{"paper_id":"05a9c592-429c-433d-ac67-898212fd5035","body_text":"Amsterdam UMC\nPharmacological and non-pharmacological strategies for obese women with\nsubfertility\nTaghavi, Seyed Abdolvahab; van Wely, Madelon; Jahanfar, Shayesteh; Bazarganipour,\nFatemeh\nPublished in:\nCochrane Database of Systematic Reviews\nDOI:\n10.1002/14651858.CD012650.pub2\nPublished: 25/03/2021\nDocument Version\nPublisher's PDF, also known as Version of record\nDocument license\nCC BY\nLink to publication\nCitation for pulished version (APA):\nTaghavi, S. A., van Wely, M., Jahanfar, S., & Bazarganipour, F. (2021). Pharmacological and non-\npharmacological strategies for obese women with subfertility. Cochrane Database of Systematic Reviews,\n2021(3), Article CD012650. https://doi.org/10.1002/14651858.CD012650.pub2\nGeneral rights\nIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),\nother than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).\nDisclaimer/Complaints regulations\nIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Amsterdam UMC\nMedical Library know, stating your reasons. In case of a legitimate complaint, the Medical Library will make the material inaccessible and/or\nremove it from the website. Contact address: outputregistratie@amsterdamumc.nl\nDownload date: 01. Aug. 2026\n\nCochrane\nLibrary\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nPharmacological and non-pharmacological strategies for obese\nwomen with subfertility (Review)\n/uni00A0\n/uni00A0Taghavi SA, van Wely M, Jahanfar S, Bazarganipour F /uni00A0\n/uni00A0 Taghavi/uni00A0SA, van/uni00A0Wely/uni00A0M, Jahanfar/uni00A0S, Bazarganipour/uni00A0F. \nPharmacological and non-pharmacological strategies for obese women with subfertility. \nCochrane Database of Systematic Reviews 2021, Issue 3. Art. No.: CD012650. \nDOI: 10.1002/14651858.CD012650.pub2.\n/uni00A0\n/uni00A0 www.cochranelibrary.com /uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)/uni00A0\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nT A B L E /uni00A0 O F /uni00A0 C O N T E N T S\nABSTRACT..................................................................................................................................................................................................... 1\nPLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2\nSUMMARY OF FINDINGS .............................................................................................................................................................................. 4\nBACKGROUND.............................................................................................................................................................................................. 10\nOBJECTIVES.................................................................................................................................................................................................. 11\nMETHODS..................................................................................................................................................................................................... 11\nFigure 1.................................................................................................................................................................................................. 14\nRESULTS........................................................................................................................................................................................................ 16\nFigure 2.................................................................................................................................................................................................. 19\nFigure 3.................................................................................................................................................................................................. 20\nDISCUSSION.................................................................................................................................................................................................. 23\nAUTHORS' CONCLUSIONS........................................................................................................................................................................... 23\nACKNOWLEDGEMENTS................................................................................................................................................................................ 24\nREFERENCES................................................................................................................................................................................................ 25\nCHARACTERISTICS OF STUDIES.................................................................................................................................................................. 32\nDATA AND ANALYSES.................................................................................................................................................................................... 50\nAnalysis 1.1. Comparison 1: Non-pharmacological intervention versus no intervention or placebo, Outcome 1: Live birth......... 51\nAnalysis 1.2. Comparison 1: Non-pharmacological intervention versus no intervention or placebo, Outcome 2: Ongoing\npregnancy..............................................................................................................................................................................................\n51\nAnalysis 1.3. Comparison 1: Non-pharmacological intervention versus no intervention or placebo, Outcome 3: Miscarriage....... 51\nAnalysis 1.4. Comparison 1: Non-pharmacological intervention versus no intervention or placebo, Outcome 4: Clinical\npregnancy..............................................................................................................................................................................................