack of data is a major concern in interpretation of these data. Only 10 studies were included in the analysis. Three studies compared non-pharmacological intervention versus no intervention or placebo. We are uncertain whether diet versus no intervention improves live birth, ongoing pregnancy, clinical pregnancy, or adverse events. A diet or lifestyle intervention may result in body mass index (BMI) weight change. Evidence was insufficient to show a difference in waist-to-hip ratio (WHR) with diet or lifestyle change compared to no intervention. No study reported on quality of life, or mental health outcomes for this comparison. One study compared non-pharmacological interventions - intensive weight loss intervention versus standard of care nutrition counselling; however due to the very low quality of evidence, we are uncertain whether intensive weight loss interventions improve live birth, clinical pregnancy, quality of life, or mental health outcomes. No study reported on adverse events, or weight changes, for this comparison. Three studies reported on pharmacological versus pharmacological interventions. Evidence was insufficient to show a difference in adverse events between metformin compared to metformin plus liraglutide. Evidence was insufficient to demonstrate a difference between the combination of metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo for miscarriage. Evidence was insufficient to reveal a difference between the combination of metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo or metformin plus liraglutide versus metformin in clinical pregnancy. Evidence was insufficient to demonstrate a difference between the combination of metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo for weight change using BMI. Moreover, evidence was insufficient to reveal a difference between dexfenfluramine versus placebo or metformin plus liraglutide versus metformin for weight loss in kilograms, or per cent of total body fat. No study reported on live birth and change in quality of life or mental health outcomes for this comparison. In the comparison of pharmacological intervention versus no intervention or placebo, three studies were included. Evidence was insufficient to show a difference between metformin and control groups related to live birth. Evidence was insufficient to reveal a difference between metformin compared to placebo in live birth, clinical pregnancy, or adverse events. Evidence was insufficient to demonstrate a difference between diet combined with metformin versus diet combined with placebo for weight change using BMI or WHR. No study reported on quality of life or mental health outcomes for this comparison. We found no study comparing non-pharmacological with pharmacological interventions. Quality of the evidence The evidence was of very low to low quality. The main limitations were due to lack of studies and poor reporting of study methods. The main reasons for downgrading of evidence were lack of details by which to judge risk of bias (randomisation and allocation concealment), lack of blinding, and imprecision. Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4 S U M M A R Y /uni00A0 O F /uni00A0 F I N D I N G S /uni00A0 Summary of findings 1. /uni00A0 Non-pharmacological intervention compared to no intervention or placebo for obese women with subfertility Non-pharmacological intervention compared to no intervention for obese women with subfertility Patient or population: obese women with subfertility Setting: hospital Intervention: non-pharmacological (diet and/or lifestyle changes) Comparison: no intervention Anticipated absolute effects* (95% CI)Outcomes Risk with non-pharmacological inter- vention Risk with no interven- tion Relative effect (95% CI) /uni2116. of partici- pants (studies) Certainty of evidence (GRADE) Comments Live birth 395 per 1000 (334 to 462) 431 per 1000 OR 0.85 (0.65 to 1.12) 917 (3 RCTs) ⊕⊕⊝⊝ lowa ,b /uni00A0 Ongoing pregnancy 536 per 1000 (453 to 617) 588 per 1000 OR 0.81 (0.58 to 1.13) 564 (1 RCT) ⊕⊕⊝⊝ lowc /uni00A0 Miscarriage 122 per 1000 (82 to 177) 83 per 1000 OR 1.54 (0.99 to 2.39) 917 (3 RCTs) ⊕⊝⊝⊝ very lowc ,d /uni00A0 Clinical pregnancy 529 per 1000 (458 to 594) 514 per 1000 OR 1.06 (0.81 to 1.40) 917 (3 RCTs) ⊕⊕⊝⊝ lowa ,b /uni00A0 Weight change BMI change (Einarsson 2017) MD 3.70 kg/m/two.sups lower (4.10 lower to 3.36 lower) Mean BMI change ranged from 0.04 to 0.7 kg/m/two.sups - 305 (1 RCT) ⊕⊕⊝⊝ lowc /uni00A0 BMI change (Sim 2014) MD 1.80 kg/m/two.sups lower (2.67 lower to 0.93 lower) Mean BMI change ranged from -1.3 to 0 kg/ m/two.sups - 43 (1 RCT) ⊕⊝⊝⊝ very lowc ,e /uni00A0 Quality of life/ Mental health out- come /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 No study re- ported this out- come *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial. Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 5 GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. aDowngraded one level for substantial heterogeneity: I/two.sups > 70%. bDowngraded one level for imprecision as reflected by the large confidence interval. cDowngraded two levels for serious imprecision. dDowngraded one level for indirectness due to differences in definition. eDowngraded one level for incomplete outcome data with an uneven dropout between groups. /uni00A0 /uni00A0 Summary of findings 2. /uni00A0 Non-pharmacological intervention compared to non-pharmacological intervention for obese women with subfertility Non-pharmacological intervention compared to non-pharmacological intervention for obese women with subfertility Patient or population: obese women with subfertility Setting: hospital Intervention: intensive weight loss intervention Comparison: standard-of-care nutrition counseling Anticipated absolute effects* (95% CI)Outcomes Risk with weight loss Risk with standard of care nutri- tion Relative effect (95% CI) /uni2116. of partici- pants (studies) Certainty of evidence (GRADE) Comments Live birth 500 per 1000 0 per 1000 (0 to 0) OR 11.00 (0.43 to 284) 11 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Miscarriage 0 per 1000 0 per 1000 /uni00A0 /uni00A0 /uni00A0 In the trial with 11 women, no pregnancy loss occurred Clinical pregnancy 500 per 1000 0 per 1000 (0 to 0) OR 11.00 (0.43 to 284) 11 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Weight change Weight change (kg) Body mass index (BMI) Mean weight change ranged from 5 to 6 kg MD 9 kg lower (15.5 lower to 2.5 lower) - 11 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 6 Mean body mass Index ranged from 2 to 3 kg/m/two.sups MD 3 kg/m/two.sups lower (5.37 lower to 0.63 lower) - 11 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Mean mental health ranged from 2 to 3 MD 7 lower (13.92 lower to 0.08 lower) - 11 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0Quality of life/Mental health outcome Mental health (at 12 weeks) Quality of life (at 12 weeks) Mean quality of life ranged from 0.01 to 0.02 MD 0.06 higher (0.03 lower to 0.15 higher) - 11 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial. GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. aDowngraded one level for selection bias due to lack of details on random sequence, random allocation, and blinding. bDowngraded two levels for serious imprecision due to small sample size. /uni00A0 /uni00A0 Summary of findings 3. /uni00A0 Pharmacological intervention compared to pharmacological intervention for obese women with subfertility Pharmacological intervention compared to pharmacological intervention for obese women with subfertility Patient or population: obese women with subfertility Setting: hospital Intervention: different pharmacological interventions Comparison: different pharmacological interventions Anticipated absolute effects* (95% CI)Outcomes Risk with pharma- cological interven- tion Risk with pharmacologi- cal intervention Relative effect (95% CI) /uni2116. of partici- pants (studies) Certainty of evidence (GRADE) Comments Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 7 Live birth /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 No study re- ported this out- come 71 per 1000 357 per 1000 (52 to 848) OR 7.22 (0.72 to 73) 28 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 71 per 1000 23 per 1000 OR 0.31 (0.01 to 8.3) 28 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Adverse events - Metformin plus liraglu- tide vs metformin Nausea Diarrhoea Headache 0 per 1000 0 per 1000 OR 5.80 (0.25 to 133) 28 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 80 per 1000 311 per 1000 (184 to 476) OR 5.20 (2.59 to 10.4) 28 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0Clinical pregnancy Metformin plus liraglutide vs metformin Met + CC + L-carnitine vs Met + CC + placebo 214 per 1000 500 per 1000 (160 to 839) OR 3.67 (0.70 to 19.1) 274 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Miscarriage Met + CC + L-carnitine vs Met + CC + placebo 15 per 1000 51 per 1000 (11 to 208) OR 3.58 ( 0.73 to 17.6) 274 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Mean BMI change was set at 0 MD 2.1 higher (0.42 lower to 4.52 higher) - 28 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Mean BMI change was set at 0 MD 0.3 lower (1.17 lower to 0.57 higher) - 274 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Mean weight change was set at 0 kg MD 0.1 kg lower (2.77 low- er to 2.57 higher) - 21 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Weight - BMI change Metformin plus liraglutide vs metformin Met + CC + L-carnitine vs Met + CC + placebo Weight change Dexfenfluramine vs placebo Weight - body fat Metformin plus liraglutide vs metformin Mean change in % to- tal body fat was set at 0 MD 0.5 lower (4.65 lower to 3.65 higher) - 28 (1 RCT) ⊕⊝⊝⊝ Very lowa ,b /uni00A0 Quality of life/Mental health outcome /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 No study re- ported this out- come *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial. Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 8 GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. aDowngraded one level for selection bias due to lack of details on random sequence, random allocation, and blinding. bDowngraded two levels for serious imprecision as reflected by the large confidence interval. /uni00A0 /uni00A0 Summary of findings 4. /uni00A0 Pharmacological intervention compared to no intervention or placebo for obese women with subfertility Pharmacological intervention compared to no intervention/placebo for obese women with subfertility Patient or population: obese women with subfertility Setting: hospital Intervention: metformin Comparison: no intervention/placebo Anticipated absolute effects* (95% CI)Outcomes Risk with pharmacological interven- tion Risk with no inter- vention/placebo Relative effect (95% CI) /uni2116. of partici- pants (studies) Certainty of evi- dence (GRADE) Comments Live birth 219 per 1000 (73 to 499) 152 per 1000 OR 1.57 (0.44 to 5.57) 65 (1 RCT) ⊕⊝⊝⊝ very lowa ,b /uni00A0 Ongoing pregnancy /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 No study re- ported this out- come Miscarriage 31 per 1000 (3 to 272) 61 per 1000 OR 0.50 (0.04 to 5.80) 65 (1 RCTs) ⊕⊝⊝⊝ very lowa ,b /uni00A0 Adverse events (GI) 313 per 1000 333 per 1000 OR 0.91 (0.32 to 2.57) 65 (1 RCT) ⊕⊝⊝⊝ very lowa ,b /uni00A0 Clinical pregnancy 237 per 1000 (95 to 480) 104 per 1000 OR 2.67 (0.90 to 7.93) 96 (2 RCTs) ⊕⊝⊝⊝ very lowa ,b /uni00A0 Weight change BMI MD 0.3 kg/m/two.sups lower (2.16 lower to 1.56 higher) Mean BMI change was set at 0 - 143 (1 RCTs) ⊕⊝⊝⊝ very lowa ,c /uni00A0 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 9 WHR MD 2 cm higher (2.21 lower to 6.21 higher) Mean WHR change was set at 0 - 143 (1 RCT) ⊕⊝⊝⊝ very lowa ,c /uni00A0 Quality of life/Mental health outcome /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 No study re- ported this out- come *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial. GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. aDowngraded twice for serious imprecision as reflected by the large confidence interval. bDowngraded once in view of inconsistency in clinical pregnancy, which could not be seen in studies in view of the presence of only a single trial with 65 women for the outcomes live birth and miscarriage. cDowngraded once for selection bias due to lack of details on random sequence, random allocation, and blinding. /uni00A0 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews B A C K G R O U N D Description of the condition Obesity rates have been rising worldwide, creating a global health problem. The World Health Organization has defined obesity as body mass index (BMI) > 30 kg/m/two.sups. According to estimates, in 2015, about 2.3 billion men and women were overweight (BMI 25 to 30 kg/ m/two.sups), and 700 million were obese (BMI > 30 kg/m/two.sups). The prevalence of obesity is estimated to range from 5% in some developing countries to more than 30% in developed countries (Hossain 2007 ; Ogden 2006). The obesity epidemic has contributed to fertility problems. Obese women have a lesser chance of conceiving naturally than non-obese women (Chong 1986; Crosignani 1994; Hamilton- Fairley 1992), and they are at greater risk of miscarriage (Boots 2011). Obesity can result in anovulation and a reduced chance of conceiving among ovulatory subfertile women (Metwally 2007; van der Steeg 2008). Furthermore, pregnancy and live birth rates following IVF appear to be lower in obese women (Koloszar 2002; Wang 2002; Fedorcsák 2004; Sermonade 2019 ). Moreover, literature suggests that obesity is related to maternal and neonatal complications such as congenital anomalies, hypertensive disorder, gestational diabetes, prolonged labour, macrosomia, and shoulder dystocia (Edwards 1996; Garbaciak 1985; Waller 1994; Weiss 2004). To prevent the adverse effects of obesity, weight loss is recommended as the first line of treatment for obese women seeking pregnancy (Thessaloniki 2008). Description of the intervention Treatment for obesity can involve both non-pharmacological and pharmacological strategies. Non-pharmacological strategies Diet Generally, weight loss occurs when energy intake is lower than energy expenditure. In two small studies, replacing protein for carbohydrate within the context of an energy-restricted diet using 12-week and 1-month dietary intervention among the overweight or obese target population (polycystic ovarian syndrome (PCOS) patients) provided the same improved reproductive outcomes that were achieved in the control group (Moran 2005; Stamets 2004), although postprandial glucose response was 3.5 times lower in the group with a higher-protein diet. Lifestyle modification through diet and exercise programmes in obese women with PCOS improves reproductive outcomes (Clark 1998 ; Huber-Buchholz 1999). An important point is that a minimal amount of weight loss (5% to 10%) over as little as four weeks is sufficient to improve the presentation of PCOS despite patients remaining clinically overweight or obese (Clark 1998; Hamilton-Fairley 1993; Wahrenberg 1999). Exercise Exercise is an important component of any lifestyle modification and weight management programme. The results of two studies that examined effects of exercise on insulin resistance in overweight or obese women with PCOS (who were followed for 16 to 24 weeks and for 6 months) were different. Neither of these studies reported changes in hormone or reproductive parameters (Brown 2009; Randeva 2002). In these studies, the impact of exercise was not evaluated separately from diet, and the result may suffer from reporting bias (Thomson 2010). Behavioural Behavioural might contribute to greater weight loss when combined with medical therapy and diet. In one study (Wadden 2005), participants were followed for 52 weeks, during which time counselling was given including regular supportive and motivational personal or group sessions. Behaviour therapy improved weight loss as well as weight maintenance and control. Complementary and traditional healthcare approaches The terms 'complementary' and 'alternative' describe practices and products that people choose as adjuncts or alternatives to Western medical approaches (Kaptchuk 2001; Straus 2004). The National Institutes of Health has grouped such interventions into five somewhat overlapping domains as follows (nccam.nih.gov/ health/whatiscam). • Biologically based practices. These include use of a vast array of vitamins and mineral supplements, natural products such as chondroitin sulphate, which is derived from bovine or shark cartilage, and herbals such as ginkgo biloba and echinacea. • Manipulative and body-based approaches. These types of therapies, which include massage, have been used throughout history. In the 19th century, additional formal manipulative disciplines emerged in the United States: chiropractic medicine and osteopathic medicine, which had a great influence in complementary medicine. • Mind-body medicine. Many ancient cultures assumed that the mind exerts powerful influences on bodily functions and vice versa. Attempts to reassert proper harmony between these bodily systems led to the development of mind-body medicine, an array of approaches that incorporate spiritual, meditative, and relaxation techniques. • Alternative medical systems. Whereas the ancient Greeks postulated that health requires a balance of vital humors, Asian cultures considered that health depends on the balance and flow of vital energies through the body. This latter theory underlies the practice of acupuncture, for example, which asserts that vital energy flow can be restored by placing needles at critical body points. • Energy medicine. This approach uses therapies that involve the use of energy - biofield-based or bioelectromagnetic-based interventions. An example of the former is Reiki therapy, which aims to realign and strengthen healthful energies through the intervention of energies radiating from the hands of a master healer. Pharmacological strategies Numerous anti-obesity medications are prescribed for weight loss. These drugs may be classified as follows. • Drugs acting on the gastrointestinal tract (GIT): lipase inhibitors (orlistat). • Centrally acting anti-obesity agents: catecholaminergic agents (phentermine). Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Serotonin and noradrenaline reuptake inhibitors such as sibutramine, selective serotonin reuptake inhibitors (SSRIs) (sertraline). • Dopamine reuptake antagonists (bupropion), anti-depressants (fluoxetine). • Exercise mimetics ephedrine, caffeine, synephrine, beta 3 adrenergic agonists, uncoupling proteins 2 and 3 (thermogenin). • Leptin-related agents: therapeutic leptin, leptin analogues, leptin receptor agonists. All of these drugs have side effects, and side effect profiles vary per drug. Sibutramine is associated with modest increases in heart rate and blood pressure; gastrointestinal symptoms predominate with the use of orlistat; phentermine can induce cardiovascular and gastrointestinal side effects; fluoxetine is associated with agitation and nervousness, in addition to gastrointestinal side effects; bupropion with paraesthesia, insomnia, and central nervous system effects; and topiramate with paraesthesia and changes in taste (Li 2005). How the intervention might work The aetiology of obesity is believed to be multi-factorial, with both genetic and environmental contributions. A key determinant of obesity is the balance between ingested calories and the body's basal energy expenditure. Obesity therefore results when small positive energy balances accumulate over a long time (Flegal 2010; Swinburn 2009 ). Weight loss can be achieved through lifestyle intervention programmes incorporating the combination of a healthy diet, increased physical activity, behavioural modification, and use of complementary and traditional healthcare approaches and medications. An adverse effect of obesity on female fertility could be mediated by several mechanisms. First, obesity potentially contributes to excess oestrogen as a result of extraglandular aromatisation of androgen precursors. Moreover, sex hormone–binding globulin levels are diminished, resulting in more bioavailable oestrogen and androgen for aromatisation. Second, obesity increases leptin levels. The actions of leptin on the hypothalamus-pituitary-ovary (HPO) axis are believed to have differential effects on central and peripheral components of the reproductive system. In the central nervous system, leptin has been shown to modulate gonadotropin- releasing hormone (GnRH) pulse frequency in vitro (Scott 2009). On the gonadal level, leptin has been found in ovarian follicular fluid, and leptin receptor has been localised to human granulosa and theca cells. In humans, leptin may interrupt normal oocyte maturation (Smith 2002 ). Weight loss improves the metabolic, endocrine, and reproductive profile of obese women (Falsetti 1992; Hollmann 1996; Kumar 1993). Evidence indicates that a 5% weight loss improves both natural and induced conception, as well as the chance of a healthy live birth (Khaskheli 2013). Weight loss can be achieved by pharmacological treatments and non-pharmacological intervention programmes. Pharmacological treatment for obesity is considered an option for infertile women who are overweight or obese because the safety of these treatments has not been fully studied (Johansson 2015; Kominiarek 2017). A systematic review suggested that sibutramine, orlistat, phentermine, probably diethylpropion, probably fluoxetine, bupropion, and topiramate might promote modest weight loss for at least six months when given along with recommendations for diet (and possibly other behavioural and exercise interventions) (Li 2005 ). Medications act on the mechanisms regulating appetite and satiety and help combat the pathophysiological adaptations that drive weight regain (Garvey 2013). Due to the potential risks associated with surgery or weight loss medications, health organisations have recommended that infertile women who are overweight or obese should follow lifestyle changes (ASRM 2015 ). Recent international guidelines strongly support the importance of pre-pregnancy lifestyle interventions in an interdisciplinary situation to encourage healthy lifestyles and maintain weight loss for obese women (Brauer 2015; Kominiarek 2017). In addition, knowledge about the effects of supplements and complementary therapy (herbal medicine and acupuncture) is emerging, but evidence for the overall effects of these interventions is incomplete. Lifestyle modification, which generally consists of a combination of nutrition, physical activity, and behavioural modification, is an o/f_t-used strategy to help patients achieve weight loss and maintenance (Berkel 2005; Lang 2006). It has been suggested that complementary and alternative medicine including acupuncture might improve weight loss by (1) regulating obesity-related neuropeptides (Cabioglu 2006 ; Gucel 2012); (2) regulating hypothalamus-pituitary-adrenal cortex and sympathetic adrenal cortex (Yin 2005); and (3) conferring lipid-lowering effects (Abdallah 2011). A systematic review and meta-analysis suggested that acupuncture for obesity might be beneficial compared to placebo or lifestyle control, but results were limited by the clinical heterogeneity and poor methodological quality of the included trials (Cho 2009). Why it is important to do this review With the growing incidence of infertility among obese women, it is becoming increasingly common for women to utilise assisted reproductive treatment to become pregnant (Kupta 2014). Overweight and obese women have poor maternity outcomes (Koning 2012; Pandey 2010; Rittenberg 2011), while weight reduction improves reproductive outcomes for these patients (Crosignani 2003; Pandey 2010). The effectiveness of pharmacological and non-pharmacological interventions for obese women with subfertility is unclear. Moreover, despite the fact that non-pharmacological interventions are commonly recommended for management of obese subfertile women, their effectiveness in comparison with pharmacological strategies has not been previously examined in a systematic review (Kim 2020). O B J E C T I V E S To assess the effectiveness and safety of pharmacological and non- pharmacological strategies compared with each other, placebo, or no treatment, for achieving weight loss in obese women with subfertility. M E T H O D S Criteria for considering studies for this review Types of studies Randomised controlled trials (RCTs) and cross-over randomised trials. For cross-over trials, only data from the first phase will be included in meta-analyses, as the cross-over is not a valid design in this context. Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 11 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Types of participants Obese women (BMI ≥ 30 kg/m/two.sups, or as appropriate for the ethnicity of women in the primary study) of childbearing age (post- menarche and pre-menopause) of any ethnic origin who have been unable to conceive for at least 12 months (including primary and secondary subfertility), with or without reasons (anovulatory, unexplained, tubal disease, endometriosis, uterine abnormalities, male factor), and with all types of fertility treatment including intrauterine insemination (IUI), in vitro fertilisation (IVF), and expectant management. Types of interventions We included all studies in which weight loss was the main treatment intervention or weight loss interventions were part of a subfertility management programme. Eligible comparisons are pharmacological, non-pharmacological, and no intervention or placebo. We considered the following comparisons. • Non-pharmacological versus pharmacological intervention (e.g. acupuncture versus SSRI). • Non-pharmacological versus non-pharmacological intervention (e.g. acupuncture versus exercise, one type of exercise versus another). • Pharmacological versus pharmacological intervention (e.g. one SSRI versus one type of pharmacological intervention, one SSRI versus another). • Pharmacological intervention versus no intervention or placebo. • Non-pharmacological intervention versus no intervention or placebo. The following interventions will be considered. Non–pharmacological interventions • Behaviour: behaviour modification, behaviour change, brief intervention, brief advice, nurse counselling, physician counselling, psychological counselling, waiting list for treatment with the promise of treatment upon achieving a weight target, behavioural advice, behaviour therapy, Internet-based support, self-directed support, social support, group therapy, family therapy, psychotherapy, support group, relaxation, health education, health promotion, motivation, meditation, religious intervention. • Diet: diet modification, dietician-led dietary advice, self- directed dietary instruction, low-carbohydrate diet, low-fat diet, hypocaloric diet. • Exercise: walking, jogging, running, swimming, aerobics, structured exercise referral/interventions, weight-li/f_ting/ training, gymnastics, resistance training, fitness training, endurance training, cycling, boxing, kick-boxing, pedometry, exercise therapy, sports therapy. • Complementary and traditional healthcare approaches: acupuncture; electro-therapy; physical therapy; aromatherapy; auricular stimulation; body therapy; acupuncture - Moxibustion; Tai-chi; phytooestrogens; soy products; phytovitamins; dietary supplements and herbal products including conjugated linoleic, pyruvate, ephedra sinica (ma huang), chromium, hydroxy citric acid (Garcinia cambogia), and Chitosan. Pharmacological interventions • Drugs acting on the GIT: lipase inhibitors (e.g. orlistat (Xenical), tetrahydrolipstatin), bulking agents (e.g. methylcellulose (Celevac), ispaghula husk, sterculia, bran, guar gum), insulin sensitisers, gastrointestinal peptides, glucagon-like peptide-1, enterostatin. • Centrally acting anti-obesity agents: catecholaminergic agents (e.g. phentermine, mazindol, diethylpropion, phenylpropanolamine), serotonergic agents (e.g. fenfluramine, dexfenfluramine, fluoxetine), combined catecholaminergic plus serotoninergic agents (e.g. phentermine plus fenfluramine). • Serotonin and noradrenaline reuptake inhibitors (e.g. sibutramine), selective serotonin reuptake inhibitors (SSRIs; e.g. sertraline). • Dopamine reuptake antagonists (e.g. bupropion), anti- depressants (e.g. fluoxetine). • Exercise mimetics (e.g. ephedrine, caffeine, synephrine), beta 3 adrenergic agonists, uncoupling proteins 2 and 3 (Thermogenin). • Leptin-related agents (e.g. therapeutic leptin, leptin analogues, leptin receptor agonists). We excluded surgical interventions. Types of outcome measures Primary outcomes • Live birth or ongoing pregnancy (when live birth is not available) /uni25E6Live birth is defined as delivery of a live fetus a/f_ter 20 completed weeks of gestation /uni25E6Ongoing pregnancy is defined as evidence of a gestational sac with fetal heart motion at 12 weeks, confirmed by ultrasound • Adverse events: miscarriage (loss of pregnancy during the first 20 weeks of gestation) or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea) Secondary outcomes • Clinical pregnancy: defined as evidence of a gestational sac, confirmed by ultrasound • Weight change (e.g. body mass index (BMI), waist to hip ratio (WHR), percentage of body fat or total body fat) • Change in endocrine parameters: total and free testosterone (ng/dL or nmol/L), sex hormone-binding globulin (SHBG; nmol/ L), testosterone-to-SHBG ratio, diabetic tests such as glucose tolerance test (GTT; mmol/L), glycated haemoglobin (HbA1c; mmol/mol) • Quality of life or mental health outcome. If studies reported more than one scale, preference will be given to the SF-36 (36- Item Short Form Health Survey), then to other validated generic scales, and finally, to condition-specific scales Search methods for identification of studies In consultation with the Cochrane Gynaecology and Fertility Group (CGF) Information Specialist, we formulated a comprehensive search strategy to identify all RCTs of pharmacological and non-pharmacological strategies for obese women with Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 12 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews subfertility regardless of language or publication status (published, unpublished, in press, or in progress). Electronic searches We searched the following electronic databases, trial registers, and websites: • Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, ProCite platform, searched on 18 August 2020 (Appendix 1). • Cochrane Central Register of Controlled Trials (CENTRAL), via the Cochrane Central Register of Studies Online (CRSO), Web platform, searched on 18 August 2020 (Appendix 2). • MEDLINE, Ovid platform, searched from 1946 to 18 August 2020 (Appendix 3). • Embase, Ovid platform, searched from 1980 to 18 August 2020 (Appendix 4). • PsycINFO, Ovid platform, searched from 1806 to 18 August 2020 (Appendix 5). • Allied and Complementary Medicine Database (AMED), Ovid platform, searched from 1985 to 18 August 2020 (Appendix 6). • Cumulative Index to Nursing and Allied Health Literature (CINAHL), Ebsco platform, searched from 1961 to 26 September 2019 ( Appendix 7 ). (CINAHL references are now included in CENTRAL; therefore the CENTRAL search on 18 August 2020 included CINAHL references). The MEDLINE search from inception to 18 August 2020 was combined with the Cochrane highly sensitive search strategy for identifying randomised trials, which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2020, Version 6.1, Chapters 4, 4.4.7; 4S1). Searches of Embase and CINAHL from inception to 18 August 2020 were combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/what- we-do/methodology/search-filters/). Searching other resources Other sources of trials below were searched on 18 August 2020: • Trial registers for ongoing and registered trials: www.clinicaltrials.gov (a service of the US National Institutes of Health), the World Health Organization International Trials Registry Platform search portal, at www.who.int/trialsearch/ Default.aspx.; • Database of Abstracts of Reviews of Effects (DARE), part of the Cochrane Library, at onlinelibrary.wiley.com/o/cochrane/ cochrane_cldare_articles_fs.html (for reference lists from relevant non-Cochrane reviews); • Relevant non-Cochrane reviews; • Web of Science wokinfo.com/ (another source of trials and conference abstracts); • OpenGrey at www.opengrey.eu/ (for unpublished literature from Europe); • PubMed (for recent trials not yet indexed in MEDLINE); • ProQuest. We checked the reference lists of relevant trials, reviews, and textbooks. We contacted experts in the field for relevant trials and to obtain additional data. Output of all searches was managed with EndNote, which lists all studies and removes duplicates. Data collection and analysis Selection of studies A/f_ter an initial screen of titles and abstracts retrieved by the search, conducted by two review authors (FB and ST), we retrieved the full text of all potentially eligible studies. These review authors independently examined these full-text articles for compliance with the inclusion criteria and selected eligible studies. We corresponded with study investigators, as required, to clarify study eligibility. Any disagreement about whether to include or exclude a study was discussed with a third review author (SJ) until consensus was achieved. We have listed excluded studies and reasons for their exclusion in the Characteristics of excluded studies tables. See Figure 1 (PRISMA flow chart) for details of the screening and selection process. /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 13 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Figure 1. /uni00A0 Study flow diagram. /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 14 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Data extraction and management Two review authors (FB and ST) independently extracted data from eligible studies using a data extraction form that had been designed and pilot-tested by review authors. Any disagreements were resolved by discussion. Data extracted included study characteristics and outcome data. When studies had multiple publications, review authors collated multiple reports of the same under a single study ID with multiple references. We corresponded with study investigators to request further data on methods and/or results, as required. Data extracted included population characteristics (e.g. female age, BMI, waist-hip ratio, ethnicity), study characteristics, and outcome data. Assessment of risk of bias in included studies Two review authors (FB and ST) assessed risk of bias using the Cochrane 'Risk of bias' assessment tool to assess selection bias (random sequence generation, allocation concealment); performance bias (blinding of women and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective reporting); and other biases (Higgins 2011). Disagreements were resolved by consensus or by discussion with a third review author (SJ). Random sequence generation was scored at low risk of bias when an appropriate method of sequence generation was described according to Cochrane methods (Higgins 2011). Allocation concealment was considered at low risk of bias if opaque and numbered envelopes or a centralised Internet-based randomisation procedure was used. Lack of blinding is unlikely to affect live birth (scored at low risk of bias) but might affect adverse events (scored at high risk of bias). Attrition bias was scored low when all or most (> 95%) of the women randomised were analysed. Reporting bias was scored low when all relevant outcomes were reported as planned in the protocol, as described in published protocols in journals or in trial registers. To score other forms of bias, we looked at differences in baseline values and treatment details. If these issues were unclear, we scored the risk of bias as unclear. We corresponded with study authors to identify any within-trial selective reporting. We sought published protocols and compared outcomes between the protocol and the final published study. The 'Risk of bias' table is presented with the table Characteristics of included studies. All judgements are fully described. Conclusions are presented in the ’Risk of bias’ table and are incorporated into the interpretation of review findings through sensitivity analyses. With respect to within-trial selective reporting, when identified studies failed to report the primary outcome of live birth but did report interim outcomes such as pregnancy, we assessed whether the interim values were similar to those reported in studies that also reported live birth. Measures of treatment effect We performed a statistical analysis in accordance with statistical guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2011 ). We used a fixed-effect model for all analyses. For dichotomous data (e.g. live birth rates), we used numbers of events in control and intervention groups of each study to calculate odds ratios (ORs). For reporting purposes, we translated primary outcomes to absolute risks. For continuous data (e.g. weight loss), if all studies reported exactly the same outcomes, we planned to calculate mean differences (MDs) between treatment groups. If similar outcomes were reported on different scales (e.g. change in weight, quality of life), we planned to calculate standardised mean differences (SMDs). We planned to reverse the direction of effect of individual studies, if required, to ensure consistency across trials. We planned to treat ordinal data (e.g. quality of life scores) as continuous data. We planned to present 95% confidence intervals for all outcomes. When data to calculate RRs or MDs were not available, we planned to utilise the most detailed numerical data available that may facilitate similar analyses of included studies (e.g. test statistics, P values). We planned to assess whether estimates calculated in the review for individual studies were compatible in each case with estimates reported in study publications. Because cluster-RCTs are included in the review, we planned to first make an assessment as to whether the trial had been analysed in such a way as to account for clustering, and if not, we planned to make an adjustment to the trial results using one of several available approaches including a generic inverse-variance