\n52\nAnalysis 1.5. Comparison 1: Non-pharmacological intervention versus no intervention or placebo, Outcome 5: BMI change....... 52\nAnalysis 2.1. Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 1: Live\nbirth........................................................................................................................................................................................................\n53\nAnalysis 2.2. Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 2: Clinical\npregnancy..............................................................................................................................................................................................\n53\nAnalysis 2.3. Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 3: BMI\nchange....................................................................................................................................................................................................\n53\nAnalysis 2.4. Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 4: Weight\nchange....................................................................................................................................................................................................\n54\nAnalysis 2.5. Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 5: Mental\nhealth.....................................................................................................................................................................................................\n54\nAnalysis 2.6. Comparison 2: Non-pharmacological intervention versus non-pharmacological intervention, Outcome 6: Quality\nof life......................................................................................................................................................................................................\n54\nAnalysis 3.1. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 1: Miscarriage......... 56\nAnalysis 3.2. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 2: Adverse event\n( nausea)................................................................................................................................................................................................\n56\nAnalysis 3.3. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 3: Adverse event\n(diarrhoea).............................................................................................................................................................................................\n56\nAnalysis 3.4. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 4: Adverse event\n(headache).............................................................................................................................................................................................\n57\nAnalysis 3.5. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 5: Clinical\npregnancy..............................................................................................................................................................................................\n57\nAnalysis 3.6. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 6: BMI change......... 58\nAnalysis 3.7. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 7: Weight loss......... 58\nAnalysis 3.8. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 8: Percent of total\nbody fat..................................................................................................................................................................................................\n58\nAnalysis 3.9. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 9: Glucose test\n(OGTT)....................................................................................................................................................................................................\n59\nAnalysis 3.10. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 10: Free\ntestosterone...........................................................................................................................................................................................\n59\nAnalysis 3.11. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 11: Total\ntestosterone...........................................................................................................................................................................................\n59\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\ni\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 3.12. Comparison 3: Pharmacological intervention versus pharmacological intervention, Outcome 12: SHBG.............. 60\nAnalysis 4.1. Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 1: Live birth..................... 60\nAnalysis 4.2. Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 2: Miscarriage.................. 61\nAnalysis 4.3. Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 3: Adverse event (GI)....... 61\nAnalysis 4.4. Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 4: Clinical pregnancy....... 61\nAnalysis 4.5. Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 5: BMI change................. 62\nAnalysis 4.6. Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 6: WHR............................ 62\nAnalysis 4.7. Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 7: Total testosterone....... 62\nAnalysis 4.8. Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 8: Free testosterone........ 63\nAnalysis 4.9. Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 9: SHBG........................... 63\nAPPENDICES................................................................................................................................................................................................. 