via effect estimates and their standard errors extracted from cluster-RCTs. Unit of analysis issues The primary analysis was planned to be per woman randomised; per pregnancy data may also be included for some outcomes (e.g. miscarriage). Data that do not allow valid analysis (e.g. 'per cycle' data) were planned to be briefly summarised in an additional table and not to be meta-analysed. Multiple births were planned to count as one live birth event. Only first-phase data from cross-over trials were planned to be included. Dealing with missing data We planned to analyse data on an intention-to-treat basis as far as possible (i.e. including all randomised women in the analysis, in the groups to which they were randomised). We planned to attempt to obtain missing data from the original study authors. When these were unobtainable, we planned to undertake imputation of individual values for live birth only: live birth was planned to be assumed not to have occurred in women without a reported outcome. For other outcomes, we planned to analyse only available data. Any imputation undertaken was planned to be subjected to Sensitivity analysis. If studies reported sufficient detail to calculate mean differences but no information on associated SD, we planned to assume the outcome to have an SD equal to the highest SD from other studies within the same analysis. Assessment of heterogeneity We planned to consider whether the clinical and methodological characteristics of included studies were sufficiently similar for meta-analysis to provide a clinically meaningful summary. We planned to assess statistical heterogeneity by using the I/two.sups value. An I/two.sups measurement greater than 50% was planned to be taken to indicate substantial heterogeneity (Higgins 2011). Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 15 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Assessment of reporting biases In view of the difficulty of detecting publication bias and other biases, review authors aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies, and by being alert for duplication of data. If 10 or more studies were included in an analysis, we planned to use a funnel plot to assess the potential for publication bias. Data synthesis If studies were sufficiently similar, we planned to combine data using a fixed-effect model for the following comparisons. • Non-pharmacological intervention versus no intervention/ placebo. • Non-pharmacological versus non-pharmacological intervention. • Pharmacological versus pharmacological intervention. • Pharmacological intervention versus no intervention/placebo. • Pharmacological versus non-pharmacological intervention. See Types of interventions for the exact study interventions we planned to investigate. An increase in the risk of all outcomes was planned to be displayed graphically in meta-analyses to the right of the centre-line, and a decrease in the risk of an outcome to the le/f_t of the centre-line. Subgroup analysis and investigation of heterogeneity When sufficient data were available (at least five RCTs), we planned to perform the following subgroup analyses for primary outcomes only. • Duration of intervention (short: 2 to 4 weeks, medium: 4 weeks to 6 months, long: longer than 6 months) (Lim 2019). • Cause of infertility: anovulatory versus unexplained versus other causes. • Maternal age: ≤ 35 or ≥ 36 years. • Severity of obesity (BMI): 30.0 < BMI < 34.9 (class I obesity) versus 35.0 < BMI < 39.9 (class II obesity) versus BMI ≥ 40.0 (class III obesity). Sensitivity analysis We planned to conduct the following sensitivity analyses for primary outcomes, to examine stability regarding pooled outcomes. • Restriction to studies without high risk of bias. • Use of a random-effects model. • Use of risk ratio rather than odds ratio. Summary of findings and assessment of the certainty of the evidence We prepared a 'Summary of findings' table using GRADEpro (GRADEpro GDT 2014) and Cochrane methods (Higgins 2011). This table evaluates the overall quality of the body of evidence for the primary review outcomes (live birth or ongoing pregnancy, adverse events, clinical pregnancy, miscarriage) for the main review comparison (pharmacological versus non-pharmacological strategies). Additional 'Summary of findings' tables were also prepared for the main review outcomes for other important comparisons. We assessed the quality of the evidence using GRADE criteria: risk of bias, consistency of effect, imprecision, indirectness and publication bias. Judgements about evidence quality (high, moderate, low or very low) were made by two review authors working independently, with disagreements resolved by discussion. Judgements were justified, documented, and incorporated into reporting of results for each outcome. We extracted study data, formatted our comparisons in data tables and prepared a 'Summary of findings' table using the GRADEpro Guideline Development Tool (GDT) (GRADEpro GDT 2014) before writing the results and conclusions of our review. R E S U L T S Description of studies We have reported the characteristics of included and excluded studies in the Characteristics of included studies and Characteristics of excluded studies tables. We did not identify any studies from the reference lists.

of the search Our search retrieved 5577 articles (910 duplicates were removed). Of these articles, 4667 studies were screened by title and abstract and 68 studies were assessed at full text for eligibility. Finally, we included 10 studies that met the inclusion criteria for the review (Figure 1). The 10 included trials varied in size from 11 to 564 women (Einarsson 2017; El 2019 ; Galletly 1996; Johnson 2010 ; Khorram 2006; Mutsaerts 2016; Rothberg 2016; Salamun 2018 ; Sim 2014 ; Tang 2006). Included studies Study design One study was a cross-over randomised clinical trial (Galletly 1996) for which we tried to extract pre-cross-over data, and the others were RCTs (Einarsson 2017; El 2019; Johnson 2010; Khorram 2006; Mutsaerts 2016; Rothberg 2016; Salamun 2018 ; Sim 2014 ; Tang 2006). Einarsson 2017, El 2019 , and Johnson 2010 used a computerised randomisation programme for the randomisation process, and Tang 2006 used a table of random numbers. Khorram 2006 explained that randomisation was done by picking a card out of a box. A web-based randomisation program was adopted for Mutsaerts 2016. It is not clear how randomisation was done in Galletly 1996, Sim 2014, Salamun 2018, and Rothberg 2016. Sample size The number of women included in the studies ranged from 11 to 564. Setting All studies except one were conducted in high-income countries (Egypt; El 2019). One study was undertaken in the UK (Tang 2006), one in The Netherlands (Mutsaerts 2016), two in the USA (Khorram 2006; Rothberg 2016), one in Sweden (Einarsson 2017), one in New Zealand (Johnson 2010), one in Slovenia (Salamun 2018), and two in Australia (Galletly 1996; Sim 2014). All trials recruited women in hospital settings. Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 16 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Participants All women in the included studies met our inclusion criteria. We found 10 randomised trials including 1490 obese women with subfertility. Einarsson 2017 included 305 participants, Sim 2014 48 participants, Mutsaerts 2016 564 participants, Rothberg 2016 11 participants, Salamun 2018 28 participants, El 2019 274 participants, Galletly 1996 21 participants, Tang 2006 143 participants, Khorram 2006 31 participants, and Johnson 2010 65 participants. The main inclusion criterion was: • age 18 to 37 (Sim 2014), 38 (Einarsson 2017), 39 (Mutsaerts 2016 Tang 2006 ), 40 (Rothberg 2016), or ≤ 38 years (Salamun 2018). The main exclusion criteria were: • insulin-dependent diabetes mellitus (Einarsson 2017); • endocrinopathy (El 2019 ; Johnson 2010 ; Mutsaerts 2016 Rothberg 2016 Salamun 2018 Sim 2014 Tang 2006 Khorram 2006); • binge eating disorder (Einarsson 2017); • current psychiatric condition (Sim 2014); • recent (within three months) participation in treatment known to affect diet or body weight (Sim 2014); • taking anti-obesity drugs or appetite suppressants within the past two months (Rothberg 2016); • previous bariatric surgery or gastrointestinal disease (Rothberg 2016); • use of medications that affect reproductive or metabolic functions within the past six weeks (Tang 2006), or in the past two or three months (Rothberg 2016; Salamun 2018 , respectively); • smoker (El 2019); and • drug user (El 2019 Khorram 2006). There were no significant differences between baseline characteristics in all studies (El 2019 Galletly 1996 Johnson 2010; Khorram 2006; Mutsaerts 2016; Rothberg 2016; Sim 2014 ; Tang 2006), except termination of pregnancy in Einarsson 2017 and 120- minute overload of insulin levels in Salamun 2018. Interventions Non-pharmacological intervention versus no intervention or placebo One study compared diet versus no intervention (IVF) (Einarsson 2017). In the intervention group, weight reduction was done before IVF, starting with 12 weeks of a low-calorie liquid formula diet (LCD) of 880 kcal/d and therea/f_ter weight stabilisation for two to five weeks. In the control group, only IVF was done. One study compared lifestyle versus no intervention (Mutsaerts 2016). In Mutsaerts 2016, the lifestyle intervention consisted of a six- month structured programme aiming at a weight loss of 5% to 10% of original body weight. It included six structured outpatient visits and four telephone consultations with a pre-trained intervention coach. Daily dietary energy intake was reduced by 600 kcal and was maintained at a minimum of 1200 kcal/d. Physical activity was stimulated to a level of 10,000 steps a day and at least 30 minutes of exercise two to three times a week. Behavioural changes were facilitated by motivational counselling. A/f_ter the six-month programme was completed, or when weight loss of 5% to 10% had been achieved, women started with appropriate infertility treatment if they were not yet pregnant. The control group received appropriate infertility treatment immediately a/f_ter randomisation. One study compared diet versus no intervention in a 12-week intervention consisting of a very low-energy diet for the first six weeks followed by a hypocaloric diet, combined with a weekly group multi-disciplinary programme (Sim 2014). The control group received recommendations for weight loss and the same printed