63\nWHAT'S NEW................................................................................................................................................................................................. 70\nHISTORY........................................................................................................................................................................................................ 71\nCONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 71\nDECLARATIONS OF INTEREST..................................................................................................................................................................... 71\nSOURCES OF SUPPORT............................................................................................................................................................................... 71\nDIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 71\nINDEX TERMS............................................................................................................................................................................................... 71\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\nii\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n[Intervention Review]\nPharmacological and non-pharmacological strategies for obese women\nwith subfertility\nSeyed Abdolvahab Taghavi1, Madelon van Wely2, Shayesteh Jahanfar3, Fatemeh Bazarganipour1\n1Social Determinants of Health Research Center, Yasuj University of Medical Sciences, Yasuj, Iran. 2Center for Reproductive Medicine,\nAmsterdam UMC, University of Amsterdam, Amsterdam, Netherlands. 3MPH Program, Department of Public Health and Community\nMedicine, Tu/f_ts University School of Medicine, Boston, Massachusetts, USA\nContact: Fatemeh Bazarganipour, f.bazarganipour@gmail.com.\nEditorial group: Cochrane Gynaecology and Fertility Group.\nPublication status and date: Edited (no change to conclusions), published in Issue 4, 2021.\nCitation: Taghavi/uni00A0SA, van/uni00A0Wely/uni00A0M, Jahanfar/uni00A0S, Bazarganipour/uni00A0F. Pharmacological and non-pharmacological strategies for obese women\nwith subfertility. Cochrane Database of Systematic Reviews 2021, Issue 3. Art. No.: CD012650. DOI: 10.1002/14651858.CD012650.pub2.\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\nA B S T R A C T\nBackground\nClinicians primarily recommend weight loss for obese women seeking pregnancy. The effectiveness of interventions aimed at weight loss\nin obese women with subfertility is unclear.\nObjectives\nTo assess the effectiveness and safety of pharmacological and non-pharmacological strategies compared with each other, placebo, or no\ntreatment for achieving weight loss in obese women with subfertility.\nSearch methods\nWe searched the CGF Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and AMED from inception to 18 August 2020. We also\nchecked reference lists and contacted experts in the field for additional relevant papers.\nSelection criteria\nWe included published and unpublished randomised controlled trials in which weight loss was the main goal of the intervention. Our\nprimary effectiveness outcomes were live birth or ongoing pregnancy and primary safety outcomes were miscarriage and adverse events.\nSecondary outcomes included clinical pregnancy, weight change, quality of life, and mental health outcome.\nData collection and analysis\nReview authors followed standard Cochrane methodology.\nMain results\nThis review includes 10 trials. Evidence was of very low to low quality: the main limitations were due to lack of studies and poor reporting\nof study methods. The main reasons for downgrading evidence were lack of details by which to judge risk of bias (randomisation and\nallocation concealment), lack of blinding, and imprecision.\nNon-pharmacological intervention versus no intervention or placebo\nEvidence is insufficient to determine whether a diet or lifestyle intervention compared to no intervention affects live birth (odds ratio (OR)\n0.85, 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\nlive birth following no intervention is assumed to be 43%, the chance following diet or lifestyle changes would be 33% to 46%. We are\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n1\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nuncertain if lifestyle change compared with no intervention affects miscarriage rate (OR 1.54, 95% CI 0.99 to 2.39; 917 women, 3 studies;\nI/two.sups = 0%; very low-quality evidence). Evidence is insufficient to determine whether lifestyle change compared with no intervention affects\nclinical 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\na 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\n-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).\nNon-pharmacological versus non-pharmacological intervention\nWe are uncertain whether intensive weight loss interventions compared to standard care nutrition counselling affects live birth (OR 11.00,\n95% 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;\nvery 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,\n95% 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;\nvery 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\nreported on adverse events .\nPharmacological versus pharmacological intervention\nFor 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\n72.7; 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),\nand 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\nplus 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\n(MD -0.50, 95% CI -4.65 to 3.65; 28 women, 1 study; very low-quality evidence).\nFor metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo, we are uncertain of an effect on miscarriage (OR\n3.58, 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,\n1 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).\nWe 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\nlow-quality evidence). No study reported on live birth, quality of life, or mental health outcomes.