as the intervention group. Non-pharmacological versus non-pharmacological intervention One study compared two different diet methods (Rothberg 2016): an intensive weight loss intervention (IWL) and standard of care nutrition counselling (SCN). IWL consisted of 12 weeks of a very low-energy diet (800 kcal/d) and four weeks of a low-calorie conventional food-based diet (CFD) to promote 15% weight loss. SCN consisted of 16 weeks of CFD to promote 5% weight loss. Pharmacological versus pharmacological intervention One study compared metformin versus metformin combined with liraglutide (Salamun 2018). Metformin (MET) was initiated at a dose of 500 mg once per day and was increased by 500 mg every three days up to 1000 mg twice daily. In the group given metformin 1000 mg twice daily combined with 1.2 mg liraglutide once daily subcutaneously (COMBI), there was a run-in period of 12 days to titrate metformin up to 1000 mg twice daily before liraglutide was added. Liraglutide was initiated at a dose of 0.6 mg injected subcutaneously once per day and was increased to 1.2 mg a/f_ter three days. Medical treatment in both groups lasted 12 weeks. One study compared dexfenfluramine/placebo versus placebo/ dexfenfluramine (Galletly 1996). Dexfenfluramine and placebo were given in a cross-over design. Dexfenfluramine dosage was 15 mg twice daily, and the duration of each treatment condition was 12 weeks. One study compared L-carnitine versus placebo (El 2019). Group 1 (clomiphene citrate (CC) plus metformin and L-carnitine) received 150 mg/d CC from day 3 to day 7 of the menstrual cycle plus oral L- carnitine (3 g) and metformin 850 mg (1 tablet daily); the dose was doubled a/f_ter one week to 1700 mg/d (2 tablets daily). Metformin was ingested before a meal once daily during the first week, and therea/f_ter twice daily. L-carnitine and metformin were stopped only when pregnancy was documented. Group 2 (CC plus metformin and placebo) received 150 mg/d CC plus metformin (as above) and placebo capsules that were designed to look exactly like L-carnitine capsules. Pharmacological intervention versus no intervention or placebo One study compared diet combined with metformin versus diet combined with placebo (Tang 2006). The intervention group took metformin (850 mg) twice daily over six months. The control group received placebo over six months. One study compared metformin versus no intervention (Khorram 2006). All patients received CC 100 mg per day on cycle days 5 through 9 only. In group 1 (CC + MET), participants received MET 500 mg three times a day, given on cycle days 1 through 14, with cycle day 1 defined as the first day of menstrual flow. Group 2 (CC) received CC 100 mg per day on cycle days 5 through 9 only. Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 17 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews One study compared metformin versus placebo (Johnson 2010 ). Women with BMI > 32 received no treatment other than advice and encouragement on a lifestyle intervention (which included advice on calorie restriction and on increasing aerobic exercise to 30 minutes at least five times per week combined with an opportunity to see a dietician and an exercise therapist if required (i.e. standard care)). Women were then allocated to placebo or intervention groups. The intervention group (in addition to standard care) received metformin 500 mg three times daily at a gradually increasing dose over two weeks for six months. Pharmacological versus non-pharmacological intervention No study was found for this comparison. Excluded studies We excluded 58 studies from the review for the following reasons. • 49 of 58 included women not of interest to this review. • 4 of 58 reported outcomes not of interest to this review and unlikely to ever be measured, as the objectives were different from the objective of this review. • 1 of 58 reported interventions not of interest to this review. • 4 of 58 studies are awaiting classification. Risk of bias in included studies We have summarised the risk of bias of included studies in Figure 2 and Figure 3. /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 18 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Figure 2. /uni00A0 Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias): All outcomes Blinding of outcome assessment (detection bias): All outcomes Incomplete outcome data (attrition bias): All outcomes Selective reporting (reporting bias) Other bias Einarsson 2017 + + - ? + + + El 2019 + + + + + + + Galletly 1996 ? ? ? ? ? - + Johnson 2010 + + + + + + + Khorram 2006 + - ? ? ? - + Mutsaerts 2016 + + - - + + + Rothberg 2016 ? - - - + + + Salamun 2018 ? - - - + + + Sim 2014 + + - ? - + + Tang 2006 + + + + + - + /uni00A0 /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 19 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Figure 3. /uni00A0 Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias): All outcomes Blinding of outcome assessment (detection bias): All outcomes Incomplete outcome data (attrition bias): All outcomes Selective reporting (reporting bias) Other bias 0% 25% 50% 75% 100% Low risk of bias Unclear risk of bias High risk of bias /uni00A0 Allocation Random sequence generation The method of random sequence generation was associated with a low risk of bias in seven trials (Einarsson 2017, El 2019, Johnson 2010, Khorram 2006, Mutsaerts 2016, Tang 2006 Sim 2014 ). The three remaining trials were rated as unclear risk of bias as they did not report the methods of randomisation (Rothberg 2016, Galletly 1996, Salamun 2018). Allocation concealment Five studies were at low risk of selection bias, for allocation to intervention was Internet-based or sequentially opaque envelopes were used (El 2019; Einarsson 2017; Johnson 2010; Mutsaerts 2016; Tang 2006). One study was at high risk of selection bias related to allocation concealment through open random allocation (Khorram 2006). Four studies were at unclear risk of selection bias, as they not report adequate details to establish whether an appropriate

of allocation and/or concealment had been used (Galletly 1996; Rothberg 2016; Salamun 2018; Sim 2014). Blinding Three studies described blinding of women and were at low risk of performance bias (El 2019; Johnson 2010; Tang 2006). In five studies (Einarsson 2017; Mutsaerts 2016; Rothberg 2016; Salamun 2018 ; Sim 2014), blinding of treatment assignments was not possible, and the studies were at high risk of performance bias. Two studies did not describe blinding; we judged them to be at unclear risk of bias (Galletly 1996; Khorram 2006). Related to detection bias (outcome), three studies described blinding of both women and outcome assessors and were at low risk of this bias ( El 2019 ; Johnson 2010 ; Tang 2006). Three study used no blinding, and we judged this trial to be at high risk (Mutsaerts 2016; Rothberg 2016; Salamun 2018). Four studies were judged to have unclear detection bias (Galletly 1996; Khorram 2006; Sim 2014; Einarsson 2017). Incomplete outcome data Eight studies mentioned dropouts or withdrawals, but the numbers were balanced across groups with similar reasons for missing data; therefore, we judged them as having low risk of attrition bias (Einarsson 2017; El 2019; Johnson 2010; Mutsaerts 2016; Rothberg 2016; Salamun 2018; Tang 2006). One study was considered to have high risk of bias for incomplete outcome data in view of the high (20%) drop-out rate (Sim 2014 ). We judged two studies to be at unclear risk of attrition bias, as they did not mention dropouts or withdrawals (Galletly 1996; Khorram 2006). Selective reporting Seven studies were at low risk of selective bias, as the protocols for these articles were available and their aims were pre-specified (Einarsson 2017; El 2019; Johnson 2010; Mutsaerts 2016; Rothberg 2016; Salamun 2018 ; Sim 2014 ). Three studies were at high risk of selective bias, as the protocols were unavailable (Galletly 1996; Khorram 2006; Tang 2006). Other potential sources of bias We did not identify any other potential sources of bias in the included studies, and we judged each of the included studies to be at low risk of other potential sources of bias. Publication bias We did not assess potential publication bias using a funnel plot or other corrective analytical methods in view of the small number of studies that could be included in the meta-analysis (maximally, three RCTs) (Egger 1997). Effects of interventions See: Summary of findings 1 Non-pharmacological intervention compared to no intervention or placebo for obese women with subfertility; Summary of findings 2 Non-pharmacological intervention compared to non-pharmacological intervention for obese women with subfertility; Summary of findings 3 Pharmacological intervention compared to pharmacological intervention for obese women with subfertility; Summary of findings 4 Pharmacological intervention compared to no intervention or placebo for obese women with subfertility Non-pharmacological intervention versus no intervention or placebo Three studies compared diet or a lifestyle intervention with no intervention: One study compared diet versus no IVF intervention (Einarsson 2017); another study compared diet versus no Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 20 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews intervention (Sim 2014 ); and another study compared lifestyle versus no intervention (Mutsaerts 2016). Primary outcomes Live birth rate or ongoing pregnancy All three studies that compared diet or a lifestyle intervention alone versus no intervention provided data on live birth rates. We found no conclusive evidence of a difference in live birth (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.65 to 1.11; 3 studies, 917 women; I/two.sups = 78%; low-quality evidence; Analysis 1.1 ). The corresponding relative risk was 0.91 (95% CI 0.78 to 1.06), and use of a random-effects model resulted in an OR of 1.17 (95% CI 0.55 to 2.48). This suggests that if the chance of live birth following no intervention is assumed to be 43%, the chance following diet or lifestyle change would be 33% to 46%. This result needs to be interpreted with caution in view of high statistical heterogeneity. Heterogeneity in results was caused mainly by the smallest study of 48 women (Sim 2014); excluding this study resulted in an OR for live birth of 0.87 (95% CI 0.75 to 1.02) and I/two.sups of 49%. In a two-year follow-up study of the Einarsson 2017 trial, the cumulative live birth rate was 57% (87/152) and 54% (82/153) for the weight loss/IVF group versus the IVF only group (OR 1.07, 95% CI 0.87 to 1.31). Adverse events We are uncertain whether miscarriage may occur more o/f_ten following diet or lifestyle change compared to no intervention (OR 1.54, 95% CI 0.99 to 2.39; 3 studies, 917 women; I/two.sups = 0%; low-quality evidence; Analysis 1.3). Secondary outcomes Clinical pregnancy For diet alone versus no intervention, we found insufficient evidence of a difference for clinical pregnancy (OR 1.06, 95% CI 0.81 to 1.40, 1.13; 3 studies, 917 women; I/two.sups = 73%; low-quality evidence; Analysis 1.4 ). This result needs to be interpreted with caution in view of high statistical heterogeneity. Heterogeneity in results was caused mainly by the smallest study of 48 women (Sim 2014 ); excluding this study resulted in an OR for live birth of 0.98 (95% CI 0.74 to 1.29) and I/two.sups of 11%. Weight change All three studies found lower BMI in the lifestyle intervention group. One study reported BMI at three months following lifestyle change compared with no intervention (mean difference (MD) -1.00, 95% CI -1.02 to -0.98; 1 study, 574 women) and at six months (MD -1.30, 95% CI -1.32 to -1.28; 1 study, 574 women), but as a large proportion of pregnant women had to be excluded from the analysis, these

are difficult to interpret (Mutsaerts 2016). Diet resulted in a decrease in BMI in two studies (Einarsson 2017; Sim 2014), but data were not pooled due to heterogeneity in effect (MD -3.70, 95% CI -4.10 to -3.36; 305 women, 1 study; low-quality evidence; and MD -1.80, 95% CI -2.67 to -0.93; 43 women, 1 study; very low-quality evidence). In a two-year follow-up study of the Einarsson 2017 trial, women in the weight loss group had regained their pre-trial weight (mean (SD) BMI a/f_ter 2 years was 32.5 (3.5) and 33.1 (3.0) for the weight loss/IVF versus IVF only arm). Change in endocrine parameters This outcome was not reported. Quality of life or mental health outcome This outcome was not reported. Non-pharmacological versus non-pharmacological intervention One study with 11 women compared two different diet methods including intensive weight loss intervention (IWL) versus standard of care nutrition counselling (SCN) (Rothberg 2016). Primary outcomes Live birth rate or ongoing pregnancy There was uncertainty about the effects of IWL versus SCN on live birth (OR 11, 95% CI 0.43 to 284; 1 study, 11 women; very low- quality evidence; Analysis 2.1). An absolute translation could not be calculated as there were no live births in the SCN group. Adverse events In the trial with 11 women, no pregnancy loss occurred. Secondary outcomes Clinical pregnancy Evidence of a difference in clinical pregnancy for IWL versus SCN was insufficient (OR 11, 95% CI 0.43 to 284; 1 study, 11 women; very low-quality evidence; Analysis 2.2). Weight change In the single trial with 11 women, we found greater weight loss and a larger decrease in BMI for IWL versus SCN (MD -9.00 kg, 95% CI -15.5 to -2.5; and MD -3.00, 95% CI -5.37 to -0.63, respectively), but In view of the very low quality of the evidence, we are uncertain whether IWL reduces weight and BMI to a greater extent than SCN. Change in endocrine parameters No data on endocrine parameters were available. Quality of life or mental health outcome Evidence of a difference between IWL and SCN in quality of life (MD 0.06, 95% CI -0.03 to 0.15; 1 study, 11 women; very low- quality evidence) and in mental health outcome (MD -7.00, 95% CI -13.92 to -0.08; 1 study, 11 women; very low-quality evidence) was insufficient. Pharmacological versus pharmacological intervention One study compared metformin plus liraglutide versus metformin (Salamun 2018); one study compared a combination of metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo (El 2019); and one study compared dexfenfluramine versus placebo (Galletly 1996); for this last study, only weight loss as an outcome could be retrieved from the pre-cross-over data. Primary outcomes Live birth rate or ongoing pregnancy No comparison of live birth rate or ongoing pregnancy was available. Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 21 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Adverse events For metformin plus CC plus L-carnitine versus metformin plus CC plus placebo (El 2019 ), we found insufficient evidence of a difference in miscarriage (OR 3.58, 95% CI 0.73 to 17.55; 243 women, 1 study; very low-quality evidence; Analysis 3.1). For metformin plus liraglutide versus metformin (Salamun 2018), we found insufficient evidence of a difference for nausea (OR 7.22, 95% CI 0.72 to 72.7; 28 women, 1 study; very low-quality evidence; Analysis 3.2); diarrhoea (OR 0.31, 95% CI 0.01 to 8.29; 28 women, 1 study; very low-quality evidence; Analysis 3.3 ) and headache (OR 5.80, 95% CI 0.25 to 133; 28 women, 1 study; very low-quality evidence; Analysis 3.4). Secondary outcomes Clinical pregnancy For metformin plus liraglutide versus metformin (Salamun 2018), we found insufficient evidence of a difference in clinical pregnancy (OR 3.67, 95% CI 0.70 to 19.12; 28 women, 1 study; very low-quality evidence; Analysis 3.5). For metformin plus clomiphene citrate (CC) plus L-carnitine versus metformin plus CC plus placebo (El 2019 ), we found evidence of a difference in favour of L-carnitine for clinical pregnancy but considered this evidence to be of very low quality (OR 5.56, 95% CI 2.57 to 12.02; 274 women, 1 study; very low-quality evidence; Analysis 3.5). Weight change For metformin plus liraglutide versus metformin (Salamun 2018), we found insufficient evidence of a difference in BMI (MD 2.10, 95% CI -0.42 to 4.62; 28 women, 1 study; very low-quality evidence). For dexfenfluramine versus placebo (Galletly 1996), we are unsure whether the data for weight loss presents pre-cross-over data. We found insufficient evidence of a difference in mean weight loss (MD -0.10, 95% CI -2.77 to 2.57; 21 women, 1 study; very low-quality evidence). The mean weight loss ranged from 3 to 4 kg in the intervention group . One study provided no evidence of a difference for metformin plus liraglutide versus metformin in percentage of body fat (MD -0.50, 95% CI -4.65 to 3.65; 28 women, 1 study; very low-quality evidence) (Salamun 2018). Change in endocrine parameters For metformin plus liraglutide versus metformin (Salamun 2018), we found insufficient evidence of a difference in the oral glucose tolerance test (OGTT) (MD -0.30, 95% CI -1.92 to 1.3; 28 women, 1 study; very low-quality evidence), free testosterone (MD 0.80, 95% CI -3.0 to 4.60; 28 women, 1 study; very low-quality evidence), total testosterone (MD 0.20, 95% CI -0.21 to 0.61; 28 women, 1 study; very low-quality evidence), and sex hormone-binding globulin (SHBG) (MD 0.30, 95% CI -12.22 to 12.82; 28 women, 1 study; very low- quality evidence). Quality of life or mental health outcome No comparison of quality of life or mental health outcome was available. Pharmacological intervention versus no intervention or placebo We found three studies: one study compared diet combined with metformin versus diet combined with placebo (Tang 2006); one study compared metformin versus no intervention (Khorram 2006); another study compared metformin versus placebo (Johnson 2010). Primary outcomes Live birth rate or ongoing pregnancy Only one study that compared metformin with placebo reported on live birth, resulting in insufficient evidence of a difference (OR 1.57, 95% CI 0.44 to 5.57; 1 study, 65 women; very low-quality evidence; Analysis 4.1) (Johnson 2010). This suggests that if the chance of live birth following placebo is assumed to be 15%, the chance following metformin would be 7.3% to 50%. Adverse events One study compared pharmacological intervention versus no treatment or placebo, with no conclusive evidence of a difference for miscarriage (OR 0.50, 95% CI 0.04 to 5.80; 65 women, 1 study; very low-quality evidence; Analysis 4.2) (Johnson 2010). We found insufficient evidence of a difference between metformin and placebo in gastrointestinal adverse events (OR 0.91, 95% CI 0.32 to 2.57; 1 study, 65 women; very low-quality evidence; Analysis 4.3) (Johnson 2010). Secondary outcomes Clinical pregnancy Two studies compared metformin versus no treatment or placebo, with no conclusive evidence of a difference for pregnancy (OR 2.67, 95% CI 0.90 to 7.93; 96 women, 2 studies; I/two.sups = 48%; very low-quality evidence; Analysis 4.4) (Johnson 2010; Khorram 2006) Weight change One study reported on weight change, with no conclusive evidence of a change in BMI (MD -0.30, 95% CI -2.16 to 1.56; 143 women, 1 study; very low-quality evidence) or WHR (MD 2.00, 95% CI -2.21 to 6.21; 1 study, 143 women; very low-quality evidence) for metformin versus placebo (Tang 2006). Change in endocrine parameters One study reported on endocrine parameters (Khorram 2006). Changes in endocrine parameters were inconclusive for free testosterone (MD 0.7 nmol/L, 95% CI -1.01 to 2.42; 31 women, 1 study; very low-quality evidence). Total testosterone and SHBG were higher following metformin versus placebo, but evidence was of very low quality (total testosterone: MD 6.20 nmol/L, 95% CI 0.46 to 11.94; 1 study, 31 women; very low-quality evidence; SHBG: 5.50 nmol/L, 95% CI 3.79 to 7.21; 1 study, 31 women; very low-quality evidence). Quality of life or mental health outcome No comparison of quality of life or mental health outcome was available. Non-pharmacological versus pharmacological intervention No study reported this comparison. Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 22 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews For this review, we did not gather enough data to perform subgroup analyses. Moreover, for this version of the review, we identified insufficient studies to perform meaningful sensitivity analyses. D I S C U S S I O N Summary of main results Based on available data, we are uncertain about the effectiveness and safety of pharmaceutical and non-pharmaceutical interventions for weight reduction in obese women with subfertility due to evidence of very low to low quality. We included 10 trials that varied in size from 11 to 564 women. The best evidence was found for diet/lifestyle interventions (three randomised controlled trials (RCTs)). Compared to no intervention or placebo, the lifestyle intervention did not appear to improve live birth or clinical pregnancy; however, lifestyle intervention may lower body mass index (BMI) among obese women. It is unclear whether intensive weight loss interventions compared to nutrition counselling had a positive or negative effect on any outcomes. For pharmaceutical interventions, all outcomes were scored to have evidence of very low quality. Whether pharmaceutical interventions such as liraglutide, L-carnitine as addition to metformin, and clomiphene result in improved fertility or weight outcomes is unclear. Similarly, we found no conclusive evidence for metformin versus placebo or no intervention in terms of live birth, clinical pregnancy, or weight change outcomes. We found no trials that compared pharmacological versus non- pharmacological interventions. Overall completeness and applicability of evidence There is a serious lack of evidence in the field of weight reduction in obese women with subfertility. The included studies only partially addressed the objectives of this review. Outcome data could not be retrieved for several of the comparisons and outcomes that we sought to investigate. The high heterogeneity of pharmacological and non-pharmacological strategies in included studies may limit the generalisability of trial results regarding the effectiveness of pharmacological and non-pharmacological strategies for obese women with subfertility. The included studies were clinically heterogeneous and differed in factors such as duration of treatment, type of intervention, dosage, and length of follow-up. Given the very low quality of evidence for the pharmaceutical interventions, the applicability of those findings is limited and does not allow us to draw conclusions. It was our intention to include studies with obese women with a BMI of at least 30. In two trials the minimal BMI was 29 (Khorram 2006, Mutsaerts 2016) with medians or means above 36. The study groups consider the effect of including a few women with a BMI of 29 instead of 30 negligible. Quality of the evidence Although evidence generated in this review was based on 10 RCTs, this evidence was of very low to low quality as determined by GRADE methods (see 'Summary of findings' for the main comparison and 'Summary of findings 2'). The main limitations were due to lack of studies and poor reporting of study methods. The quality of individual studies was generally low, with over 40% failing to describe adequate methods of blinding of participants and personnel, outcome assessment, and selective reporting (see Figure 2 and Figure 3). Potential biases in the review process To minimise bias and issues related to subjectivity of judgement, any disagreements that occurred during the review process were discussed among all review authors until consensus was reached. Two review authors independently carried out data extraction. The accuracy of data was further checked by a third review author. Potential risk of bias in each study and the overall quality of evidence for each outcome were assessed by two independent review authors. We adopted a highly sensitive search strategy. However, the literature identified was predominantly written in English, and most studies were conducted in high-income countries. Agreements and disagreements with other studies or reviews One systematic review evaluated the effectiveness of non- pharmacological interventions for overweight or obese infertile women (Kim 2020). On the basis of 21 RCTs, it was suggested that non-pharmacological interventions could have a positive effect on pregnancy and natural conception rates, whereas it remains unclear whether they improve the live birth rate. Not all women in the included studies were overweight, and most were not obese, which may explain the medium to high heterogeneity of effect sizes for pregnancy rates and live birth rates in all non-pharmacological interventions. An earlier systematic review evaluated first whether weight loss interventions for infertile patients achieve their goal in reducing weight, and second whether they result in improved fertility outcomes (Best 2017). A total of 40 studies were included, of which 14 were RCTs. Results suggest that weight loss interventions, particularly diet and exercise, may improve pregnancy rates and ovulatory status. In a Cochrane Review aiming to assess the effectiveness of lifestyle treatment (diet, exercise, behavioural, or combined treatments) for women with PCOS, lifestyle intervention improved body composition, hyperandrogenism, and insulin resistance, but evidence for an effect of diet on reproductive outcomes was lacking (Lim 2019). Our review differs from previous reviews in that it is focused on obese women only. We conducted an extensive search until 2020 and could include data from 10 studies. In contrast to previous reviews, we are uncertain whether pharmacological or non- pharmacological strategies improve live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life, or mental health outcomes. However, for obese women with subfertility, a lifestyle intervention may reduce BMI. A U T H O R S ' /uni00A0 C O N C L U S I O N S Implications for practice Evidence is yet insufficient to support the use of pharmacological and non-pharmacological strategies for weight reduction for obese women with subfertility. No data are available for the comparison of pharmacological versus non-pharmacological strategies. We are uncertain whether pharmacological or non-pharmacological Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 23 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews strategies improve live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life, or mental health outcomes. Our findings were based on very low-quality evidence from studies that may contribute to these outcomes. Thus, we are not able to draw firm conclusions with regard to the impact of pharmacological and non-pharmacological strategies for weight reduction. However, limited information suggests that lifestyle intervention for obese women with subfertility may reduce BMI. Although obese women should be counselled about the risk of obesity for fertility and pregnancy outcomes, healthcare providers should caution women that the existing research is of poor quality and of limited quantity. Implications for research In view of the high prevalence of obesity-related subfertility and lack of good evidence, we need well-designed and well-conducted RCTs with double-blinding and adequately powered trials reporting

such as randomisation and allocation concealment in detail and aiming to share data a/f_ter the trial. Future studies are advised to focus on lifestyle interventions with or without pharmacological interventions for obese women with subfertility. Follow-up time needs to be long enough for these clinically relevant outcome data to be obtained. The duration of follow-up for assessing outcomes should be at least three months, but longer follow-up is advised to enable reporting of natural pregnancies. Finally, the economic impact of different weight reduction methods should be reported. A C K N O W L E D G E M E N T S We thank Marian Showell (the Information Specialist of the Cochrane Gynaecology and Fertility Group) for preparing the search strategy, and Helen Nagels and Melissa Vercoe (Managing Editors of the Cochrane Gynaecology and Fertility Group) for their continuous support. We thank the peer reviewers, Jack Wilkinson, Abha Maheshwari, Harry Siristatidis, for providing valuable clinical and editorial advice. Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 24 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews

/uni00A0

to studies included in this review Einarsson 2017 {published data only} */uni00A0 Einarsson/uni00A0S, Bergh/uni00A0C, Friberg/uni00A0B, Pinborg/uni00A0A, Klajnbard/uni00A0A, Karlström/uni00A0PO, et al. Weight reduction intervention for obese infertile women prior to IVF: a randomised controlled trial. Human Reproduction 2017;8(32):1621-30. Kluge/uni00A0L, Bergh/uni00A0C, Einarsson/uni00A0S, Pinborg/uni00A0A, Mikkelsen Englund A- L, Thurin-Kjellberg/uni00A0A. Cumulative live birth rates a/f_ter weight reduction in obese women scheduled for IVF: follow-up of a randomized controlled trial. Human Reproduction Open 2019;2019:hoz030. El 2019 {published data only} El Sharkwy/uni00A0I, Sharaf El-Din/uni00A0M. l-Carnitine plus metformin in clomiphene-resistant obese PCOS women, reproductive and metabolic effects: a randomized clinical trial. Gynecological Endocrinology 2019;35:701-5. Galletly 1996 {published data only} Galletly/uni00A0C, Clark/uni00A0A, Tomlinson/uni00A0L. Evaluation of dexfenfluramine in a weight loss program for obese infertile women. International Journal of Eating Disorders 1996;2(19):209-12. Johnson 2010 {published data only} Johnson/uni00A0NP, Stewart/uni00A0AW, Falkiner/uni00A0J, Farquhar/uni00A0CM, Milsom/uni00A0S, Singh/uni00A0VP, et al, REACT-NZ (REproduction And Collaborative Trials in New Zealand), a Multi-centre Fertility Trials Group. PCOSMIC: a multi-centre randomised trial in women with polycystic ovary syndrome evaluating metformin for infertility with clomiphene. Human Reproduction 2010;7(25):1675-83. Khorram 2006 {published data only} Khorram/uni00A0O, Helliwell/uni00A0JP, Katz/uni00A0S, Bonpane/uni00A0CM, Jaramillo/uni00A0L. Two weeks of metformin improves clomiphene citrate-induced ovulation and metabolic profiles in women with polycystic ovary syndrome. Fertility and Sterility 2006;5(85):1448-51. Mutsaerts 2016 {published data only} */uni00A0 Mutsaerts/uni00A0MA, Van Oers/uni00A0AM, Groen/uni00A0H, Burggraaff/uni00A0JM, Kuchenbecker/uni00A0WK, Perquin/uni00A0DA, et al. Randomized trial of a lifestyle program in obese infertile women. New England Journal of Medicine 2016;374(20):1942-1953. Rothberg 2016 {published data only} Rothberg/uni00A0A, Lanham/uni00A0M, Randolph/uni00A0J, Fowler/uni00A0C, Miller/uni00A0N, Smith/uni00A0Y. Feasibility of a brief, intensive weight loss intervention to improve reproductive outcomes in obese, subfertile women: a pilot study. Fertility and Sterility 2016;5(106):1212-20. Salamun 2018 {published data only} Salamun/uni00A0V, Jensterle/uni00A0M, Janez/uni00A0A, Bokal/uni00A0EV. Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study. European Journal of Endocrinology 2018;179(1):1-11. Sim 2014 {published data only} Sim/uni00A0KA, Dezarnaulds/uni00A0GM, Denyer/uni00A0GS, Skilton/uni00A0MR, Caterson/uni00A0ID. Weight loss improves reproductive outcomes in obese women undergoing fertility treatment: a randomized controlled trial. Clinical Obesity 2014;2(4):61-8. Tang 2006 {published data only} Tang/uni00A0T, Glanville/uni00A0J, Hayden/uni00A0CJ, White/uni00A0D, Barth/uni00A0JH, Balen/uni00A0AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Human Reproduction 2005;1(21):80-9. /uni00A0

to studies excluded from this review Asemi 2014 {published data only} Asemi/uni00A0Z, Esmaillzadeh/uni00A0A. DASH diet, insulin resistance, and serum hs-CRP in polycystic ovary syndrome: a randomized controlled clinical trial. Hormone and Metabolic Research 2015;47(03):232-8. Asemi 2014a {published data only} Asemi/uni00A0Z, Samimi/uni00A0M, Tabassi/uni00A0Z, Shakeri/uni00A0H, Sabihi/uni00A0SS, Esmaillzadeh/uni00A0A. Effects of DASH diet on lipid profiles and biomarkers of oxidative stress in overweight and obese women with polycystic ovary syndrome: a randomized clinical trial. Nutrition 2014;30(11-12):1287-93. Asemi 2015 {published data only} Asemi/uni00A0Z, Foroozanfard/uni00A0F, Hashemi/uni00A0T, Bahmani/uni00A0F, Jamilian/uni00A0M, Esmaillzadeh/uni00A0A. Calcium plus vitamin D supplementation affects glucose metabolism and lipid concentrations in overweight and obese vitamin D deficient women with polycystic ovary syndrome. Clinical Nutrition 2015;34(4):586-92. Ashoush 2016 {published data only} Ashoush/uni00A0S, Abou-Gamrah/uni00A0A, Bayoumy/uni00A0H, Othman/uni00A0N. Chromium picolinate reduces insulin resistance in polycystic ovary syndrome: randomized controlled trial. Journal of Obstetrics and Gynaecology Research 2016;42(3):279-85. Attarzadeh 2012 {published data only} Attarzadeh Hosseini/uni00A0R, Sardar/uni00A0M, Taghavi/uni00A0M, Ayaz Khosh Hava/uni00A0F. The effects of an aerobic exercise program on LH, FSH, TST and DHEA levels in obese women with polycystic ovary syndrome. Iranian Journal of Endocrinology and Metabolism 2012;14(1):39-94. Baillargeon 2004 {published data only} Baillargeon/uni00A0JP, Iuorno/uni00A0MJ, Jakubowicz/uni00A0DJ, Apridonidze/uni00A0T, He/uni00A0N, Nestler/uni00A0JE. Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositol phosphoglycan mediator in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2004;89(1):242-9. Becker 2015 {published data only} Becker/uni00A0GF, Passos/uni00A0EP, Moulin/uni00A0CC. Short-term effects of a hypocaloric diet with low glycemic index and low glycemic Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 25 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews load on body adiposity, metabolic variables, ghrelin, leptin, and pregnancy rate in overweight and obese infertile women: a randomized controlled trial. American Journal of Clinical Nutrition 2015;102(6):1365-72. Cheraghi 2014 {published data only} Cheraghi/uni00A0E, Mehranjani/uni00A0MS, Shariatzadeh/uni00A0MA, Esfahani/uni00A0MH, Ebrahimi/uni00A0Z. Co-administration of metformin and N-acetyl cysteine fails to improve clinical manifestations in PCOS individual undergoing ICSI. International Journal of Fertility and Sterility 2014;8(2):119-28. Gambineri 2004 {published data only} Gambineri/uni00A0A, Pelusi/uni00A0C, Genghini/uni00A0S, Morselli-Labate/uni00A0AM, Cacciari/uni00A0M, Pagotto/uni00A0U, et al. Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome. Clinical Endocrinology 2004;60(2):241-9. Hanjalic-Beck 2010 {published data only} Hanjalic-Beck/uni00A0A, Gabriel/uni00A0B, Schaefer/uni00A0W, Zahradnik/uni00A0HP, Schories/uni00A0M, Tempfer/uni00A0C, et al. Metformin versus acarbose therapy in patients with polycystic ovary syndrome (PCOS): a prospective randomised double-blind study. Gynecological Endocrinology 2010;26(9):690-7. Janez 2017 {published data only} Janez/uni00A0A, Salamun/uni00A0V, Jensterle/uni00A0M, Bokal/uni00A0EV. Short-term intervention with liraglutide and metformin increased fertility potential in a subset of obese PCOS preceding in vitro sterilisation. Diabetes 2017;66(Suppl 1):A561. Janez 2018 {published data only} Janez/uni00A0A, Jensterle/uni00A0M. GLP-1 receptor agonist liraglutide increased IVF pregnancy rates in obese women with PCOS and previous poor response to first-line reproductive treatments. Diabetes 2018;67(Suppl 1):A392-3. Jensterle 2017 {published data only} Jensterle/uni00A0M, Kravos/uni00A0NA, Goričar/uni00A0K, Janez/uni00A0A. Short-term effectiveness of low dose liraglutide in combination with metformin versus high dose liraglutide alone in treatment of obese PCOS: randomized trial. BMC Endocrine Disorders 2017;17(1):5. Karsten 2018 {published data only} Karsten/uni00A0MDA, van/uni00A0Oers/uni00A0AM, Groen/uni00A0H, Mutsaerts/uni00A0MAQ, van/uni00A0Poppel/uni00A0MNM, Geelen/uni00A0A, et al. Determinants of successful lifestyle change during a 6-month preconception lifestyle intervention in women with obesity and infertility. European Journal of Nutrition 2019;58(6):2463-75. Kocak 2002 {published data only} Kocak/uni00A0M, Caliskan/uni00A0E, Simsir/uni00A0C, Haberal/uni00A0A. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertility and Sterility 2002;77(1):101-6. Legro 2007 {published data only} Legro/uni00A0RS, Zaino/uni00A0RJ, Demers/uni00A0LM, Kunselman/uni00A0AR, Gnatuk/uni00A0CL, Williams/uni00A0NI, et al. The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome. American Journal of Obstetrics and Gynecology 2007;196(4):402.e1-402.e11. Liao 2011 {published data only} Liao/uni00A0L, Tian/uni00A0YJ, Zhao/uni00A0JJ, Xin/uni00A0Y, Xing/uni00A0HY, Dong/uni00A0JJ. Metformin versus metformin plus rosiglitazone in women with polycystic ovary syndrome. Chinese Medical Journal 2011;124(5):714-8. Ma 2007 {published data only} Ma/uni00A0LK, Jin/uni00A0LN, Yu/uni00A0Q, Xu/uni00A0L. Effect of lifestyle adjustment, metformin and rosiglitazone in polycystic ovary syndrome. [Chinese]. Zhonghua Fu Chan Ke Za Zhi 2007;42(5):294-7. Moran 2006 {published data only} Moran/uni00A0LJ, Noakes/uni00A0M, Cli/f_ton/uni00A0PM, Wittert/uni00A0GA, Williams/uni00A0G, Norman/uni00A0RJ. Short-term meal replacements followed by dietary macronutrient restriction enhance weight loss in polycystic ovary syndrome. American Journal of Clinical Nutrition 2006;84(1):77-87. Morin-Papunen 1998 {published data only} Morin-Papunen/uni00A0LC, Koivunen/uni00A0RM, Tomas/uni00A0C, Ruokonen/uni00A0A, Martikainen/uni00A0HK. Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 1998;83(7):2566-8. Morin-Papunen 2000 {published data only} Morin-Papunen/uni00A0LC, Vauhkonen/uni00A0I, Koivunen/uni00A0RM, Ruokonen/uni00A0A, Martikainen/uni00A0HK, Tapanainen/uni00A0JS. Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. Journal of Clinical Endocrinology and Metabolism 2000;85(9):3161-8. Morin-Papunen 2012 {published data only} Morin-Papunen/uni00A0L, Rantala/uni00A0AS, Unkila-Kallio/uni00A0L, Tiitinen/uni00A0A, Hippeläinen/uni00A0M, Perheentupa/uni00A0A, et al. Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double-blind, placebo- controlled randomized trial. Journal of Clinical Endocrinology 2012;97(5):1492-500. Pasquali 1986 {published data only} Pasquali/uni00A0R, Fabbri/uni00A0R, Venturoli/uni00A0S, Paradisi/uni00A0R, Antenucci/uni00A0D, Melchionda/uni00A0N. Effect of weight loss and antiandrogenic therapy on sex hormone blood levels and insulin resistance in obese patients with polycystic ovaries. American Journal of Obstetrics and Gynecology 1986;154(1):139-44. Pasquali 2000 {published data only} Pasquali/uni00A0R, Gambineri/uni00A0A, Biscotti/uni00A0D, Vicennati/uni00A0V, Gagliardi/uni00A0L, Colitta/uni00A0D, et al. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2000;85(8):2767-74. Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 26 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Pastore 2011 {published data only} Pastore/uni00A0LM, Williams/uni00A0CD, Jenkins/uni00A0J, Patrie/uni00A0JT. True and sham acupuncture produced similar frequency of ovulation and improved LH to FSH ratios in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2011;96(10):3143-50. Penna 2005 {published data only} Penna/uni00A0IA, Canella/uni00A0PR, Reis/uni00A0RM, Silva de Sa/uni00A0MF, Ferriani/uni00A0RA. Acarbose in obese patients with polycystic ovarian syndrome: a double-blind, randomized, placebo-controlled study. Human Reproduction 2005;20(9):2396-401. Petranyi 2011 {published data only} Petranyi/uni00A0G, Zaoura-Petranyi/uni00A0M. Metformin treatment with or without life style changes in patients with polycystic ovary syndrome. [Hungarian]. Orvosi Hetilap 2011;152(16):628-32. Pourmatroud 2015 {published data only} Pourmatroud/uni00A0E, Mohammadjafari/uni00A0R, Roozitalab/uni00A0M. Comparison of metformin and simvastatin administration in women with polycystic ovary syndrome before intra-cytoplasmic sperm injection cycle: a prospective, randomized, clinical trial study. Iranian Red Crescent Medical Journal 2015;17(12):e20082. Premawardhana 1994 {published data only} Premawardhana/uni00A0LD, Ismail/uni00A0IS, Riad Fahmy/uni00A0D, Miell/uni00A0JP, Peters/uni00A0JR, Scanlon/uni00A0MF. Acute cholinergic blockade with low dose pirenzepine reduces the insulin and glucose responses to a mixed meal in obese women with the polycystic ovary syndrome. Clinical Endocrinology 1994;40(5):617-21. Qin 2016 {published data only} Qin/uni00A0W, Zhao/uni00A0K, Yang/uni00A0H. Effect of acupoint catgut embedding therapy combined with Chinese medicine for nourishing the kidneys and promoting blood circulation and improving blood glucose and lipid levels as well as the pregnancy rate in obese PCOS patients with infertility. Experimental and Therapeutic Medicine 2016;12(5):2909-14. Qublan 2007 {published data only} Qublan/uni00A0HS, Yannakoula/uni00A0EK, Al-Qudad/uni00A0MA, El-Uri/uni00A0FI. Dietary intervention versus metformin to improve the reproductive outcome in women with polycystic ovary syndrome. A prospective comparative study. Saudi Medical Journal 2007;28(11):1694-8. Seibel 2008 {published data only} Seibel/uni00A0SA, Chou/uni00A0KH, Capp/uni00A0E, Spritzer/uni00A0PM, von/uni00A0Eye Corleta/uni00A0H. Effect of metformin on IGF-1 and IGFBP-1 levels in obese patients with polycystic ovary syndrome. European Journal of Obstetrics and Gynecology and Reproductive Biology 2008;138(1):122-4. Shahebrahimi 2016 {published data only} Shahebrahimi/uni00A0K, Jalilian/uni00A0N, Bazgir/uni00A0N, Rezaei/uni00A0M. Comparison clinical and metabolic effects of metformin and pioglitazone in polycystic ovary syndrome. Indian Journal of Endocrinology and Metabolism 2016;20(6):805-9. Siebert 2009 {published data only} Siebert/uni00A0T, Kruger/uni00A0T, Lombard/uni00A0C. Evaluating the equivalence of clomiphene citrate with and without metformin in ovulation induction in PCOS patients. Journal of Assisted Reproduction and Genetics 2009;26(4):165-71. Sonmez 2005 {published data only} Sönmez/uni00A0AS, Yasar/uni00A0L, Savan/uni00A0K, Koç/uni00A0S, Ozcan/uni00A0J, Toklar/uni00A0A, et al. Comparison of the effects of acarbose and metformin use on ovulation rates in clomiphene citrate-resistant polycystic ovary syndrome. Human Reproduction 2005;20(1):175-9. Sordia-Hernandez 2016 {published data only} Sordia-Hernández/uni00A0LH, Ancer Rodríguez/uni00A0P, Saldivar Rodriguez/uni00A0D, Trejo Guzman/uni00A0S, Servín Zenteno/uni00A0ES, Guerrero González/uni00A0G, et al. Effect of a low glycemic diet in patients with polycystic ovary syndrome and anovulation: a randomized controlled trial. Clinical and Experimental Obstetrics and Gynecology 2016;43(4):555-9. Sorensen 2012 {published data only} Sorensen/uni00A0LB, Soe/uni00A0M, Halkier/uni00A0KH, Stigsby/uni00A0B, Astrup/uni00A0A. Effects of increased dietary protein-to-carbohydrate ratios in women with polycystic ovary syndrome. American Journal of Clinical Nutrition 2012;95(1):39-48. Stamets 2004 {published data only} Stamets/uni00A0K, Taylor/uni00A0DS, Kunselman/uni00A0A, Demers/uni00A0LM, Pelkman/uni00A0CL, Legro/uni00A0RS. A randomized trial of the effects of two types of short- term hypocaloric diets on weight loss in women with polycystic ovary syndrome. Fertility and Sterility 2004;81(3):630-7. Swora-Cwynar 2016 {published data only} Swora-Cwynar/uni00A0E, Kujawska-Łuczak/uni00A0M, Suliburska/uni00A0J, Reguła/uni00A0J, Kargulewicz/uni00A0A, Kręgielska-Narożna/uni00A0M, et al. The effects of a low-calorie diet or an isocaloric diet combined with metformin on sex hormones In obese women of child-bearing age. Acta Scientiarum Polonorum Technologia Alimentaria 2016;15(2):213-20. Tang 2006a {published data only} Tang/uni00A0T, Glanville/uni00A0J, Orsi/uni00A0N, Barth/uni00A0JH, Balen/uni00A0AH. The use of metformin for women with PCOS undergoing IVF treatment. Human Reproduction 2006;21(6):1416-25. Toscani 2011 {published data only} Toscani/uni00A0MK, Mario/uni00A0FM, Radavelli-Bagatini/uni00A0S, Wiltgen/uni00A0D, Matos/uni00A0MC, Spritzer/uni00A0PM. Effect of high-protein or normal-protein diet on weight loss, body composition, hormone, and metabolic profile in southern Brazilian women with polycystic ovary syndrome: a randomized study. Gynecological Endocrinology 2011;27(11):925-30. Tsagareli 2006 {published data only} Tsagareli/uni00A0V, Noakes/uni00A0M, Norman/uni00A0RJ. Effect of a very-low-calorie diet on in vitro fertilization outcomes. Fertility and Sterility 2006;86(1):227-9. Turner-McGrievy 2014 {published data only} Turner-McGrievy/uni00A0GM, Davidson/uni00A0CR, Wingard/uni00A0EE, Billings/uni00A0DL. Low glycemic index vegan or low-calorie weight loss diets for women Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 27 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews with polycystic ovary syndrome: a randomized controlled feasibility study. Nutrition Research 2014;34(6):552-8. Vandermolen 2001 {published data only} Vandermolen/uni00A0DT, Ratts/uni00A0VS, Evans/uni00A0WS, Stovall/uni00A0DW, Kauma/uni00A0SW, Nestler/uni00A0JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertility and Sterility 2001;75(2):310-5. [PMID: 11172832] Vanky 2004 {published data only} Vanky/uni00A0E, Salvesen/uni00A0KA, Carlsen/uni00A0SM. Six-month treatment with low-dose dexamethasone further reduces androgen levels in PCOS women treated with diet and lifestyle advice, and metformin. Human Reproduction (Oxford, England) 2004;19(3):529-33. [PMID: 14998946] Van Oers 2016a {published data only} van/uni00A0Oers/uni00A0AM, Groen/uni00A0H, Mutsaerts/uni00A0MA, Burggraaff/uni00A0JM, Kuchenbecker/uni00A0WK, Perquin/uni00A0DA, et al, LIFEstyle Study Group. Effectiveness of lifestyle intervention in subgroups of obese infertile women: a subgroup analysis of an RCT. Human Reproduction 2016;31(12):2704-13. Van Oers 2017 {published data only} van/uni00A0Oers/uni00A0AM, Mutsaerts/uni00A0MAQ, Burggraaff/uni00A0JM, Kuchenbecker/uni00A0WKH, Perquin/uni00A0DAM, Koks/uni00A0CAM, et al, LIFEstyle Study Group. Cost-effectiveness analysis of lifestyle intervention in obese infertile women. Human Reproduction 2017;32(7):1418-26. van Oers 2018 {published data only} van/uni00A0Oers/uni00A0AM, Mutsaerts/uni00A0MAQ, Burggraaff/uni00A0JM, Kuchenbecker/uni00A0WKH, Perquin/uni00A0DAM, Koks/uni00A0CAM, et al, LIFEstyle Study Group. Association between periconceptional weight loss and maternal and neonatal outcomes in obese infertile women. PloS One 2018;13(3). van Santbrink 2005 {published data only} van/uni00A0Santbrink/uni00A0EJ, Hohmann/uni00A0FP, Eijkemans/uni00A0MJ, Laven/uni00A0JS, Fauser/uni00A0BC. Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment. European Journal of Endocrinology 2005;152(4):611-7. Vigerust 2012 {published data only} Vigerust/uni00A0NF, Bohov/uni00A0P, Bjørndal/uni00A0B, Seifert/uni00A0R, Nygård/uni00A0O, Svardal/uni00A0A, et al. Free carnitine and acylcarnitines in obese patients with polycystic ovary syndrome and effects of pioglitazone treatment. Fertility and Sterility 2012;98(6):1620-6. Vosnakis 2013 {published data only} Vosnakis/uni00A0C, Georgopoulos/uni00A0NA, Rousso/uni00A0D, Mavromatidis/uni00A0G, Katsikis/uni00A0I, Roupas/uni00A0ND, et al. Diet, physical exercise and orlistat administration increase serum anti-Mullerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS). Gynecological Endocrinology 2013;29(3):242-5. Wiweko 2017 {published data only} Wiweko/uni00A0B, Susanto/uni00A0CA. The effect of metformin and cinnamon on serum anti-Mullerian hormone in women having PCOS: a double-blind, randomized, controlled trial. Journal of Human Reproductive Sciences 2017;10(1):31. Yang 2005 {published data only} Yang/uni00A0YS, Zhang/uni00A0YL. Clinical study of ganshao capsule in treating clomiphene-resistant polycystic ovarian syndrome. Chinese Journal of Integrated Traditional and Western Medicine 2005;25(8):704-6. Yang 2017 {published data only} Yang/uni00A0D, Zhao/uni00A0M, Tan/uni00A0J. Effect of polycystic ovary syndrome treated with the periodic therapy of acupuncture. Chinese Acupuncture & Moxibustion 2017;37(8):825-9. Yin 2018 {published data only} Yin/uni00A0Y, Zhang/uni00A0Y, Zhang/uni00A0H, Jiang/uni00A0D, Guo/uni00A0G. Clinical therapeutic effects of acupuncture combined with Chinese herbal medicine on infertility of polycystic ovary syndrome in the patients with ovulation induction with letrozole. Chinese Acupuncture and Moxibustion 2018;38(1):27-32. Zhang 2015 {published data only} Zhang/uni00A0T. Effect of qingre yangyin recipe on endocrine and metabolism of polycystic ovary syndrome patients. Chinese Journal of Integrated Traditional and Western Medicine 2015;35(10):1175-80. Zhang 2017 {published data only} Zhang/uni00A0J, Si/uni00A0Q, Li/uni00A0J. Therapeutic effects of metformin and clomiphene in combination with lifestyle intervention on infertility in women with obese polycystic ovary syndrome. Pakistan Journal of Medical Sciences 2017;33(1):8. Zheng 2013 {published data only} Zheng/uni00A0YH, Wang/uni00A0XH, Lai/uni00A0MH, Yao/uni00A0H, Liu/uni00A0H, Ma/uni00A0HX. Effectiveness of abdominal acupuncture for patients with obesity-type polycystic ovary syndrome: a randomized controlled trial. Journal of Alternative and Complementary Medicine 2013;19(9):740-5. /uni00A0