\nPharmacological intervention versus no intervention or placebo\nWe 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\nevidence). This suggests that if the chance of live birth following placebo is assumed to be 15%, the chance following metformin would be\n7% 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\nwomen, 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)\nor 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\ndiet 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\nevidence) or waist-to-hip ratio (WHR) (MD 2.00, 95% CI -2.21 to 6.21; 143 women, 1 study; very low-quality evidence).\nPharmacological versus non-pharmacological intervention\nNo study undertook this comparison.\nAuthors' conclusions\nEvidence is insufficient to support the use of pharmacological and non-pharmacological strategies for obese women with subfertility.\nNo data are available for the comparison of pharmacological versus non-pharmacological strategies. We are uncertain whether\npharmacological or non-pharmacological strategies effect live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life,\nor mental health outcomes. However, for obese women with subfertility, a lifestyle intervention may reduce BMI. Future studies should\ncompare a combination of pharmacological and lifestyle interventions for obese women with subfertility.\nP L A I N /uni00A0 L A N G U A G E /uni00A0 S U M M A R Y\nDo pharmacological and non-pharmacological strategies reduce weight in obese women with subfertility?\nTo assess the effectiveness and safety of pharmacological and non-pharmacological strategies compared with each other, placebo, or no\ntreatment for weight reduction in obese women with subfertility.\nBackground\nTo prevent the adverse effects of obesity, weight loss is recommended as the first line of treatment for obese women seeking pregnancy.\nThe effectiveness of pharmacological and non-pharmacological interventions for obese women with subfertility is unclear.\nStudy characteristics\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n2\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nWe found 10 randomised trials comparing pharmacological and non-pharmacological strategies in 1490 obese women with subfertility.\nKey results\nLack of data is a major concern in interpretation of these data. Only 10 studies were included in the analysis. Three studies compared\nnon-pharmacological intervention versus no intervention or placebo. We are uncertain whether diet versus no intervention improves live\nbirth, ongoing pregnancy, clinical pregnancy, or adverse events. A diet or lifestyle intervention may result in body mass index (BMI) weight\nchange. Evidence was insufficient to show a difference in waist-to-hip ratio (WHR) with diet or lifestyle change compared to no intervention.\nNo study reported on quality of life, or mental health outcomes for this comparison.\nOne study compared non-pharmacological interventions - intensive weight loss intervention versus standard of care nutrition counselling;\nhowever due to the very low quality of evidence, we are uncertain whether intensive weight loss interventions improve live birth, clinical\npregnancy, quality of life, or mental health outcomes. No study reported on adverse events, or weight changes, for this comparison.\nThree studies reported on pharmacological versus pharmacological interventions. Evidence was insufficient to show a difference in\nadverse events between metformin compared to metformin plus liraglutide. Evidence was insufficient to demonstrate a difference between\nthe combination of metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo for miscarriage. Evidence was\ninsufficient to reveal a difference between the combination of metformin, clomiphene, and L-carnitine versus metformin, clomiphene,\nand placebo or metformin plus liraglutide versus metformin in clinical pregnancy. Evidence was insufficient to demonstrate a difference\nbetween the combination of metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo for weight change using\nBMI. Moreover, evidence was insufficient to reveal a difference between dexfenfluramine versus placebo or metformin plus liraglutide\nversus 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\nmental health outcomes for this comparison.\nIn the comparison of pharmacological intervention versus no intervention or placebo, three studies were included. Evidence was\ninsufficient to show a difference between metformin and control groups related to live birth. Evidence was insufficient to reveal a difference\nbetween metformin compared to placebo in live birth, clinical pregnancy, or adverse events. Evidence was insufficient to demonstrate\na difference between diet combined with metformin versus diet combined with placebo for weight change using BMI or WHR. No study\nreported on quality of life or mental health outcomes for this comparison.\nWe found no study comparing non-pharmacological with pharmacological interventions.\nQuality of the evidence\nThe evidence was of very low to low quality. The main limitations were due to lack of studies and poor reporting of study methods. The\nmain reasons for downgrading of evidence were lack of details by which to judge risk of bias (randomisation and allocation concealment),\nlack of blinding, and imprecision.\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n3\n\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n4\nS U M M A R Y /uni00A0 O F /uni00A0 F I N D I N G S\n/uni00A0\nSummary of findings 1. /uni00A0 Non-pharmacological intervention compared to no intervention or placebo for obese women with subfertility\nNon-pharmacological intervention compared to no intervention for obese women with subfertility\nPatient or population: obese women with subfertility\nSetting: hospital\nIntervention: non-pharmacological (diet and/or lifestyle changes)\nComparison: no intervention\nAnticipated absolute effects* (95% CI)Outcomes\nRisk with non-pharmacological inter-\nvention\nRisk with no interven-\ntion\nRelative effect\n(95% CI)\n/uni2116. of partici-\npants\n(studies)\nCertainty of\nevidence\n(GRADE)\nComments\nLive birth 395 per 1000\n(334 to 462)\n431 per 1000 OR 0.85\n(0.65 to 1.12)\n917\n(3 RCTs)\n⊕⊕⊝⊝\nlowa ,b\n/uni00A0\nOngoing pregnancy 536 per 1000\n(453 to 617)\n588 per 1000 OR 0.81\n(0.58 to 1.13)\n564\n(1 RCT)\n⊕⊕⊝⊝\nlowc\n/uni00A0\nMiscarriage 122 per 1000\n(82 to 177)\n83 per 1000 OR 1.54\n(0.99 to 2.39)\n917\n(3 RCTs)\n⊕⊝⊝⊝\nvery lowc ,d\n/uni00A0\nClinical pregnancy 529 per 1000\n(458 to 594)\n514 per 1000 OR 1.06\n(0.81 to 1.40)\n917\n(3 RCTs)\n⊕⊕⊝⊝\nlowa ,b\n/uni00A0\nWeight change\nBMI change (Einarsson\n2017)\nMD 3.70 kg/m/two.sups lower\n(4.10 lower to 3.36 lower)\nMean BMI change\nranged from 0.04 to 0.7\nkg/m/two.sups\n- 305\n(1 RCT)\n⊕⊕⊝⊝\nlowc\n/uni00A0\nBMI change (Sim 2014) MD 1.80 kg/m/two.sups lower (2.67 lower to 0.93\nlower)\nMean BMI change\nranged from -1.3 to 0 kg/\nm/two.sups\n- 43\n(1 RCT)\n⊕⊝⊝⊝ very lowc\n,e\n/uni00A0\nQuality of life/\nMental health out-\ncome\n/uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 No study re-\nported this out-\ncome\n*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\nits 95% CI).\nCI: confidence interval; OR: odds ratio; RCT: randomised controlled trial.\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n5\nGRADE Working Group grades of evidence.\nHigh certainty: we are very confident that the true effect lies close to that of the estimate of the effect.\nModerate 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\nsubstantially different.\nLow certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.\nVery 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.\naDowngraded one level for substantial heterogeneity: I/two.sups > 70%.\nbDowngraded one level for imprecision as reflected by the large confidence interval.\ncDowngraded two levels for serious imprecision.\ndDowngraded one level for indirectness due to differences in definition.\neDowngraded one level for incomplete outcome data with an uneven dropout between groups.\n/uni00A0\n/uni00A0\nSummary of findings 2. /uni00A0 Non-pharmacological intervention compared to non-pharmacological intervention for obese women with subfertility\nNon-pharmacological intervention compared to non-pharmacological intervention for obese women with subfertility\nPatient or population: obese women with subfertility\nSetting: hospital\nIntervention: intensive weight loss intervention\nComparison: standard-of-care nutrition counseling\nAnticipated absolute effects* (95% CI)Outcomes\nRisk with weight loss Risk with standard of care nutri-\ntion\nRelative effect\n(95% CI)\n/uni2116. of partici-\npants\n(studies)\nCertainty of\nevidence\n(GRADE)\nComments\nLive birth 500 per 1000 0 per 1000\n(0 to 0)\nOR 11.00\n(0.43 to 284)\n11\n(1 RCT)\n⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nMiscarriage 0 per 1000 0 per 1000 /uni00A0 /uni00A0 /uni00A0 In the trial with\n11 women, no\npregnancy loss\noccurred\nClinical pregnancy 500 per 1000 0 per 1000\n(0 to 0)\nOR 11.00\n(0.43 to 284)\n11\n(1 RCT)\n⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nWeight change\nWeight change (kg)\nBody mass index (BMI)\nMean weight change ranged\nfrom 5 to 6 kg\nMD 9 kg lower\n(15.5 lower to 2.5 lower)\n- 11\n(1 RCT)\n⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n6\nMean body mass Index\nranged from 2 to 3 kg/m/two.sups\nMD 3 kg/m/two.sups lower\n(5.37 lower to 0.63 lower)\n- 11\n(1 RCT)\n⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nMean mental health ranged\nfrom 2 to 3\nMD 7 lower\n(13.92 lower to 0.08 lower)\n- 11\n(1 RCT)\n⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0Quality of life/Mental\nhealth outcome\nMental health (at 12\nweeks)\nQuality of life (at 12\nweeks)\nMean quality of life ranged\nfrom 0.01 to 0.02\nMD 0.06 higher\n(0.03 lower to 0.15 higher)\n- 11\n(1 RCT)\n⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\n*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\nits 95% CI).\nCI: confidence interval; OR: odds ratio; RCT: randomised controlled trial.\nGRADE Working Group grades of evidence.\nHigh certainty: we are very confident that the true effect lies close to that of the estimate of the effect.\nModerate 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\nsubstantially different.\nLow certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.\nVery 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.\naDowngraded one level for selection bias due to lack of details on random sequence, random allocation, and blinding.\nbDowngraded two levels for serious imprecision due to small sample size.\n/uni00A0\n/uni00A0\nSummary of findings 3. /uni00A0 Pharmacological intervention compared to pharmacological intervention for obese women with subfertility\nPharmacological intervention compared to pharmacological intervention for obese women with subfertility\nPatient or population: obese women with subfertility\nSetting: hospital\nIntervention: different pharmacological interventions\nComparison: different pharmacological interventions\nAnticipated absolute effects* (95% CI)Outcomes\nRisk with pharma-\ncological interven-\ntion\nRisk with pharmacologi-\ncal intervention\nRelative effect\n(95% CI)\n/uni2116. of partici-\npants\n(studies)\nCertainty of\nevidence\n(GRADE)\nComments\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n7\nLive birth /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 No study re-\nported this out-\ncome\n71 per 1000 357 per 1000\n(52 to 848)\nOR 7.22\n(0.72 to 73)\n28 (1 RCT) ⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\n71 per 1000 23 per 1000 OR 0.31 (0.01 to\n8.3)\n28 (1 RCT) ⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nAdverse events - Metformin plus liraglu-\ntide vs metformin\nNausea\nDiarrhoea\nHeadache 0 per 1000 0 per 1000 OR 5.80 (0.25 to\n133)\n28 (1 