to studies awaiting assessment Duval 2015 {published data only} Duval/uni00A0K, Belan/uni00A0M, Jean-Denis/uni00A0F, Carranza-Mamane/uni00A0B, Pesant/uni00A0MH, Langlois/uni00A0MF, et al. An interdisciplinary lifestyle intervention improves clinically relevant fertility outcomes in obese infertile women: preliminary results of a randomized controlled trial. Canadian Journal of Diabetes 2015;39:529-47. Egbase 2001 {published data only} Egbase/uni00A0P, Al Sharhan/uni00A0M, Buzaber/uni00A0M, Grudzinskas/uni00A0J. Prospective randomised study of metformin in IVF and embryo transfer treatment cycles in obese patients with polycystic ovarian syndrome. Human Reproduction 2001;16(Suppl 1):202. Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 28 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Li 2015 {published data only} Li/uni00A0SS. Metformin and auxiliary acupuncture in the treatment of obese women infertility with polycystic ovary syndrome for 75 cases. Chinese Medicine Modern Distance Education of China [zhong guo zhong yi yao xian dai yuan cheng jiao yu] 2015;13(6):78-9. Pfüller 2004 {published data only} Pfüller/uni00A0B, Ibragimova/uni00A0E, Klaua/uni00A0S, Machlitt/uni00A0A, Rohde/uni00A0W, Voigt/uni00A0K. Effect of metformin treatment combined with lifestyle modification on reproductive features, endocrine and metabolic profiles in obese infertile women with PCOS. Human Reproduction 2004;19:i176. /uni00A0 Additional references Abdallah 2011 Abdallah Ismail/uni00A0N, Ragab/uni00A0SH, Abd Elbaky/uni00A0A, Shoeib/uni00A0AR, Alhosary/uni00A0Y, Fekry/uni00A0D. Frequency of firmicutes and bacteroidetes in gut microbiota in obese and normal weight Egyptian children and adults. Archives of Medical Science 2011;7(3):501-7. ASRM 2015 Practice Committee of the American Society for Reproductive Medicine. Obesity and reproduction: a committee opinion. Fertility and Sterility 2015;104:1116-26. Berkel 2005 Berkel/uni00A0LA, Poston/uni00A0WS, Reeves/uni00A0RS, Foreyt/uni00A0JP. Behavioral interventions for obesity. Journal of the American Dietetic Association 2005;105(5 Suppl 1):S35-43. Best 2017 Best/uni00A0D, Avenell/uni00A0A, Bhattacharya/uni00A0S. How effective are weight-loss interventions for improving fertility in women and men who are overweight or obese? A systematic review and meta-analysis of the evidence. Human Reproduction Update 2017;23(6):681-705. Boots 2011 Boots/uni00A0C, Stephenson/uni00A0MD. Does obesity increase the risk of miscarriage in spontaneous conception: a systematic review. Seminars in Reproductive Medicine 2011;29(6):507-13. 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Acupuncture for obesity: a systematic review and meta-analysis. International Journal of Obesity 2009;33(2):183-96. Chong 1986 Chong/uni00A0AP, Rafael/uni00A0RW, Forte/uni00A0CC. Influence of weight in the induction of ovulation with human menopausal gonadotropin and human chorionic gonadotropin. Fertility and Sterility 1986;46:599-603. Clark 1998 Clark/uni00A0AM, Thornley/uni00A0B, Tomlinson/uni00A0L, Galletley/uni00A0C, Norman/uni00A0RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Human Reproduction 1998;13(6):1502-5. Crosignani 1994 Crosignani/uni00A0PG, Ragni/uni00A0G, Parazzini/uni00A0F, Wyssling/uni00A0H, Lombroso/uni00A0G, Perotti/uni00A0L. Anthropometric indicators and response to gonadotrophin for ovulation induction. Human Reproduction 1994;9:420-3. Crosignani 2003 Crosignani/uni00A0PG, Colombo/uni00A0M, Vegetti/uni00A0W, Somigliana/uni00A0E, Gessati/uni00A0A, Ragni/uni00A0G. 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Obesity, obstetric Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 31 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews complications and cesarean delivery rate: a population-based screening study. American Journal of Obstetrics and Gynecology 2004;190:1091-7. Yin 2005 Yin/uni00A0S, Lin-shan/uni00A0Z. Therapeutic idea and approaches to obesity with acupuncture. Journal of Acupuncture and Tuina Science 2005;3(4):54-7. /uni00A0 * Indicates the major publication for the study /uni00A0 C H A R A C T E R I S T I C S /uni00A0 O F /uni00A0 S T U D I E S Characteristics of included studies [ordered by study ID] /uni00A0 Study characteristics

Multi-centre, multi-disciplinary, prospective, randomised controlled trial Participants • Setting: 9 infertility clinics in Sweden, Denmark, and Iceland • Inclusion: infertile women between 18 and 38 years of age with indications for IVF and planning to start their first, second, or third IVF treatment and with BMI ≥ 30 and < 35 kg/m/two.sups • Exclusion: women were excluded from the trial if they had insulin-dependent diabetes mellitus and other exclusion factors such as planned oocyte donation, planned pre-implantation genetic diagno- sis, husband with azoospermia known at randomisation, less than adequate knowledge of the local language, binge eating disorder, or previous study participation Interventions Comparison • Intervention group: weight reduction before IVF, starting with 12 weeks of a low-calorie liquid formula diet (LCD) of 880 kcal/d and thereafter weight stabilisation for 2 to 5 weeks • Control group: IVF only Outcomes Live birth rate Weight reduction (change in BMI) Clinical pregnancy Ongoing pregnancy Miscarriage Notes Conflicts of interest: some issues are presented in the article Funding: Sahlgrenska University Hospital (ALFGBG-70 940), Merck AB Solna Sweden (an affiliate of Merck KGaA, Darmstadt, Germany), Impolin AB, Hjalmar Svensson Foundation, and Jane and Dan Ols- son Foundation for Science. Funders had no role in the design of the study, statistical analysis, or inter- pretation of study results, nor in writing the article or deciding to submit it for publication Date study was conducted: 10 May 2010 Clinical trial registration number: NCT01566929 Trial authors contacted: Ann Thurin-Kjellberg Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Computerised randomisation programme Allocation concealment (selection bias) Low risk Online concealed allocation of patients in the proportion of 1:1. Optimal allo- cation was applied according to Pocock’s minimisation technique for sequen- tial randomisation, taking account of the number of previously performed Einarsson 2017/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 32 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews fresh IVF cycles and age of the woman, as well as parity, polycystic ovarian syndrome (PCOS), fertilisation method planned, tubal factor, smoking, BMI, and waist circumference Blinding of participants and personnel (perfor- mance bias) All outcomes High risk Blinding was not possible for patients or physicians Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk Embryologists and statisticians were unaware as to which group participants were allocated but as the women and investigators were aware we can't rule out detection bias Incomplete outcome data (attrition bias) All outcomes Low risk Missing outcome data were balanced in numbers across intervention groups, with similar reasons for missing data across groups • In the weight reduction and IVF group, 1 patient did not receive the allocat- ed intervention and 7 discontinued the intervention. In the IVF only group, 2 patients did not receive the allocated intervention and 2 discontinued the intervention. No patients were lost to follow-up Selective reporting (re- porting bias) Low risk The study protocol is available, and all of the study's pre-specified outcomes have been reported in the results https://clinicaltrials.gov/ct2/show/NCT01566929 Other bias Low risk We did not identify any other potential sources of bias in the study, and we judged low risk for other potential sources of bias Einarsson 2017/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Double-blinded randomised controlled clinical trial Participants • Setting: Department of Obstetrics and Gynecology, Faculty of Medicine, Zagazig University, Zagazig, Egypt • Inclusion:obesity, infertility • Exclusion: smokers, drug users, those with other causes of infertility such as male factor or tubal fac- tor, those with endocrine disorders such as thyroid dysfunction or hyperprolactinaemia Interventions Group 1 (CC plus metformin and L-carnitine): received 150 mg/d CC from day 3 till day 7 of menstrual cycle plus oral L-carnitine 3 g and metformin 850 mg (1 tablet daily), then the dose was doubled after 1 week to 1700 mg/d (2 tablets daily). Metformin was ingested before a meal once daily during the first week and thereafter twice daily. L-carnitine and metformin were stopped only when pregnancy was documented. Group 2 (CC plus metformin and placebo): received 150 mg/d CC plus metformin (as above) and place- bo capsules that were designed to look exactly like L-carnitine capsules. Outcomes Pregnancy rate Miscarriage rate BMI Free testosterone El 2019/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 33 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Notes Conflicts of interest: no Funding: Zagazig University Date study was conducted: January 2017 Clinical trial registration number: NCT03108963 Trial authors contacted: El Sharkwy I. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Computerised randomisation programme Allocation concealment (selection bias) Low risk Allocation was concealed in opaque, sealed, serially numbered envelopes Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Women, treating physicians, and investigators were blinded to treatment allo- cation Blinding of outcome as- sessment (detection bias) All outcomes Low risk Women, treating physicians, and investigators were blinded to treatment allo- cation Incomplete outcome data (attrition bias) All outcomes Low risk Missing outcome data were balanced in numbers across intervention groups, with similar reasons for missing data across groups • A total of 375 women were assessed for eligibility. Of them, 95 were exclud- ed (60 did not meet the inclusion criteria and 35 refused to participate). The consenting 280 women were randomly allocated to group 1 (n = 140) or group 2 (n = 140). Six women were excluded from analysis due to loss to follow-up: 2 women in group 1 and 4 women in group 2 Selective reporting (re- porting bias) Low risk The study protocol is available, and all of the study's pre-specified outcomes have been reported in the results Other bias Low risk We did not identify any other potential sources of bias in the study, and we judged low risk for other potential sources of bias El 2019/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Double-blind, cross-over design Participants • Setting: reproductive medicine clinic, Australia • Inclusion: obese infertile women • Exclusion: not mentioned Interventions Comparison: dexfenfluramine and placebo were given in a double-blind cross-over design • Dexfenfluramine dosage was 15 mg twice daily, and the duration of each treatment condition was 12 weeks for placebo/dexfenfluramine (n = 11) and dexfenfluramine/placebo (n = 10). We tried to extract only the pre-cross-over data Galletly 1996/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 34 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcomes Weight loss, this was the only useable outcome but not sure whether truly pre-cross-over data Self-esteem score Depression score Anxiety score Notes Data regarding self-esteem, depression, and BMI are not presented separately for each group. Conflicts of interest: not mentioned Funding: not mentioned Date study was conducted: not mentioned Clinical trial registration number: not mentioned Trial authors contacted: Cherrie Galletly Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk Insufficient information about sequence generation Allocation concealment (selection bias) Unclear risk Method of concealment not described Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk Insufficient information to permit judgement Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk Insufficient information to permit judgement Incomplete outcome data (attrition bias) All outcomes Unclear risk The study did not address this outcome Selective reporting (re- porting bias) High risk The study protocol is unavailable, and all of the study's pre-specified out- comes have not been reported in the results • At the beginning, midpoint, and end of the study, patients completed the Rosenberg Self-Esteem Scale and the Hospital Anxiety and Depression Scale. Weight patients were weighed weekly throughout the study BMI is not an outcome measure but it was evaluated Other bias Low risk We did not identify any other potential sources of bias in the study, and we judged low risk for other potential sources of bias Galletly 1996/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Double-blinded multi-centre randomised trial Johnson 2010/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 35 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Participants • Setting: multi-centre, New Zealand • Inclusion: anovulatory or oligo-ovulatory women with PCOS • Exclusion: couples who had undergone previous fertility treatment involving more than 5 months of treatment with CC or metformin; with any other important infertility factor known to be present, in- cluding known tubal factor in which at least 1 fallopian tube was blocked (although a tubal potency test was not a prerequisite for trial entry); with important medical disorders in women Interventions Comparison • Women with BMI > 32 received no treatment other than advice and encouragement on lifestyle inter- vention (which included advice on calorie restriction and on increasing aerobic exercise to 30 minutes at least 5 times per week with an opportunity to see a dietician and an exercise therapist if required (i.e. standard care)): • Placebo • Intervention: metformin (in addition to standard care) for 6 months; metformin 500 mg 3 times daily at a gradually increasing dose over 2 weeks was given; for CC, 50 mg was the initial dose and 150 mg the highest dose used Outcomes Clinical pregnancy Live birth Spontaneous abortion Adverse events In this study, patients were divided according to BMI < 32 and BMI ≥ 32. We included only data from BMI ≥ 32 in this review Notes Conflicts of interest: NPJ reports receiving travel support from Serono, Organon, Bayer-Schering, and Device Technologies New Zealand, and funding for a research meeting from Serono. VPS reports receiv- ing travel support from Serono Funding: Auckland Medical Research Foundation, Mercia Barnes Trust, and University of Auckland Re- search Committee. Funders played no role in the design, the conduct of the research, or the decision to publish Date study was conducted: August 2003 Clinical trial registration number: NCT00795808 Trial authors contacted: NP Johnson Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk In this study, it was mentioned that complete description of patients is provid- ed Randomisation was done through a computer-generated randomisation process Allocation concealment (selection bias) Low risk Concealment was strictly maintained by a telephone call from the recruiting research nurse to the pharmacy Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Blinding (masking) of all parties (women and personnel) was maintained in all cases by placebo control until the end of the course of treatment or, in the event of pregnancy, until after the pregnancy Blinding of outcome as- sessment (detection bias) All outcomes Low risk The research pharmacist executed the assignment by dispensing pre-prepared drugs by true third party randomisation. Blinding (masking) of all parties was Johnson 2010/uni00A0/uni00A0(Continued) Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 36 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews maintained in all cases by placebo control until the end of the course of treat- ment or, in the event of pregnancy, until after the pregnancy Incomplete outcome data (attrition bias) All outcomes Low risk • Of 33 women with BMI ≥ 32 kg/m/two.sups receiving placebo, 30 completed treatment and follow-up (2 of whom were not fully adherent to treatment - 1 experi- enced side effects so took a reduced dose; 1 misunderstood the gradual in- crease in dose and did this every month) • 3 breached the protocol by stopping trial medications; 25 women who had not had confirmed ovulation 3 months into the trial received CC thereafter. Among 32 women with BMI ≥ 32 kg/m/two.sups receiving metformin, 29 completed treatment and follow-up (all of whom were fully adherent to treatment) - 2 women were lost to follow-up, 1 of whom was pregnant at the time of emi- gration to Australia, and 1 who stopped trial medication; 22 women who had not had confirmed ovulation 3 months into the trial received CC thereafter Selective reporting (re- porting bias) Low risk The study protocol is available, but all of the study's pre-specified outcomes have been reported in the results https://clinicaltrials.gov/ct2/show/NCT00795808 Other bias Low risk We did not identify any other potential sources of bias in the study, and we judged low risk for other potential sources of bias Johnson 2010/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

A randomised prospective trial Participants • Setting: university-based medical centre, California • Inclusion: anovulatory or oligo-ovulatory cycles (35 days or 8 cycles/year), polycystic ovaries on a baseline ultrasound, hyperandrogenism (hirsutism, acne, alopecia, or elevated testosterone), BMI > 29 kg/m/two.sups, desire for fertility • Exclusion: pregnancy, hepatic disease, renal disease, heart disease, alcoholism, pulmonary disease, thyroid disease, prolactinoma, congenital adrenal hyperplasia, androgen-secreting tumour Interventions Comparison • Group 1 (CC + met): participants received MET 500 mg 3 times a day, given on cycle days 1 through 14, with cycle day 1 defined as the first day of menstrual flow after a 10-day course of medroxyproges- terone acetate (10 mg daily) challenge in combination with CC 100 mg per day taken on days 5 through 9 of the cycle. In the group receiving MET, the entire dose of the medication (1500 mg/d) was taken from the start of treatment (n = 16) • Group 2 (CC): participants received CC 100 mg per day on cycle days 5 through 9 only. The dose of CC chosen (100 mg/d) was based on significant obesity in the population and the known ineffectiveness of lower doses of CC in these patients (n = 15) Outcomes Free glucose Total and free Testosterone SHBG Pregnancy rate Notes Conflicts of interest: not mentioned Funding: not mentioned Khorram 2006/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 37 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Date study was conducted: not found Clinical trial registration number: not found, at https://clinicaltrials.gov/ Trial authors contacted: Khorram O Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Randomisation was done by picking a card out of a box, which had 1 or the other treatment written on it; the participant was assigned to that group Allocation concealment (selection bias) High risk Randomisation was done by picking a card out of a box, which had 1 or the other treatment written on it; the participant was assigned to that group Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk Probably not blinded Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk Probably not blinded Incomplete outcome data (attrition bias) All outcomes Unclear risk The study lacks details of dropout rates Selective reporting (re- porting bias) High risk The study protocol is unavailable Other bias Low risk We did not identify any other potential sources of bias in the study, and we judged low risk for other potential sources of bias Khorram 2006/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Secondary analysis of a multi-centre RCT (randomised controlled trial) Participants • Setting: 6 university medical centres and 17 general hospitals in The Netherlands • Inclusion: infertile women between 18 and 39 years of age with BMI ≥ 29 • Exclusion: women with severe endometriosis, premature ovarian failure, or endocrinopathy (e.g. women with type 1 diabetes, women with Cushing’s syndrome). Those who were eligible for donor insemination because of azoospermia were excluded, as were women with untreated preexisting hy- pertension and those with hypertension-related complications in a previous pregnancy Interventions Comparison • Intervention: lifestyle intervention consisted of a 6-month structured programme aiming at weight loss of 5% to 10% of original body weight. It included 6 structured outpatient visits and 4 telephone consultations with a pre-trained intervention coach. Daily dietary energy intake was reduced by 600 kcal and was maintained at a minimum of 1200 kcal/d • Physical activity was stimulated to a level of 10,000 steps a day and at least 30 minutes of exercise 2 to 3 times a week. Behavioural changes were facilitated by motivational counselling. After com- pletion of the 6-month programme, or when weight loss of 5% to 10% had been achieved, women started to receive appropriate infertility treatment if they were not yet pregnant Mutsaerts 2016/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 38 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Control: appropriate infertility treatment immediately after randomisation. Outcomes Live birth Ongoing pregnancy Clinical pregnancy Miscarriage Notes This lifestyle project and some data are presented in the papers below • Mutsaerts MA, Groen H, ter Bogt NC, Bolster JH, Land JA, Bemelmans WJ, Kuchenbecker WK, Hompes PG, Macklon NS, Stolk RP, et al. The LIFESTYLE study: costs and effects of a structured lifestyle program in overweight and obese subfertile women to reduce the need for fertility treatment and improve re- productive outcome. A randomised controlled trial. BMC Womens Health 2010;10:22-6874-10-22 • Mutsaerts MA, van Oers AM, Groen H, Burggraaff JM, Kuchenbecker WK, Perquin DA, Koks CA, van Golde R, Kaaijk EM, Schierbeek JM, et al. Randomized trial of a lifestyle program in obese infertile women. N Engl J Med 2016;374:1942–1953 • Karsten MDA, van Oers AM, Groen H, Mutsaerts MAQ, van Poppel MNM, Geelen A, van de Beek C, Painter RC, Mol BWJ, Roseboom TJ , Hoek A; LIFEstyle study group.Determinants of successful lifestyle change during a 6-month preconception lifestyle intervention in women with obesity and infertility. Eur J Nutr • van Oers AM, Mutsaerts MAQ, Burggraaff JM, Kuchenbecker WKH, Perquin DAM, Koks CAM, van Golde R, Kaaijk EM, Schierbeek JM, Klijn NF, van Kasteren YM, Land JA, Mol BWJ, Hoek A, Groen H; LIFEstyle Study Group. Cost-effectiveness analysis of lifestyle intervention in obese infertile women. Hum Re- prod 2017;32(7):1418-1426. doi: 10.1093/humrep/dex092 • van Oers AM , Mutsaerts MAQ. Association between periconceptional weight loss and maternal and neonatal outcomes in obese infertile women. PLoS One 2018;13(3):e0192670. doi: 0.1371/jour- nal.pone.0192670 Conflicts of interest: the Department of Obstetrics and Gynaecology of the UMCG received an unre- stricted educational grant from Ferring Pharmaceuticals BV, The Netherlands. BWJM is a consultant for ObsEva, Geneva Funding: Netherlands Organization for Health Research and Development Date study was conducted: 1 April 2009 Clinical trial registration number: NTR1530 Trial authors contacted: Zon MW Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Randomisation was performed through a web-based randomisation pro- gramme and was stratified according to trial centre and ovulatory status Allocation concealment (selection bias) Low risk Web-based randomisation programme Blinding of participants and personnel (perfor- mance bias) All outcomes High risk Blinding to treatment assignments was not possible Blinding of outcome as- sessment (detection bias) All outcomes High risk Blinding to treatment assignments was not possible Incomplete outcome data (attrition bias) All outcomes Low risk Missing outcome data were balanced in numbers across intervention groups, with similar reasons for missing data across groups Mutsaerts 2016/uni00A0/uni00A0(Continued) Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 39 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • We randomised 577 women, of whom 290 were randomised to the lifestyle in- tervention preceding infertility treatment arm (9 were lost to follow-up and 1 withdrew informed consent) and 287 to the prompt infertility treatment arm (1 was lost to follow-up and 2 withdrew informed consent). So, in total, data for 280 women in the intervention group and for 284 women in the control group were available for analysis Selective reporting (re- porting bias) Low risk The study protocol is available, and all of the study's pre-specified outcomes have been reported in the results Other bias Low risk We did not identify any other potential sources of bias in the study, and we judged low risk for other potential sources of bias Mutsaerts 2016/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Open-label, single-site, pilot study Participants • Setting: single-site, academic institution, Michigan • Inclusion: 18 to 35 years old. Obesity (BMI ≥ 35 and ≤ 45 kg/m/two.sups). Infertility. Evidence of normal uterine anatomy and at least 1 patent tube documented by hysterosalpingogram or saline infusion sonogram. Polycystic ovary syndrome. Ovulatory dysfunction (amenorrhoea, irregular cycles, or progesterone level < 10 ng/mL in the luteal phase). Partner with semen analysis demonstrating ≥ 20 million sperm/ mL, 50% motility, and normal morphology by Kruger criteria of 8% • Exclusion: women who were using donor sperm, had FSH > 10 mIU/mL, or had endometriosis Ameri- can Fertility Society class III or IV; were taking anti-obesity drugs or appetite suppressants within the past 2 months; had previous bariatric surgery or gastrointestinal disease; used hormone medications within the past 2 months; had elevated prolactin, type 1 diabetes, uncorrected thyroid disease, or evi- dence of adrenal disease; had evidence of conditions that would complicate pregnancy (liver disease, kidney disease, autoimmune disorders such as systemic lupus erythematosus, significant anaemia, history of clotting disorder, uncontrolled hypertension, heart disease, or cancer) Interventions Comparison • Intensive weight loss intervention (IWL): IWL consisted of 12 weeks of very low-energy diet (800 kcal/ d) and 4 weeks of a low-calorie conventional food-based diet (CFD) to promote 15% weight loss (n = 6) • Standard of care nutrition counselling (SCN): SCN consisted of 16 weeks of CFD to promote 5% weight loss (n = 5) Outcomes Live birth Weight loss (BMI) Fasting glucose Confirmed pregnancy Depression (IDS-SR) Quality of life (EQ-5D health score) Adverse events Notes Thirty-nine women were screened; 25 (64%) were eligible to participate, and 14 of those eligible (56%) agreed to be randomised, 7 to each group. One withdrew from the IWL group and 2 from the SCN group Conflicts of interest: not mentioned Rothberg 2016/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 40 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Funding: supported by a grant from the Michigan Institute for Clinical Research (grant U040012 PI to A.R.); core services of the Michigan Nutrition Obesity Research Center (grant DK089503); and the Michi- gan Center for Diabetes Research (grant P30DK020572) Date study was conducted: October 2013 Clinical trial registration number: NCT01894074 Trial authors contacted: Rothberg A Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk Information insufficient to permit judgement Allocation concealment (selection bias) High risk Open-label trial, not concealed Blinding of participants and personnel (perfor- mance bias) All outcomes High risk Open-label trial, not blinded Blinding of outcome as- sessment (detection bias) All outcomes High risk Open-label trial, not blinded Incomplete outcome data (attrition bias) All outcomes Low risk • We screened 39 women, of whom 25 were found to be eligible and 14 agreed to participate. Our inability to achieve a target sample size of 32 was due to the extremely restrictive eligibility criteria and the reluctance of eligible women to delay ovulation induction. After the baseline oral glucose toler- ance test, participants were randomly allocated to treatment. Seven partic- ipants were randomised to each group. One participant withdrew from the IWL group (did not tolerate diet) after 1 week of starting the dietary interven- tion and 2 participants withdrew (decided not to pursue pregnancy and were dissatisfied with the randomisation arm) from the SCN group before the di- etary intervention Selective reporting (re- porting bias) Low risk The study protocol is available, but all of the study's pre-specified outcomes have been reported in the results https://clinicaltrials.gov/ct2/show/NCT01894074 Other bias Low risk We did not identify any other potential sources of bias in the study, and we judged low risk for other potential sources of bias Rothberg 2016/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

A prospective, randomised, open-label study Participants • Setting: Slovenia • Inclusion: PCOS diagnosed according to revised Rotterdam criteria, body mass index (BMI) ≥ 30 kg/ m/two.sups, age ≤ 38, first or second IVF attempt; no severe male infertility • Exclusion: type 1 or type 2 diabetes mellitus; history of carcinoma; personal or family history of MEN2; significant cardiovascular, kidney, or liver disease; use of medications other than metformin known or Salamun 2018/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 41 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews suspected to affect reproductive or metabolic functions or statins within 90 days before study entry; no coexisting ovarian pathology Interventions Comparison • Metformin (MET) 1000 mg twice daily: metformin was initiated at a dose of 500 mg once per day and was increased by 500 mg every 3 days up to 1000 mg twice daily • Metformin 1000 mg twice daily combined with 1.2 mg liraglutide every day subcutaneously (COMBI): in the COMBI arm, there was a run-in period of 12 days to titrate metformin up to 1000 mg twice daily before liraglutide was added. Liraglutide was initiated at a dose of 0.6 mg injected subcutaneously once per day and increased to 1.2 mg after 3 days. Medical treatment in both groups lasted 12 weeks Outcomes Clinical pregnancy Weight loss (BMI) Total body fat (%) Glu OGTT Free T Total T SHBG Adverse events Notes Conflicts of interest: no Funding: grant number 20140031 of the University Medical Center, Ljubljana, Slovenia Date study was conducted: 1 September 2014 Clinical trial registration number: NCT03353948 Trial authors contacted: Vesna Salamun Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk This is not described in sufficient detail to allow a definitive judgement Allocation concealment (selection bias) High risk Open-label trial, not concealed Blinding of participants and personnel (perfor- mance bias) All outcomes High risk Open-label trial, not blinded Blinding of outcome as- sessment (detection bias) All outcomes High risk Open-label trial, not blinded Incomplete outcome data (attrition bias) All outcomes Low risk Missing outcome data were balanced in numbers across intervention groups, with similar reasons for missing data across groups • 28 patients started the study, and 27 (14 on MET, 13 on COMBI) completed treatment according to the protocol and were included in the analysis (Fig. 1). 1 patient in the COMBI group discontinued the study because of proto- col violation, 2 patients in the MET group refused IVF. 1 patient in the COMBI group and 1 in the MET group conceived spontaneously immediately after Salamun 2018/uni00A0/uni00A0(Continued) Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 42 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews treatment completion. The remaining 23 patients (11 in the MET group and 12 in the COMBI group) attended an IVF after treatment completion Selective reporting (re- porting bias) Low risk The study protocol is available, and all of the study's pre-specified outcomes have been reported in the results https://clinicaltrials.gov/ct2/show/NCT03353948 Other bias Low risk We did not identify any other potential sources of bias in the study, and we judged low risk for other potential sources of bias Salamun 2018/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Evaluator-blinded, randomised controlled trial Participants • Setting: Australian • Inclusion: obese (BMI ≥ 30 kg/m/two.sups) female patients aged 18 to 37 years, intending to commence their IVF, ICSI, or cryo-stored embryo transfer treatment at RPAH Fertility Unit • Exclusion: current psychiatric condition (i.e. bulimia nervosa, overt psychosis, severe depression, drug or alcohol abuse); significant physical condition (i.e. acute cerebrovascular or cardiovascular disease, malignancy, significant hepatic or renal dysfunction, musculoskeletal disease); endocrine condition other than polycystic ovarian syndrome (PCOS) (i.e. type 1 diabetes, uncontrolled thyroid disease, Cushing’s syndrome, hyperprolactinaemia (> 450 IU L –1)); pancreatitis; porphyria; recent (within 3 months) participation in treatment known to affect diet or body weight; unable to follow both verbal and written English instructions; unwilling to suspend fertility treatment for up to 3 months Interventions Comparison • Intervention (n = 27): 12-week intervention consisting of a very low-energy diet for the first 6 weeks followed by a hypocaloric diet, combined with a weekly group multi-disciplinary programme • Control (n = 22): received recommendations for weight loss and the same printed material as the in- tervention group Outcomes Clinical pregnancy rate Live birth Changes in anthropometric measures (weight, BMI, and waist circumference (WC)) Miscarriage rate Notes Conflicts of interest: no Funding: not mentioned. Date study was conducted: February 2007 Clinical trial registration number: 12606000448549 Trial authors contacted: KA Sim Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk The code was prepared before study start, as the allocation was performed us- ing sealed envelopes Sim 2014/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 43 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Allocation concealment (selection bias) Low risk Randomisation was done by the sequentially numbered, opaque-sealed enve- lope method Blinding of participants and personnel (perfor- mance bias) All outcomes High risk The dietician, midwives, counsellor, fertility fellow, and participants were aware of randomisation, but fertility specialists were not Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk The fertility fellow who was aware of randomisation was not involved with cy- cle management and did not perform any assisted conception procedures for these patients. The dietician, midwives, counsellor, fertility fellow, and partici- pants were aware of randomisation, but fertility specialists and patients were not. This may have affected detection bias Incomplete outcome data (attrition bias) All outcomes High risk Very small study (26 versus 22). Missing outcome data problematic, especially for weight loss data as a 20% loss can have a lot of impact on the outcomes./uni00A0 • An estimated 86 patients were identified in consultation at the fertility unit and were approached by the research leader for discussion of participation in the study. Forty-nine were screened for eligibility, and 37 chose not to participate. The physicians identifying patients referred only 86 for an ini- tial discussion; it was estimated that more were eligible. All of the 49 partic- ipants who entered the trial completed a baseline assessment. 6 separate weight loss intervention programmes were run, with groups of participants varying in number between 3 and 8. At 12 weeks, 10 (20%) participants had withdrawn or dropped out of the trial. No participants reported any serious adverse events during the dietary intervention. There were no statistically significant differences between completers and dropouts in both groups in terms of pregnancy rates, fertility treatment outcomes, or maternal and fetal complications (results not shown) Selective reporting (re- porting bias) Low risk The study protocol is available, and all of the study's pre-specified outcomes have been reported in the results https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=81639 Other bias Low risk We did not identify any other potential sources of bias in the study, and we judged low risk for other potential sources of bias Sim 2014/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

A randomised, placebo-controlled, double-blind study Participants • Setting: England • Inclusion: anovulatory PCOS and BMI ≥ 30 kg/m/two.sups, between 18 and 39 years of age inclusive, a desire to conceive, presence of ≥ 1 patent fallopian tube and normal semen analysis from male partner. All par- ticipants had normal serum prolactin concentrations; thyroid, renal, and liver function; and haema- tological indices, including serum B12 concentrations • Exclusion: concurrent hormone therapy within the previous 6 weeks; any chronic disease that could interfere with absorption, distribution, metabolism, or excretion of metformin; renal or liver disease. Patients with significant systemic disease or diabetes (type 1 or 2) were excluded. Patients with irreg- ular menstrual bleeding were thoroughly assessed to exclude pathology of the genital tract other than PCOS, and a negative pregnancy test was a prerequisite for commencing treatment Interventions Comparison Tang 2006/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 44 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Intervention: metformin (850 mg) twice daily over 6 months (n = 69) • Control: placebo over 6 months (n = 74) All received the same advice from a dietician Outcomes Change in anthropometric measurements (BMI, WHR) Testosterone SHBG Pregnancy rate Notes Randomised: 143 patients: 69 metformin (56 completed) and 74 placebo (66 completed) Conflicts of interest: not mentioned Funding: not mentioned Date study was conducted: 1999 Clinical trial registration number: not found Trial authors contacted: Adam H. Balen Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk A block-of-four randomisation technique was performed using random tables Allocation concealment (selection bias) Low risk Double-blind, placebo tablets for metformin were identical in appearance (size and colour) to metformin. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk The randomisation process was carried out by the clinical trials office in the pharmacy department and blinded to patients and investigators. Blinding of outcome as- sessment (detection bias) All outcomes Low risk The randomisation process was carried out by the clinical trials office in the pharmacy department and blinded to patients and investigators. Incomplete outcome data (attrition bias) All outcomes Low risk • A total of 8 centres took part in the recruitment process. A total of 183 women were screened for inclusion in the study. Of these, 40 women were exclud- ed due to previously undiagnosed tubal disease or coexisting male factor in- fertility. As a result, a total of 143 subjects were randomised to receive met- formin (n = 69) or to receive placebo (n = 74) (Fig. 1). In the metformin arm, 13 participants withdrew within the first 4 months of the trial (11 due to side effects and 2 due to spontaneous pregnancies). 8 women withdrew from the placebo arm (6 due to ‘side effects’ and 2 due to spontaneous pregnancies) within the first 2 months of the study. The difference in dropout rates, exclud- ing those due to pregnancy (metformin 15.9% versus placebo 8.0%) was not significant (P = 0.229; 95% CI –2.69 to 18.5). At the end of the study, the num- bers of participants who completed the trial in the metformin and placebo arms were 56 and 66, respectively. Compliance was high and the dropout rate relatively low, as these patients were motivated by a desire to conceive and the knowledge that they needed to attain BMI < 30 kg/m/two.sups to qualify for ovu- lation induction Selective reporting (re- porting bias) High risk The study protocol is unavailable. It is not described in sufficient detail to al- low a definitive judgement Tang 2006/uni00A0/uni00A0(Continued) Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 45 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Other bias Low risk We did not identify any other potential sources of bias in the study, and we judged low risk for other potential sources of bias Tang 2006/uni00A0/uni00A0(Continued) BMI: body mass index. CC: clomiphene citrate. CFD: conventional food-based diet. EQ-5D: EuroQoL Group Quality of Life Questionnaire based on 5 dimensions. FSH: follicle-stimulating hormone. ICSI: intracytoplasmic sperm injection. IDS-SR: Inventory of Depressive Symptomatology-Self-Report. IVF: in vitro fertilisation. IWL: intensive weight loss intervention. MEN2: multiple endocrine neoplasia type 2. MET: metformin. OGTT: oral glucose tolerance test. PCOS: polycystic ovarian syndrome. RCT: randomised controlled trial. SCN: standard of care nutrition counselling. SD: standard deviation. SHBG: sex hormone-blinding globulin. WC: waist circumference. /uni00A0 Characteristics of excluded studies [ordered by study ID] /uni00A0 Study Reason for exclusion Asemi 2014 Wrong patient population Asemi 2014a Wrong patient population Asemi 2015 Wrong patient population Ashoush 2016 Wrong patient population Attarzadeh 2012 Wrong patient population Baillargeon 2004 Wrong patient population Becker 2015 Wrong patient population Cheraghi 2014 Wrong patient population Gambineri 2004 Wrong patient population Hanjalic-Beck 2010 Wrong patient population Janez 2017 Wrong patient population Janez 2018 Wrong patient population Jensterle 2017 Wrong patient population Karsten 2018 Wrong outcome Kocak 2002 Wrong patient population Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 46 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Study Reason for exclusion Legro 2007 Wrong patient population Liao 2011 Wrong patient population Ma 2007 Wrong patient population Moran 2006 Wrong patient population Morin-Papunen 1998 Wrong patient population Morin-Papunen 2000 Wrong patient population Morin-Papunen 2012 Wrong patient population Pasquali 1986 Wrong patient population Pasquali 2000 Wrong patient population Pastore 2011 Wrong patient population Penna 2005 Wrong patient population Petranyi 2011 Wrong patient population Pourmatroud 2015 Wrong patient population Premawardhana 1994 Wrong patient population Qin 2016 Wrong patient population Qublan 2007 Wrong patient population Seibel 2008 Wrong patient population Shahebrahimi 2016 Wrong patient population Siebert 2009 Wrong patient population Sonmez 2005 Wrong patient population Sordia-Hernandez 2016 Wrong patient population Sorensen 2012 Wrong patient population Stamets 2004 Wrong patient population Swora-Cwynar 2016 Wrong patient population Tang 2006a Wrong patient population Toscani 2011 Wrong patient population Tsagareli 2006 Wrong patient population Turner-McGrievy 2014 Wrong patient population Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 47 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Study Reason for exclusion Vandermolen 2001 Wrong patient population Vanky 2004 Wrong patient population Van Oers 2016a Wrong outcome Van Oers 2017 Wrong outcome van Oers 2018 Wrong outcome van Santbrink 2005 Wrong patient population Vigerust 2012 Wrong patient population Vosnakis 2013 Wrong patient population Wiweko 2017 Wrong patient population Yang 2005 Wrong patient population Yang 2017 Wrong patient population Yin 2018 Wrong patient population Zhang 2015 Wrong patient population Zhang 2017 Wrong study design Zheng 2013 Wrong patient population /uni00A0 Characteristics of studies awaiting classification [ordered by study ID] /uni00A0

RCT Participants Obese infertile women Interventions Comparison • Intervention: lifestyle intervention without fertility treatment for the first 6 months • Control: standard fertility treatment Participants were followed for 18 months or until the end of pregnancy Outcomes Pregnancy rate Spontaneous pregnancy rate Live birth Weight loss Notes This study did not report the number of participants Duval 2015/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 48 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 /uni00A0

RCT Participants 68 obese infertile PCOS patients Interventions Group 1: patients received metformin (500 mg tds) from day 2 of same index treatment menstrual cycle and continued until the day of administration of trigger dose of HCG Group 2: control (no drug) Outcomes Serum levels of T DHAS SHBG FBS/FBI ratio Fertilization and cleavage rates Clinical pregnancy rate Implantation rate Miscarriage rate Notes Metformin reduced insulin resistance in obese PCOS patients with a statistically significant positive effect on folliculogenesis (follicular synchrony) and embryo quality (good quality embryos and im- plantation rates) Egbase 2001/uni00A0 /uni00A0 /uni00A0

RCT Participants Obese women with infertility with polycystic ovary syndrome Interventions Control group: metformin Observation group: auxiliary acupuncture 75 cases in each group Outcomes Cycle ovulation rate Pregnancy rate Notes Cycle ovulation rate and pregnancy rate of the observation (auxiliary acupuncture) group were sig- nificantly better than those of the control (metformin) group Li 2015/uni00A0 /uni00A0 /uni00A0