RCT) ⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\n80 per 1000 311 per 1000\n(184 to 476)\nOR 5.20 (2.59 to\n10.4)\n28 (1 RCT) ⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0Clinical pregnancy\nMetformin plus liraglutide vs metformin\nMet + CC + L-carnitine vs Met + CC +\nplacebo 214 per 1000 500 per 1000\n(160 to 839)\nOR 3.67\n(0.70 to 19.1)\n274 (1 RCT) ⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nMiscarriage\nMet + CC + L-carnitine vs Met + CC +\nplacebo\n15 per 1000 51 per 1000\n(11 to 208)\nOR 3.58 ( 0.73 to\n17.6)\n274 (1 RCT) ⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nMean BMI change\nwas set at 0\nMD 2.1 higher (0.42 lower\nto 4.52 higher)\n- 28 (1 RCT) ⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nMean BMI change\nwas set at 0\nMD 0.3 lower (1.17 lower\nto 0.57 higher)\n- 274 (1 RCT) ⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nMean weight change\nwas set at 0 kg\nMD 0.1 kg lower (2.77 low-\ner to 2.57 higher)\n- 21 (1 RCT) ⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nWeight - BMI change\nMetformin plus liraglutide vs metformin\nMet + CC + L-carnitine vs Met + CC +\nplacebo\nWeight change\nDexfenfluramine vs placebo\nWeight - body fat\nMetformin plus liraglutide vs metformin Mean change in % to-\ntal body fat was set\nat 0\nMD 0.5 lower\n(4.65 lower to 3.65 higher)\n- 28 (1 RCT) ⊕⊝⊝⊝\nVery lowa ,b\n/uni00A0\nQuality of life/Mental health outcome /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 No study re-\nported this out-\ncome\n*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\nits 95% CI).\nCI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial.\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n8\nGRADE Working Group grades of evidence.\nHigh certainty: we are very confident that the true effect lies close to that of the estimate of the effect.\nModerate 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\nsubstantially different.\nLow certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.\nVery 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.\naDowngraded one level for selection bias due to lack of details on random sequence, random allocation, and blinding.\nbDowngraded two levels for serious imprecision as reflected by the large confidence interval.\n/uni00A0\n/uni00A0\nSummary of findings 4. /uni00A0 Pharmacological intervention compared to no intervention or placebo for obese women with subfertility\nPharmacological intervention compared to no intervention/placebo for obese women with subfertility\nPatient or population: obese women with subfertility\nSetting: hospital\nIntervention: metformin\nComparison: no intervention/placebo\nAnticipated absolute effects* (95% CI)Outcomes\nRisk with pharmacological interven-\ntion\nRisk with no inter-\nvention/placebo\nRelative effect\n(95% CI)\n/uni2116. of partici-\npants\n(studies)\nCertainty of evi-\ndence\n(GRADE)\nComments\nLive birth 219 per 1000\n(73 to 499)\n152 per 1000 OR 1.57\n(0.44 to 5.57)\n65 (1 RCT) ⊕⊝⊝⊝\nvery lowa ,b\n/uni00A0\nOngoing pregnancy /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 No study re-\nported this out-\ncome\nMiscarriage 31 per 1000\n(3 to 272)\n61 per 1000 OR 0.50\n(0.04 to 5.80)\n65 (1 RCTs) ⊕⊝⊝⊝\nvery lowa ,b\n/uni00A0\nAdverse events (GI) 313 per 1000 333 per 1000 OR 0.91 (0.32 to\n2.57)\n65 (1 RCT) ⊕⊝⊝⊝\nvery lowa ,b\n/uni00A0\nClinical pregnancy 237 per 1000\n(95 to 480)\n104 per 1000 OR 2.67\n(0.90 to 7.93)\n96 (2 RCTs) ⊕⊝⊝⊝\nvery lowa ,b\n/uni00A0\nWeight change\nBMI\nMD 0.3 kg/m/two.sups lower\n(2.16 lower to 1.56 higher)\nMean BMI change was\nset at 0\n- 143\n(1 RCTs)\n⊕⊝⊝⊝\nvery lowa ,c\n/uni00A0\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n9\nWHR MD 2 cm higher\n(2.21 lower to 6.21 higher)\nMean WHR change was\nset at 0\n- 143\n(1 RCT)\n⊕⊝⊝⊝\nvery lowa ,c\n/uni00A0\nQuality of life/Mental\nhealth outcome\n/uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 No study re-\nported this out-\ncome\n*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\nits 95% CI).\nCI: confidence interval; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial.\nGRADE Working Group grades of evidence.\nHigh certainty: we are very confident that the true effect lies close to that of the estimate of the effect.\nModerate 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\nsubstantially different.\nLow certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.\nVery 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.\naDowngraded twice for serious imprecision as reflected by the large confidence interval.\nbDowngraded 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\nlive birth and miscarriage.\ncDowngraded once for selection bias due to lack of details on random sequence, random allocation, and blinding.\n/uni00A0\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nB A C K G R O U N D\nDescription of the condition\nObesity rates have been rising worldwide, creating a global health\nproblem. The World Health Organization has defined obesity as\nbody mass index (BMI) > 30 kg/m/two.sups. According to estimates, in 2015,\nabout 2.3 billion men and women were overweight (BMI 25 to 30 kg/\nm/two.sups), and 700 million were obese (BMI > 30 kg/m/two.sups). The prevalence of\nobesity is estimated to range from 5% in some developing countries\nto more than 30% in developed countries (Hossain 2007 ; Ogden\n2006).\nThe obesity epidemic has contributed to fertility problems.\nObese women have a lesser chance of conceiving naturally\nthan non-obese women (Chong 1986; Crosignani 1994; Hamilton-\nFairley 1992), and they are at greater risk of miscarriage (Boots\n2011). Obesity can result in anovulation and a reduced chance\nof conceiving among ovulatory subfertile women (Metwally\n2007; van der Steeg 2008). Furthermore, pregnancy and live\nbirth rates following IVF appear to be lower in obese women\n(Koloszar 2002; Wang 2002; Fedorcsák 2004; Sermonade 2019 ).