RCT Participants 46 infertile women with PCOS, between 22 and 39 years of age; mean BMI 38.1, range 28.1 to 49.0 kg/m/two.sups Pfüller 2004/uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 49 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Interventions Group 1: M and lifestyle modification Group 2: Lifestyle modification only; patients received placebo Outcomes In the metformin group, mean BMI decreased significantly (-5.6 kg vs.-2.2 kg). Neither metformin nor placebo modified levels of testosterone (T), free T, FAI (free androgen index), LH/FSH ratio. After treatment, SHBG concentrations were significantly increased in the metformin-taking group (+7.5 vs. +3.2). Cholesterol, LDL, and triglycerides have not revealed any changes in either group. Serum HDL levels were significantly higher in the drug-treated group (+3.7 vs –1.7) Notes /uni00A0 Pfüller 2004/uni00A0/uni00A0(Continued) BMI: body mass index. DHAS: dehydroepiandrosterone sulphate. FBS/FBI: fasting blood sugar/fasting blood insulin. FSH: follicle-stimulating hormone. HCG: human chorionic gonadotropin. HDL: high-density lipoprotein. LDL: low-density lipoprotein. LH: luteinising hormone. PCOS: polycystic ovarian syndrome. RCT: randomised controlled trial. SHBG: sex hormone-binding globulin. /uni00A0 /uni00A0 D A T A /uni00A0 A N D /uni00A0 A N A L Y S E S /uni00A0 Comparison 1. /uni00A0 Non-pharmacological intervention versus no intervention or placebo Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 1.1 Live birth 3 918 Odds Ratio (M-H, Fixed, 95% CI) 0.85 [0.65, 1.11] 1.2 Ongoing pregnancy 1 564 Odds Ratio (M-H, Fixed, 95% CI) 0.81 [0.58, 1.13] 1.3 Miscarriage 3 917 Odds Ratio (M-H, Fixed, 95% CI) 1.54 [0.99, 2.39] 1.4 Clinical pregnancy 3 917 Odds Ratio (M-H, Fixed, 95% CI) 1.06 [0.81, 1.40] 1.5 BMI change 2 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only /uni00A0 /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 50 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 1.1. /uni00A0 Comparison 1: Non-pharmacological intervention versus no intervention or placebo, Outcome 1: Live birth Study or Subgroup Einarsson 2017Mutsaerts 2016Sim 2014 Total (95% CI) Total events: Heterogeneity: Chi² = 9.02, df = 2 (P = 0.01); I² = 78% Test for overall effect: Z = 1.18 (P = 0.24) Test for subgroup differences: Not applicable non-pharmacological interventionEvents 4512312 180 Total 15228027 459 No interventionEvents 421533 198 Total 15328422 459 Weight 25.3%73.1%1.6% 100.0% Odds RatioM-H, Fixed, 95% CI 1.11 [0.68 , 1.83]0.67 [0.48 , 0.93]5.07 [1.21 , 21.28] 0.85 [0.65 , 1.11] Odds RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Increased with no interventionIncreased with non-pharmacological intervention Risk of BiasA +++ B +++ C --- D ?-? E ++- F +++ G +++ Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 1.2. /uni00A0 Comparison 1: Non-pharmacological intervention versus no intervention or placebo, Outcome 2: Ongoing pregnancy Study or Subgroup Mutsaerts 2016 Total (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.25 (P = 0.21) Test for subgroup differences: Not applicable non-pharmacological interventionEvents 150 150 Total 280 280 No interventionEvents 167 167 Total 284 284 Weight 100.0% 100.0% Odds RatioM-H, Fixed, 95% CI 0.81 [0.58 , 1.13] 0.81 [0.58 , 1.13] Odds RatioM-H, Fixed, 95% CI 0.2 0.51 2 5Increased with no interventionIncreased with non-pharmacological intervention Risk of BiasA + B + C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 1.3. /uni00A0 Comparison 1: Non-pharmacological intervention versus no intervention or placebo, Outcome 3: Miscarriage Study or Subgroup Einarsson 2017Mutsaerts 2016Sim 2014 Total (95% CI) Total events: Heterogeneity: Chi² = 0.54, df = 2 (P = 0.76); I² = 0% Test for overall effect: Z = 1.92 (P = 0.06) Test for subgroup differences: Not applicable non-pharmacological interventionEvents 8417 56 Total 15228026 458 No interventionEvents 5276 38 Total 15328422 459 Weight 14.6%70.7%14.7% 100.0% Odds RatioM-H, Fixed, 95% CI 1.64 [0.53 , 5.15]1.63 [0.97 , 2.74]0.98 [0.27 , 3.52] 1.54 [0.99 , 2.39] Odds RatioM-H, Fixed, 95% CI 0.020.1 1 10 50Increased with no interventionIncreased with non-pharmacological intervention Risk of BiasA +++ B +++ C --- D ?-? E ++- F +++ G +++ Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 51 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 /uni00A0 Analysis 1.4. /uni00A0 Comparison 1: Non-pharmacological intervention versus no intervention or placebo, Outcome 4: Clinical pregnancy Study or Subgroup Einarsson 2017Mutsaerts 2016Sim 2014 Total (95% CI) Total events: Heterogeneity: Chi² = 7.36, df = 2 (P = 0.03); I² = 73% Test for overall effect: Z = 0.45 (P = 0.65) Test for subgroup differences: Not applicable non-pharmacological interventionEvents 5317513 241 Total 15228026 458 No interventionEvents 471863 236 Total 15328422 459 Weight 30.1%68.3%1.6% 100.0% Odds RatioM-H, Fixed, 95% CI 1.21 [0.75 , 1.95]0.88 [0.62 , 1.24]6.33 [1.50 , 26.73] 1.06 [0.81 , 1.40] Odds RatioM-H, Fixed, 95% CI 0.10.20.51 2 510Increased with no interventionIncreased with non-pharmacological intervention Risk of BiasA +++ B +++ C --- D ?-? E ++- F +++ G +++ Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 1.5. /uni00A0 Comparison 1: Non-pharmacological intervention versus no intervention or placebo, Outcome 5: BMI change Study or Subgroup Einarsson 2017Sim 2014 Test for subgroup differences: Not applicable non-pharmacological interventionMean -3.25-2.4 SD 2.421.6 Total 15226 No interventionMean 0.45-0.6 SD 0.721.3 Total 15317 Mean Difference IV, Fixed, 95% CI -3.70 [-4.10 , -3.30]-1.80 [-2.67 , -0.93] Mean Difference IV, Fixed, 95% CI -10-5 0 5 10Increased with no interventionIncreased with non-pharmacological intervention Risk of BiasA ++ B ++ C -- D ?? E +- F ++ G ++ Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Comparison 2. /uni00A0 Non-pharmacological intervention versus non-pharmacological intervention Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 2.1 Live birth 1 11 Odds Ratio (M-H, Fixed, 95% CI) 11.00 [0.43, 284.30] 2.2 Clinical pregnancy 1 11 Odds Ratio (M-H, Fixed, 95% CI) 11.00 [0.43, 284.30] 2.3 BMI change 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 2.4 Weight change 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 2.5 Mental health 1 11 Mean Difference (IV, Fixed, 95% CI) -7.00 [-13.92, -0.08] 2.6 Quality of life 1 11 Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.03, 0.15] /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 52 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 2.1. /uni00A0 Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 1: Live birth Study or Subgroup Rothberg 2016 Total (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 1.45 (P = 0.15)Test for subgroup differences: Not applicable Intensive weight loss intervention (IWL)Events 3 3 Total 6 6 Standard-of-care nutrition counseling (SCN)Events 0 0 Total 5 5 Weight 100.0% 100.0% Odds RatioM-H, Fixed, 95% CI 11.00 [0.43 , 284.30] 11.00 [0.43 , 284.30] Odds RatioM-H, Fixed, 95% CI 0.0010.11 10 1000Increased with SCNIncreased with IWL Risk of BiasA ? B - C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 2.2. /uni00A0 Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 2: Clinical pregnancy Study or Subgroup Rothberg 2016 Total (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 1.45 (P = 0.15)Test for subgroup differences: Not applicable Intensive weight loss intervention (IWL)Events 3 3 Total 6 6 Standard-of-care nutrition counselling (SCN)Events 0 0 Total 5 5 Weight 100.0% 100.0% Odds RatioM-H, Fixed, 95% CI 11.00 [0.43 , 284.30] 11.00 [0.43 , 284.30] Odds RatioM-H, Fixed, 95% CI 0.0010.11 10 1000Increased with SCNIncreased with IWL Risk of BiasA ? B - C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 2.3. /uni00A0 Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 3: BMI change Study or Subgroup Rothberg 2016 Intensive weight loss intervention (IWL)Mean -5 SD 2 Total 6 Standard-of-care nutrition counselling (SCN).Mean -2 SD 2 Total 5 Mean DifferenceIV, Fixed, 95% CI -3.00 [-5.37 , -0.63] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Increased with SCNIncreased with IWL Risk of BiasA ? B - C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 53 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 2.4. /uni00A0 Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 4: Weight change Study or Subgroup Rothberg 2016 Intensive weight loss intervention (IWL)Mean -14 SD 6 Total 6 Standard-of-care nutrition counselling (SCN)Mean -5 SD 5 Total 5 Mean DifferenceIV, Fixed, 95% CI -9.00 [-15.50 , -2.50] Mean DifferenceIV, Fixed, 95% CI -10-50 5 10Increased with SCNIncreased with IWL Risk of BiasA ? B - C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 2.5. /uni00A0 Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 5: Mental health Study or Subgroup Rothberg 2016 Total (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.98 (P = 0.05)Test for subgroup differences: Not applicable Intensive weight loss intervention (IWL)Mean -5 SD 4 Total 6 6 Standard-of-care nutrition counselling (SCN)Mean 2 SD 7 Total 5 5 Weight 100.0% 100.0% Mean DifferenceIV, Fixed, 95% CI -7.00 [-13.92 , -0.08] -7.00 [-13.92 , -0.08] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Increased with IWLIncreased with SCN Risk of BiasA ? B - C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 2.6. /uni00A0 Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 6: Quality of life Study or Subgroup Rothberg 2016 Total (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.33 (P = 0.18)Test for subgroup differences: Not applicable Intensive weight loss intervention (IWL)Mean 0.05 SD 0.08 Total 6 6 Standard-of-care nutrition counselling (SCN)Mean -0.01 SD 0.07 Total 5 5 Weight 100.0% 100.0% Mean DifferenceIV, Fixed, 95% CI 0.06 [-0.03 , 0.15] 0.06 [-0.03 , 0.15] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Increased with SCNIncreased with IWL Risk of BiasA ? B - C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Comparison 3. /uni00A0 Pharmacological intervention versus pharmacological intervention Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 3.1 Miscarriage 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only 3.2 Adverse event ( nausea) 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only 3.3 Adverse event (diarrhoea) 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 54 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 3.4 Adverse event (headache) 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only 3.5 Clinical pregnancy 2 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only 3.5.1 Metformin plus liraglutide vs metformin 1 28 Odds Ratio (M-H, Fixed, 95% CI) 3.67 [0.70, 19.12] 3.5.2 Metformin + CC + L-carnitine vs metformin + CC + placebo 1 274 Odds Ratio (M-H, Fixed, 95% CI) 5.56 [2.57, 12.02] 3.6 BMI change 2 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 3.6.1 Metformin + CC + L-carnitine vs metformin + CC + placebo 1 274 Mean Difference (IV, Fixed, 95% CI) -0.30 [-1.17, 0.57] 3.6.2 Metformin plus liraglutide vs metformin 1 28 Mean Difference (IV, Fixed, 95% CI) 2.10 [-0.42, 4.62] 3.7 Weight loss 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 3.7.1 Dexfenfluramine vs placebo 1 21 Mean Difference (IV, Fixed, 95% CI) -0.10 [-2.77, 2.57] 3.8 Percent of total body fat 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 3.8.1 Metformin plus liraglutide vs metformin 1 28 Mean Difference (IV, Fixed, 95% CI) -0.50 [-4.65, 3.65] 3.9 Glucose test (OGTT) 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 3.9.1 Metformin plus liraglutide vs metformin 1 28 Mean Difference (IV, Fixed, 95% CI) -0.30 [-1.90, 1.30] 3.10 Free testosterone 2 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 3.10.1 Metformin plus liraglutide vs metformin 1 28 Mean Difference (IV, Fixed, 95% CI) 0.80 [-3.00, 4.60] 3.10.2 Metformin + CC + L-carnitine vs metformin + CC + placebo 1 274 Mean Difference (IV, Fixed, 95% CI) -1.76 [-2.06, -1.46] 3.11 Total testosterone 1 28 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.21, 0.61] 3.11.1 Metformin plus liraglutide vs metformin 1 28 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.21, 0.61] 3.12 SHBG 1 28 Mean Difference (IV, Fixed, 95% CI) 0.30 [-12.22, 12.82] Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 55 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 3.12.1 Metformin plus liraglutide vs metformin 1 28 Mean Difference (IV, Fixed, 95% CI) 0.30 [-12.22, 12.82] /uni00A0 /uni00A0 Analysis 3.1. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 1: Miscarriage Study or Subgroup El 2019 Test for subgroup differences: Not applicable Metformin combined with CC + L-carnitineEvents 7 Total 138 Metformin combined with CCEvents 2 Total 136 Odds RatioM-H, Fixed, 95% CI 3.58 [0.73 , 17.55] Odds RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Increased with met+CCIncreased with met+CC+L-carnitine Risk of BiasA + B + C + D + E + F + G + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 3.2. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 2: Adverse event ( nausea) Study or Subgroup Salamun 2018 Test for subgroup differences: Not applicable Metformin combined with LiragutideEvents 5 Total 14 MetforminEvents 1 Total 14 Odds RatioM-H, Fixed, 95% CI 7.22 [0.72 , 72.70] Odds RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Increased with metforminIncreased with metformin + liragutide Risk of BiasA ? B - C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 3.3. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 3: Adverse event (diarrhoea) Study or Subgroup Salamun 2018 Test for subgroup differences: Not applicable Metformin combined with LiragutideEvents 0 Total 14 MetforminEvents 1 Total 14 Odds RatioM-H, Fixed, 95% CI 0.31 [0.01 , 8.29] Odds RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Increased with metformin + LiragutideIncreased with metformin Risk of BiasA ? B - C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 56 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 /uni00A0 Analysis 3.4. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 4: Adverse event (headache) Study or Subgroup Salamun 2018 Test for subgroup differences: Not applicable Metformin combined with LiragutideEvents 2 Total 14 MetforminEvents 0 Total 14 Odds RatioM-H, Fixed, 95% CI 5.80 [0.25 , 132.56] Odds RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Increased with metforminIncreased with metformin + liragutide Risk of BiasA ? B - C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 3.5. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 5: Clinical pregnancy Study or Subgroup 3.5.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 1.54 (P = 0.12) 3.5.2 Metformin + CC + L-carnitine vs metformin + CC + placeboEl 2019Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 4.36 (P < 0.0001) Test for subgroup differences: Chi² = 0.20, df = 1 (P = 0.65), I² = 0% Metformin with co-interventionsEvents 7 7 39 39 Total 1414 138138 Metformin/metformin with CC + placeboEvents 3 3 9 9 Total 1414 136136 Weight 100.0%100.0% 100.0%100.0% Odds RatioM-H, Fixed, 95% CI 3.67 [0.70 , 19.12]3.67 [0.70 , 19.12] 5.56 [2.57 , 12.02]5.56 [2.57 , 12.02] Odds RatioM-H, Fixed, 95% CI 0.0010.11 10 1000Increased with metformin/metformin + CC + placeboIncreased with metformin + co-interventions Risk of BiasA ? + B - + C - + D - + E + + F + + G + + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 57 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 3.6. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 6: BMI change Study or Subgroup 3.6.1 Metformin + CC + L-carnitine vs metformin + CC + placeboEl 2019Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.68 (P = 0.50) 3.6.2 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.63 (P = 0.10) Test for subgroup differences: Chi² = 3.11, df = 1 (P = 0.08), I² = 67.9% Metformin combined with co-medicationMean 32.2 35.1 SD 4.1 3.5 Total 138138 1414 Metformin/Metformin combined with co-medicationMean 32.5 33 SD 3.2 3.3 Total 136136 1414 Weight 100.0%100.0% 100.0%100.0% Mean DifferenceIV, Fixed, 95% CI -0.30 [-1.17 , 0.57]-0.30 [-1.17 , 0.57] 2.10 [-0.42 , 4.62]2.10 [-0.42 , 4.62] Mean DifferenceIV, Fixed, 95% CI -100-500 50 100Increased with metformin/metformin+co-medicationIncreased with metformin+co-medication Risk of BiasA + ? B + - C + - D + - E + + F + + G + + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 3.7. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 7: Weight loss Study or Subgroup 3.7.1 Dexfenfluramine vs placeboGalletly 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.07 (P = 0.94) Test for subgroup differences: Not applicable DexfenfluramineMean 3.21 SD 3.09 Total 1010 PlaceboMean 3.31 SD 3.15 Total 11 11 Weight 100.0%100.0% Mean Difference IV, Fixed, 95% CI -0.10 [-2.77 , 2.57]-0.10 [-2.77 , 2.57] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Increased with dexfenfluramine + placeboIncreased with placebo + dexfenfluramine Risk of BiasA ? B ? C ? D ? E ? F - G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 3.8. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 8: Percent of total body fat Study or Subgroup 3.8.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.24 (P = 0.81) Metformin combined with LiragutideMean 43 SD 5.5 Total 1414 MetforminMean 43.5 SD 5.7 Total 1414 Weight 100.0%100.0% Mean Difference IV, Fixed, 95% CI -0.50 [-4.65 , 3.65]-0.50 [-4.65 , 3.65] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Increased with metformin + LiragutideIncreased with metformin /uni00A0 /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 3.9. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 9: Glucose test (OGTT) Study or Subgroup 3.9.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.37 (P = 0.71) Test for subgroup differences: Not applicable Metformin combined with LiragutideMean 6.3 SD 2 Total 1414 MetforminMean 6.6 SD 2.3 Total 1414 Weight 100.0%100.0% Mean DifferenceIV, Fixed, 95% CI -0.30 [-1.90 , 1.30]-0.30 [-1.90 , 1.30] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Increased with metformin + LiragutideIncreased with metformin Risk of BiasA ? B - C - D - E + F + G + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 3.10. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 10: Free testosterone Study or Subgroup 3.10.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.41 (P = 0.68) 3.10.2 Metformin + CC + L-carnitine vs metformin + CC + placeboEl 2019Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 11.52 (P < 0.00001) Test for subgroup differences: Chi² = 1.73, df = 1 (P = 0.19), I² = 42.3% Metformin combined with LiragutideMean 8.9 1.45 SD 6.3 1.11 Total 1414 138138 MetforminMean 8.1 3.21 SD 3.6 1.4 Total 1414 136136 Weight 100.0%100.0% 100.0%100.0% Mean DifferenceIV, Fixed, 95% CI 0.80 [-3.00 , 4.60]0.80 [-3.00 , 4.60] -1.76 [-2.06 , -1.46]-1.76 [-2.06 , -1.46] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Increased with metformin + co-medicationsIncreased with metformin/metformin+CC+placebo Risk of BiasA ? + B - + C - + D - + E + + F + + G + + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 3.11. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 11: Total testosterone Study or Subgroup 3.11.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.96 (P = 0.34) Total (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.96 (P = 0.34) Test for subgroup differences: Not applicable Metformin combined with LiragutideMean 1.5 SD 0.6 Total 1414 14 MetforminMean 1.3 SD 0.5 Total 1414 14 Weight 100.0%100.0% 100.0% Mean Difference IV, Fixed, 95% CI 0.20 [-0.21 , 0.61]0.20 [-0.21 , 0.61] 0.20 [-0.21 , 0.61] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Increased with metformin + LiragutideIncreased with metformin /uni00A0 /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 59 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 3.12. /uni00A0 Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 12: SHBG Study or Subgroup 3.12.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.05 (P = 0.96) Total (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.05 (P = 0.96) Test for subgroup differences: Not applicable Metformin combined with LiragutideMean 36 SD 13.4 Total 1414 14 MetforminMean 35.7 SD 19.8 Total 1414 14 Weight 100.0%100.0% 100.0% Mean Difference IV, Fixed, 95% CI 0.30 [-12.22 , 12.82]0.30 [-12.22 , 12.82] 0.30 [-12.22 , 12.82] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Increased with metformin + LiragutideIncreased with metformin /uni00A0 /uni00A0 Comparison 4. /uni00A0 Pharmacological intervention versus no intervention/placebo Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 4.1 Live birth 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only 4.2 Miscarriage 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only 4.3 Adverse event (GI) 1 65 Odds Ratio (M-H, Fixed, 95% CI) 0.91 [0.32, 2.57] 4.4 Clinical pregnancy 2 96 Odds Ratio (M-H, Fixed, 95% CI) 2.67 [0.90, 7.93] 4.5 BMI change 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 4.6 WHR 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 4.7 Total testosterone 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 4.8 Free testosterone 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 4.9 SHBG 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only /uni00A0 /uni00A0 Analysis 4.1. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 1: Live birth Study or Subgroup Johnson 2010 MetforminEvents 7 Total 32 PlaceboEvents 5 Total 33 Odds RatioM-H, Fixed, 95% CI 1.57 [0.44 , 5.57] Odds RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Increased with placeboIncreased with metformin Risk of BiasA + B + C + D + E + F + G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 60 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.2. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 2: Miscarriage Study or Subgroup Johnson 2010 Metformin/L-carnitineEvents 1 Total 32 PlaceboEvents 2 Total 33 Odds RatioM-H, Fixed, 95% CI 0.50 [0.04 , 5.80] Odds RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Increased with placeboIncreased with metformin/L-carnitine Risk of BiasA + B + C + D + E + F + G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 4.3. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 3: Adverse event (GI) Study or Subgroup Johnson 2010 Total (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.18 (P = 0.86) Test for subgroup differences: Not applicable metforminEvents 10 10 Total 32 32 placeboEvents 11 11 Total 33 33 Weight 100.0% 100.0% Odds RatioM-H, Fixed, 95% CI 0.91 [0.32 , 2.57] 0.91 [0.32 , 2.57] Odds RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Increased with placeboIncreased with metformin /uni00A0 /uni00A0 Analysis 4.4. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 4: Clinical pregnancy Study or Subgroup Johnson 2010Khorram 2006 Total (95% CI) Total events: Heterogeneity: Chi² = 1.94, df = 1 (P = 0.16); I² = 48% Test for overall effect: Z = 1.77 (P = 0.08) Test for subgroup differences: Not applicable MetforminEvents 75 12 Total 3216 48 No intervention/placeboEvents 50 5 Total 3315 48 Weight 91.7%8.3% 100.0% Odds RatioM-H, Fixed, 95% CI 1.57 [0.44 , 5.57]14.83 [0.74 , 295.97] 2.67 [0.90 , 7.93] Odds RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Increased with no intervention/placeboIncreased with metformin Risk of BiasA ++ B +- C +? D +? E +? F +- G ++ Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 61 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.5. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 5: BMI change Study or Subgroup Tang 2006 Diet combined metforminMean 37.1 SD 5.04 Total 69 Diet combined placeboMean 37.4 SD 6.3 Total 74 Mean Difference IV, Fixed, 95% CI -0.30 [-2.16 , 1.56] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Increased with diet + metforminIncreased with diet + placebo Risk of BiasA + B + C + D + E + F - G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 4.6. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 6: WHR Study or Subgroup Tang 2006 Diet combined with metforminMean 111.1 SD 12.3 Total 69 Diet combined with placeboMean 109.1 SD 13.4 Total 74 Mean Difference IV, Fixed, 95% CI 2.00 [-2.21 , 6.21] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Increased with diet+metforminIncreased with diet+placebo Risk of BiasA + B + C + D + E + F - G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 4.7. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 7: Total testosterone Study or Subgroup Khorram 2006 Metformin plus clomiphene citrateMean 51.8 SD 10 Total 16 Clomiphene citrate onlyMean 45.6 SD 5.9 Total 15 Mean Difference IV, Fixed, 95% CI 6.20 [0.46 , 11.94] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Increased with metformin + ccIncreased with cc only Risk of BiasA + B - C ? D ? E ? F - G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 62 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.8. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 8: Free testosterone Study or Subgroup Khorram 2006 Metformin plus clomiphene citrate/L-carnitineMean 12.4 SD 2 Total 16 Clomiphene citrate only/placeboMean 11.7 SD 2.8 Total 15 Mean DifferenceIV, Fixed, 95% CI 0.70 [-1.02 , 2.42] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Increased with metformin + cc/L-carnitineIncreased with cc/placebo Risk of BiasA + B - C ? D ? E ? F - G + Risk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 Analysis 4.9. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 9: SHBG Study or Subgroup Khorram 2006 Metformin plus clomiphene citrateMean 25.4 SD 1.8 Total 16 Clomiphene citrate onlyMean 19.9 SD 2.9 Total 15 Mean Difference IV, Fixed, 95% CI 5.50 [3.79 , 7.21] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Increased with metformin + ccIncreased with cc only Risk of BiasA + B - C ? D ? E ? F - G + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias /uni00A0 /uni00A0 A P P E N D I C E S Appendix 1. Cochrane Gynaecology and Fertility Specialised Register search strategy ProCite platform Searched on 18 August 2020