\nMoreover, literature suggests that obesity is related to maternal\nand neonatal complications such as congenital anomalies,\nhypertensive disorder, gestational diabetes, prolonged labour,\nmacrosomia, and shoulder dystocia (Edwards 1996; Garbaciak\n1985; Waller 1994; Weiss 2004).\nTo prevent the adverse effects of obesity, weight loss is\nrecommended as the first line of treatment for obese women\nseeking pregnancy (Thessaloniki 2008).\nDescription of the intervention\nTreatment for obesity can involve both non-pharmacological and\npharmacological strategies.\nNon-pharmacological strategies\nDiet\nGenerally, weight loss occurs when energy intake is lower than\nenergy expenditure. In two small studies, replacing protein for\ncarbohydrate within the context of an energy-restricted diet using\n12-week and 1-month dietary intervention among the overweight\nor obese target population (polycystic ovarian syndrome (PCOS)\npatients) provided the same improved reproductive outcomes\nthat were achieved in the control group (Moran 2005; Stamets\n2004), although postprandial glucose response was 3.5 times lower\nin the group with a higher-protein diet. Lifestyle modification\nthrough diet and exercise programmes in obese women with PCOS\nimproves reproductive outcomes (Clark 1998 ; Huber-Buchholz\n1999). An important point is that a minimal amount of weight\nloss (5% to 10%) over as little as four weeks is sufficient to\nimprove the presentation of PCOS despite patients remaining\nclinically overweight or obese (Clark 1998; Hamilton-Fairley 1993;\nWahrenberg 1999).\nExercise\nExercise is an important component of any lifestyle modification\nand weight management programme. The results of two studies\nthat examined effects of exercise on insulin resistance in\noverweight or obese women with PCOS (who were followed for\n16 to 24 weeks and for 6 months) were different. Neither of these\nstudies reported changes in hormone or reproductive parameters\n(Brown 2009; Randeva 2002). In these studies, the impact of\nexercise was not evaluated separately from diet, and the result may\nsuffer from reporting bias (Thomson 2010).\nBehavioural\nBehavioural might contribute to greater weight loss when\ncombined with medical therapy and diet. In one study (Wadden\n2005), participants were followed for 52 weeks, during which\ntime counselling was given including regular supportive and\nmotivational personal or group sessions. Behaviour therapy\nimproved weight loss as well as weight maintenance and control.\nComplementary and traditional healthcare approaches\nThe terms 'complementary' and 'alternative' describe practices\nand products that people choose as adjuncts or alternatives to\nWestern medical approaches (Kaptchuk 2001; Straus 2004). The\nNational Institutes of Health has grouped such interventions into\nfive somewhat overlapping domains as follows (nccam.nih.gov/\nhealth/whatiscam).\n• Biologically based practices. These include use of a vast array\nof vitamins and mineral supplements, natural products such\nas chondroitin sulphate, which is derived from bovine or shark\ncartilage, and herbals such as ginkgo biloba and echinacea.\n• Manipulative and body-based approaches. These types of\ntherapies, which include massage, have been used throughout\nhistory. In the 19th century, additional formal manipulative\ndisciplines emerged in the United States: chiropractic medicine\nand osteopathic medicine, which had a great influence in\ncomplementary medicine.\n• Mind-body medicine. Many ancient cultures assumed that the\nmind exerts powerful influences on bodily functions and vice\nversa. Attempts to reassert proper harmony between these\nbodily systems led to the development of mind-body medicine,\nan array of approaches that incorporate spiritual, meditative,\nand relaxation techniques.\n• Alternative medical systems. Whereas the ancient Greeks\npostulated that health requires a balance of vital humors, Asian\ncultures considered that health depends on the balance and\nflow of vital energies through the body. This latter theory\nunderlies the practice of acupuncture, for example, which\nasserts that vital energy flow can be restored by placing needles\nat critical body points.\n• Energy medicine. This approach uses therapies that involve\nthe use of energy - biofield-based or bioelectromagnetic-based\ninterventions. An example of the former is Reiki therapy, which\naims to realign and strengthen healthful energies through the\nintervention of energies radiating from the hands of a master\nhealer.\nPharmacological strategies\nNumerous anti-obesity medications are prescribed for weight loss.\nThese drugs may be classified as follows.\n• Drugs acting on the gastrointestinal tract (GIT): lipase inhibitors\n(orlistat).\n• Centrally acting anti-obesity agents: catecholaminergic agents\n(phentermine).\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n10\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Serotonin and noradrenaline reuptake inhibitors such as\nsibutramine, selective serotonin reuptake inhibitors (SSRIs)\n(sertraline).\n• Dopamine reuptake antagonists (bupropion), anti-depressants\n(fluoxetine).\n• Exercise mimetics ephedrine, caffeine, synephrine, beta 3\nadrenergic agonists, uncoupling proteins 2 and 3 (thermogenin).\n• Leptin-related agents: therapeutic leptin, leptin analogues,\nleptin receptor agonists.\nAll of these drugs have side effects, and side effect profiles vary\nper drug. Sibutramine is associated with modest increases in heart\nrate and blood pressure; gastrointestinal symptoms predominate\nwith the use of orlistat; phentermine can induce cardiovascular and\ngastrointestinal side effects; fluoxetine is associated with agitation\nand nervousness, in addition to gastrointestinal side effects;\nbupropion with paraesthesia, insomnia, and central nervous\nsystem effects; and topiramate with paraesthesia and changes in\ntaste (Li 2005).