CONTAINS "IVF" or "ICSI" or "in-vitro fertilisation " or "in-vitro fertilisation procedure" or "in vitro fertilization" or "intracytoplasmic sperm injection" or "intracytoplasmic morphologically selected sperm injection" or "superovulation" or "superovulation induction" or "IUI" or "insemination, intrauterine " or "Intrauterine Insemination" or "ART" or "artificial insemination" or "assisted reproduction techniques" or "subfertility-Female" or "pregnancy" or "live birth" or"unexplained and endometriosis related infertility" or"unexplained infertility" or "unexplained subfertility" or "anovulation" or "infertile"or "infertility" or "ovulation" or "subfertility" or "ovarian hyperstimulation"or "ovarian stimulation"or"controlled ovarian "or "timed intercourse" or "in vivo maturation" or"in vitro maturation" or "IMSI" or "implantation" or "oocyte"or"oocytes"or"embryo" or "polycystic ovary syndrome" or "PCOS" or "assisted reproduction" or "assisted reproductive technology" or Title CONTAINS "infertile" AND

CONTAINS "*Obesity" or "obese women" or "obese" or "overweight" or "overweight-to-obese" or "fat body mass" or "fat distribution" or "BMI" or "body mass index" or "body composition" or "body fat distribution" or "body fat mass" or "Body Mass" or "Body Mass Index" or"Body weight"or "Weight Loss"or "Diet" or"diet therapy"or "dietary intervention"or"Weight "or"Weight Gain" or Title CONTAINS "*Obesity" or "obese women" or "obese" or"overweight" or "overweight-to-obese" or "fat body mass" or "fat distribution" or "BMI" or "body mass index" or "body composition" or "body fat distribution" or "body fat mass" or "Body Mass" or "Body Mass Index" or "Body weight" or "Weight Loss" or "Diet" or "diet therapy" or "dietary intervention" or "Weight" or"Weight Gain" 1167 records Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 63 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Appendix 2. CENTRAL via the Cochrane Central Register of Studies Online (CRSO) search strategy Web platform Searched on 18 August 2020 #1 MESH DESCRIPTOR Obesity EXPLODE ALL TREES 13487 #2 MESH DESCRIPTOR Overweight EXPLODE ALL TREES 16016 #3 (Obesity or obese or overweight):TI,AB,KY 43053 #4 MESH DESCRIPTOR Obesity, Morbid EXPLODE ALL TREES 1165 #5 MESH DESCRIPTOR Body Mass Index EXPLODE ALL TREES 9957 #6 (High BMI or BMI above or BMI greater):TI,AB,KY 562 #7 (High body mass index or body mass index above or body mass index greater):TI,AB,KY 348 #8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 48495 #9 MESH DESCRIPTOR Infertility, Female EXPLODE ALL TREES 1390 #10 MESH DESCRIPTOR Polycystic Ovary Syndrome EXPLODE ALL TREES 1482 #11 MESH DESCRIPTOR Fertilization in Vitro EXPLODE ALL TREES 2050 #12 (infertil* or subfertil*):TI,AB,KY 8830 #13 (Polycystic Ovar*):TI,AB,KY 3520 #14 PCOS:TI,AB,KY 2823 #15 (ivf or icsi):TI,AB,KY 6480 #16 (intrauterine insemination*):TI,AB,KY 981 #17 iui:TI,AB,KY 881 #18 MESH DESCRIPTOR Ovulation Induction EXPLODE ALL TREES 1340 #19 (Ovulation Induction):TI,AB,KY 2571 #20 (ovar* hyperstimulation):TI,AB,KY 1625 #21 (ovar* adj2 stimulation):TI,AB,KY 2263 #22 MESH DESCRIPTOR Reproductive Techniques, Assisted EXPLODE ALL TREES 3136 #23 (assisted reproduct*):TI,AB,KY 1401 #24 #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 16115 #25 #8 AND #24 1098 Appendix 3. MEDLINE search strategy Ovid platform Searched from 1946 to 18 August 2020 1 (Obesity or obese or overweight).tw. (315125) 2 exp Obesity/ or exp Overweight/ or exp Body Weight/ (466482) 3 exp Body Composition/ or exp Body Fat Distribution/ (54864) 4 exp Body Mass Index/ (126990) 5 exp Obesity, Morbid/ or exp Waist-Hip Ratio/ (23856) 6 (High BMI or BMI above).tw. (4009) 7 (BMI adj3 over).tw. (1563) Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 64 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews 8 Body Mass Index.tw. (183850) 9 or/1-8 (743472) 10 exp Infertility, Female/ (28492) 11 exp Polycystic Ovary Syndrome/ (14478) 12 exp Fertilization in Vitro/ (35811) 13 (infertil$ adj5 female$).tw. (3518) 14 (infertil$ adj5 wom?n).tw. (9574) 15 (subfertil$ adj5 wom?n).tw. (635) 16 (subfertil$ adj5 female$).tw. (253) 17 Polycystic Ovar$.tw. (16819) 18 PCOS.tw. (11371) 19 exp Amenorrhea/ (9855) 20 amenorrh?ea.tw. (13347) 21 oligomenorrh$.tw. (1437) 22 exp Oligomenorrhea/ (720) 23 exp Hyperandrogenism/ (2019) 24 hyperandrogenism.tw. (3816) 25 (ivf or icsi).tw. (27791) 26 intrauterine insemination$.tw. (2524) 27 iui.tw. (1785) 28 exp Ovarian Hyperstimulation Syndrome/ (2262) 29 exp Ovulation Induction/ (13151) 30 ovar$ hyperstimulation.tw. (5118) 31 ovar$ stimulation.tw. (6023) 32 exp Reproductive Techniques, Assisted/ (69677) 33 assisted reproduct$.tw. (15166) 34 or/10-33 (139274) 35 randomized controlled trial.pt. (511179) 36 controlled clinical trial.pt. (93800) 37 randomized.ab. (489167) 38 randomised.ab. (97651) 39 placebo.tw. (215911) 40 clinical trials as topic.sh. (192520) 41 randomly.ab. (338981) 42 trial.ti. (223326) 43 (crossover or cross-over or cross over).tw. (85722) 44 or/35-43 (1373935) 45 exp animals/ not humans.sh. (4725508) 46 44 not 45 (1265255) 47 9 and 34 and 46 (1266) Appendix 4. Embase search strategy Ovid platform Searched from 1980 to 18 August 2020 1 exp obesity/ (512611) 2 (obesity or obese or overweight).tw. (457990) 3 exp body weight/ or exp body mass/ (832100) 4 waist hip ratio/ (14604) 5 body mass index.tw. (268127) 6 (High BMI or BMI above).tw. (7500) 7 (BMI adj3 over).tw. (3104) 8 (weight adj3 above).tw. (1994) 9 (weight adj3 over).tw. (10556) 10 or/1-9 (1244347) 11 exp female infertility/ or exp ovary polycystic disease/ or exp fertilization in vitro/ (122255) 12 (infertil$ adj5 female$).tw. (5121) 13 (infertil$ adj5 wom?n).tw. (14133) 14 (subfertil$ adj5 wom?n).tw. (1029) 15 (subfertil$ adj5 female$).tw. (369) 16 Polycystic Ovar$.tw. (23277) Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 65 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews 17 PCOS.tw. (17262) 18 exp amenorrhea/ (17330) 19 amenorrh?ea.tw. (15407) 20 oligomenorrh$.tw. (1973) 21 exp oligomenorrhea/ or exp "amenorrhea and oligomenorrhea"/ (27942) 22 exp hyperandrogenism/ (7408) 23 hyperandrogenism.tw. (5559) 24 (ivf or icsi).tw. (47745) 25 intrauterine insemination$.tw. (3780) 26 iui.tw. (3278) 27 exp ovary hyperstimulation/ or exp ovulation induction/ (22001) 28 ovar$ hyperstimulation.tw. (7484) 29 ovar$ stimulation.tw. (9753) 30 or/11-29 (177709) 31 exp Diet Therapy/ (340480) 32 diet$.tw. (681613) 33 (weight adj3 reduc$).tw. (48577) 34 (body mass index adj2 loss).tw. (677) 35 (body mass index adj2 reduc$).tw. (1197) 36 (body mass index adj2 decreas$).tw. (1359) 37 (BMI adj2 loss).tw. (1727) 38 (BMI adj2 redu$).tw. (4064) 39 (BMI adj2 decreas$).tw. (4800) 40 exercise$.tw. (376424) 41 exp sport/ (160081) 42 (run$ or jog$).tw. (253096) 43 (sport$ or walk$).tw. (255446) 44 (swim$ or cycl$).tw. (1430222) 45 (train or training).tw. (553768) 46 exp cognitive therapy/ or exp psychotherapy/ (235459) 47 (cognitive adj2 therap$).tw. (29865) 48 Psychotherapy.tw. (40737) 49 exp behavior therapy/ (42495) 50 exp lifestyle/ (129810) 51 (lifestyle adj2 change$).tw. (15252) 52 (lifestyle adj2 intervention$).tw. (11337) 53 exp social support/ (91720) 54 (social adj2 support).tw. (49798) 55 weight loss.tw. (138913) 56 (weight adj2 control).tw. (12071) 57 dynamic exercise/ or isotonic exercise/ or exercise/ or aquatic exercise/ or leg exercise/ or anaerobic exercise/ or stretching exercise/ or aerobic exercise/ or isometric exercise/ (289306) 58 behavio?r modif$.tw. (3258) 59 exp weight control/ or exp weight reduction/ (39254) 60 behavio?r therap$.tw. (9492) 61 low calorie$.tw. (4447) 62 fitness.tw. (81610) 63 exp health behavior/ (409721) 64 (decrease adj2 weight).tw. (3343) 65 hypnosis.tw. (7140) 66 group therap$.tw. (5887) 67 or/31-66 (4363927) 68 exp antiobesity agent/ (4884) 69 antiobesity.tw. (2254) 70 lipase inhibitor$.tw. (1255) 71 (xenical or tetrahydrolipstatin or orlistat).tw. (3754) 72 exp tetrahydrolipstatin/ (6440) 73 exp metformin/ or exp pioglitazone/ or exp insulin sensitizing agent/ (75303) 74 insulin sensitizer$.tw. (2157) 75 exp antidiabetic agent/ (461406) 76 exp 2,4 thiazolidinedione derivative/ (12894) 77 exp thiazole derivative/ (168176) Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 66 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews 78 metformin.tw. (35181) 79 (Appetite adj3 (suppress$ or depress$)).tw. (2798) 80 exp serotonin uptake inhibitor/ (256753) 81 exp serotonin antagonist/ (221959) 82 exp antidepressant agent/ (419880) 83 exp noradrenalin uptake inhibitor/ (216863) 84 (Reductil or sibutramine or fenfluramine).tw. (4271) 85 fenfluramine/ (5653) 86 exp dexfenfluramine/ (2264) 87 exp phentermine/ (2547) 88 exp phenylpropanolamine/ (3042) 89 exp fluoxetine/ (46337) 90 antidepressant$.tw. (89208) 91 anti depressant$.tw. (3456) 92 exp mazindol/ (1611) 93 exp amfepramone/ (1320) 94 antiandrogen/ (11465) 95 androgen$ antagonist$.tw. (323) 96 bulking agent$.tw. (1853) 97 fluoxetine.tw. (16185) 98 (methylcellulose or celevac).tw. (7244) 99 guar gum.tw. (2212) 100 anti obesity.tw. (4963) 101 exp Ephedra/ (1143) 102 ephedra.tw. (1024) 103 bupropion.tw. (6245) 104 exp amfebutamone/ (18316) 105 (Wellbutrin or Zyban or Amfebutamone).tw. (2481) 106 zonisamide.tw. (2062) 107 (Excegran or Zonegran).tw. (379) 108 sertraline.tw. (6775) 109 exp sertraline/ (25989) 110 (Serad or Serlain or Tresleen or Zolo/f_t).tw. (2616) 111 leptin/ae, dt [Adverse Drug Reaction, Drug Therapy] (853) 112 topiramate.tw. (7652) 113 or/68-112 (1157634) 114 (lap band$ or lapband$).tw. (629) 115 roux-en-y.tw. (19567) 116 bariatric surger$.tw. (30089) 117 exp gastroplasty/ or exp bariatric surgery/ (46918) 118 exp gastrectomy/ (52328) 119 (GASTROPLASTY or Gastrectomy or gastric surgery or Gastric Bypass or gastric band$).tw. (60946) 120 (Biliopancreatic Diversion$ or biliopancreatic bypass$ or gastro$gastrostomy or restrictive surgery).tw. (2030) 121 (obesity adj3 surg$).tw. (6397) 122 (obese adj3 surg$).tw. (3076) 123 (jejunoileal bypass$ or jejuno ileal bypass$).tw. (789) 124 exp gastric banding/ (7411) 125 or/114-124 (106478) 126 67 or 113 or 125 (5321490) 127 Clinical Trial/ (970755) 128 Randomized Controlled Trial/ (611928) 129 exp randomization/ (87710) 130 Single Blind Procedure/ (39825) 131 Double Blind Procedure/ (172019) 132 Crossover Procedure/ (63930) 133 Placebo/ (339738) 134 Randomi?ed controlled trial$.tw. (234558) 135 Rct.tw. (38031) 136 random allocation.tw. (2043) 137 randomly allocated.tw. (35686) 138 allocated randomly.tw. (2562) 139 (allocated adj2 random).tw. (822) Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 67 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews 140 Single blind$.tw. (25054) 141 Double blind$.tw. (204347) 142 ((treble or triple) adj blind$).tw. (1172) 143 placebo$.tw. (305406) 144 prospective study/ (618991) 145 or/127-144 (2217034) 146 case study/ (71157) 147 case report.tw. (408717) 148 abstract report/ or letter/ (1110703) 149 or/146-148 (1579736) 150 145 not 149 (2163027) 151 10 and 30 and 126 and 150 (3462) Appendix 5. PsycINFO search strategy Ovid platform Searched from 1806 to 18 August 2020 1 exp Obesity/ (24601) 2 (obesity or obese or overweight).tw. (44923) 3 exp Body Weight/ or exp Body Mass Index/ (56375) 4 Body Mass Index.tw. (20444) 5 Body Weight.tw. (16156) 6 BMI.tw. (17893) 7 or/1-6 (88421) 8 exp Infertility/ (2185) 9 (infertil$ adj5 female$).tw. (357) 10 (infertil$ adj5 wom?n).tw. (742) 11 (subfertil$ adj5 wom?n).tw. (16) 12 (subfertil$ adj5 female$).tw. (6) 13 Polycystic Ovar$.tw. (426) 14 PCOS.tw. (290) 15 exp Amenorrhea/ (264) 16 amenorrh?ea.tw. (830) 17 oligomenorrh$.tw. (52) 18 exp Menstrual Disorders/ (1270) 19 hyperandrogenism.tw. (97) 20 (ivf or icsi).tw. (604) 21 intrauterine insemination$.tw. (32) 22 iui.tw. (41) 23 exp Reproductive Technology/ (1847) 24 ovar$ hyperstimulation.tw. (13) 25 ovar$ stimulation.tw. (26) 26 or/8-25 (6184) 27 7 and 26 (572) 28 random.tw. (59084) 29 control.tw. (448804) 30 double-blind.tw. (23062) 31 clinical trials/ (11727) 32 placebo/ (5682) 33 exp Treatment/ (1052281) 34 or/28-33 (1452988) 35 27 and 34 (225) Appendix 6. AMED search strategy Ovid platform Searched from 1985 to 18 August 2020 1 exp Obesity/ (2115) 2 (obesity or obese or overweight).tw. (3015) 3 exp Body weight/ (848) Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 68 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews 4 BMI.tw. (1134) 5 body mass index.tw. (2127) 6 weight.tw. (9971) 7 or/1-6 (13101) 8 exp Fertility/ (68) 9 exp Infertility female/ (215) 10 exp Ovarian disease/ (275) 11 (infertil$ adj5 female$).tw. (227) 12 (infertil$ adj5 wom?n).tw. (57) 13 (subfertil$ adj5 wom?n).tw. (2) 14 (subfertil$ adj5 female$).tw. (0) 15 Polycystic Ovar$.tw. (98) 16 PCOS.tw. (54) 17 exp Amenorrhea/ (39) 18 amenorrh?ea.tw. (95) 19 oligomenorrh$.tw. (11) 20 exp Menstruation disorders/ (589) 21 hyperandrogenism.tw. (6) 22 (ivf or icsi).tw. (52) 23 intrauterine insemination$.tw. (8) 24 iui.tw. (6) 25 ovar$ hyperstimulation.tw. (5) 26 or/8-25 (1202) 27 7 and 26 (64) Appendix 7. CINAHL search strategy Ebsco platform Searched from 1961 to 26 September 2019. The CENTRAL search on 18 August 2020 includes CINAHL references. /uni00A0 # Query Results S35 S20 AND S34 771 S34 S21 OR S22 or S23 or S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 1,352,629 S33 TX allocat* random* 11,021 S32 (MH "Quantitative Studies") 23,323 S31 (MH "Placebos") 11,475 S30 TX placebo* 59,197 S29 TX random* allocat* 11,021 S28 (MH "Random Assignment") 56,644 S27 TX randomi* control* trial* 175,687 S26 TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (dou- bl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) 1,033,852 S25 TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) 241 /uni00A0 Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 69 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews S24 TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) 241 S23 TX clinic* n1 trial* 251,068 S22 PT Clinical trial 86,871 S21 (MH "Clinical Trials+") 267,348 S20 S9 AND S19 3,829 S19 S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 27,803 S18 TX intrauterine insemination 462 S17 (MH "Fertilization in Vitro") OR (MH "Fertility") 9,858 S16 TX (ivf or icsi) 4,846 S15 TX hyperandrogenism 697 S14 TX subfertil* 885 S13 TX infertil* 16,371 S12 TX Polycystic Ovar* 4,117 S11 (MM "Polycystic Ovary Syndrome") 2,587 S10 (MM "Infertility") 7,396 S9 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 343,194 S8 TX weight 211,089 S7 TX BMI 43,745 S6 TX Body Mass Index 102,302 S5 (MM "Body Mass Index") 11,041 S4 TX overweight 27,892 S3 TX obese 35,589 S2 TX Obesity 119,085 S1 (MH "Obesity+") 88,246 /uni00A0/uni00A0(Continued) /uni00A0 W H A T ' S /uni00A0 N E W /uni00A0 Date Event Description 1 April 2021 Amended Typo corrected in/uni00A0abstract and PLS Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 70 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 H I S T O R Y Protocol first published: Issue 4, 2017 Review first published: Issue 3, 2021 /uni00A0 Date Event Description 8 February 2020 Amended Correction to affiliation of 2 authors. Changes to the methods as noted in the section Differences between protocol and review. /uni00A0 C O N T R I B U T I O N S /uni00A0 O F /uni00A0 A U T H O R S FB and SAT were involved in the design and conduct of the review, data analysis, dra/f_ting of the manuscript, and critical discussion. SHJ and MvW were involved in the design and conduct of the review, supervised data analysis, checked data extraction, and were involved in manuscript revision and critical discussion. All review authors read and approved the final manuscript. D E C L A R A T I O N S /uni00A0 O F /uni00A0 I N T E R E S T None of the review authors have or have had affiliations or involvement in organisations with an interest in the review findings. MvW is a Cochrane Editor and Deputy Editor of Human Reproduction. S O U R C E S /uni00A0 O F /uni00A0 S U P P O R T Internal sources • None, Other External sources • None, Other D I F F E R E N C E S /uni00A0 B E T W E E N /uni00A0 P R O T O C O L /uni00A0 A N D /uni00A0 R E V I E W The review objective was amended to improve clarity that the interventions are targeted to weight reduction in obese women with subfertility. The inclusion of cluster-randomised trials was excluded from the review as they are not an appropriate study design. Lastly, the measure of treatment effect for dichotomous data was calculated using odds ratios (OR) rather than risk ratios (RR). We chose the OR while this is considered a mathematically more stable effect measure . I N D E X /uni00A0 T E R M S Medical Subject Headings (MeSH) Abortion, Spontaneous /uni00A0[epidemiology];/uni00A0 Appetite Depressants /uni00A0[therapeutic use];/uni00A0 Bias;/uni00A0 Carnitine /uni00A0[therapeutic use];/uni00A0 Clomiphene /uni00A0[therapeutic use];/uni00A0 Dexfenfluramine /uni00A0[therapeutic use];/uni00A0 Drug Therapy, Combination /uni00A0[methods];/uni00A0 Hypoglycemic Agents /uni00A0[adverse effects] /uni00A0[therapeutic use];/uni00A0 Infertility, Female /uni00A0[diet therapy] /uni00A0[*therapy];/uni00A0 Life Style;/uni00A0 Liraglutide /uni00A0[adverse effects] /uni00A0[therapeutic use];/uni00A0 Live Birth /uni00A0[*epidemiology];/uni00A0 Mental Health;/uni00A0 Metformin /uni00A0[adverse effects] /uni00A0[therapeutic use];/uni00A0 Obesity /uni00A0[diet therapy] /uni00A0[*therapy];/uni00A0 Quality of Life;/uni00A0 Randomized Controlled Trials as Topic;/uni00A0 *Weight Loss MeSH check words Female; Humans; Pregnancy Pharmacological and non-pharmacological strategies for obese women with subfertility (Review) Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 71