\nHow the intervention might work\nThe aetiology of obesity is believed to be multi-factorial, with both\ngenetic and environmental contributions. A key determinant of\nobesity is the balance between ingested calories and the body's\nbasal energy expenditure. Obesity therefore results when small\npositive energy balances accumulate over a long time (Flegal 2010;\nSwinburn 2009 ). Weight loss can be achieved through lifestyle\nintervention programmes incorporating the combination of a\nhealthy diet, increased physical activity, behavioural modification,\nand use of complementary and traditional healthcare approaches\nand medications.\nAn adverse effect of obesity on female fertility could be mediated\nby several mechanisms. First, obesity potentially contributes to\nexcess oestrogen as a result of extraglandular aromatisation of\nandrogen precursors. Moreover, sex hormone–binding globulin\nlevels are diminished, resulting in more bioavailable oestrogen\nand androgen for aromatisation. Second, obesity increases leptin\nlevels. The actions of leptin on the hypothalamus-pituitary-ovary\n(HPO) axis are believed to have differential effects on central and\nperipheral components of the reproductive system. In the central\nnervous system, leptin has been shown to modulate gonadotropin-\nreleasing hormone (GnRH) pulse frequency in vitro (Scott 2009).\nOn the gonadal level, leptin has been found in ovarian follicular\nfluid, and leptin receptor has been localised to human granulosa\nand theca cells. In humans, leptin may interrupt normal oocyte\nmaturation (Smith 2002 ). Weight loss improves the metabolic,\nendocrine, and reproductive profile of obese women (Falsetti 1992;\nHollmann 1996; Kumar 1993). Evidence indicates that a 5% weight\nloss improves both natural and induced conception, as well as the\nchance of a healthy live birth (Khaskheli 2013).\nWeight loss can be achieved by pharmacological treatments and\nnon-pharmacological intervention programmes. Pharmacological\ntreatment for obesity is considered an option for infertile\nwomen who are overweight or obese because the safety\nof these treatments has not been fully studied (Johansson\n2015; Kominiarek 2017). A systematic review suggested that\nsibutramine, orlistat, phentermine, probably diethylpropion,\nprobably fluoxetine, bupropion, and topiramate might promote\nmodest weight loss for at least six months when given along\nwith recommendations for diet (and possibly other behavioural\nand exercise interventions) (Li 2005 ). Medications act on the\nmechanisms regulating appetite and satiety and help combat the\npathophysiological adaptations that drive weight regain (Garvey\n2013). Due to the potential risks associated with surgery or weight\nloss medications, health organisations have recommended that\ninfertile women who are overweight or obese should follow lifestyle\nchanges (ASRM 2015 ). Recent international guidelines strongly\nsupport the importance of pre-pregnancy lifestyle interventions in\nan interdisciplinary situation to encourage healthy lifestyles and\nmaintain weight loss for obese women (Brauer 2015; Kominiarek\n2017). In addition, knowledge about the effects of supplements\nand complementary therapy (herbal medicine and acupuncture) is\nemerging, but evidence for the overall effects of these interventions\nis incomplete.\nLifestyle modification, which generally consists of a combination\nof nutrition, physical activity, and behavioural modification, is\nan o/f_t-used strategy to help patients achieve weight loss and\nmaintenance (Berkel 2005; Lang 2006). It has been suggested that\ncomplementary and alternative medicine including acupuncture\nmight improve weight loss by (1) regulating obesity-related\nneuropeptides (Cabioglu 2006 ; Gucel 2012); (2) regulating\nhypothalamus-pituitary-adrenal cortex and sympathetic adrenal\ncortex (Yin 2005); and (3) conferring lipid-lowering effects (Abdallah\n2011). A systematic review and meta-analysis suggested that\nacupuncture for obesity might be beneficial compared to placebo\nor lifestyle control, but results were limited by the clinical\nheterogeneity and poor methodological quality of the included\ntrials (Cho 2009).\nWhy it is important to do this review\nWith the growing incidence of infertility among obese women,\nit is becoming increasingly common for women to utilise\nassisted reproductive treatment to become pregnant (Kupta\n2014). Overweight and obese women have poor maternity\noutcomes (Koning 2012; Pandey 2010; Rittenberg 2011), while\nweight reduction improves reproductive outcomes for these\npatients (Crosignani 2003; Pandey 2010). The effectiveness of\npharmacological and non-pharmacological interventions for obese\nwomen with subfertility is unclear. Moreover, despite the fact that\nnon-pharmacological interventions are commonly recommended\nfor management of obese subfertile women, their effectiveness\nin comparison with pharmacological strategies has not been\npreviously examined in a systematic review (Kim 2020).\nO B J E C T I V E S\nTo assess the effectiveness and safety of pharmacological and non-\npharmacological strategies compared with each other, placebo,\nor no treatment, for achieving weight loss in obese women with\nsubfertility.\nM E T H O D S\nCriteria for considering studies for this review\nTypes of studies\nRandomised controlled trials (RCTs) and cross-over randomised\ntrials. For cross-over trials, only data from the first phase will be\nincluded in meta-analyses, as the cross-over is not a valid design in\nthis context.\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n11\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nTypes of participants\nObese women (BMI ≥ 30 kg/m/two.sups, or as appropriate for the ethnicity\nof women in the primary study) of childbearing age (post-\nmenarche and pre-menopause) of any ethnic origin who have\nbeen unable to conceive for at least 12 months (including primary\nand secondary subfertility), with or without reasons (anovulatory,\nunexplained, tubal disease, endometriosis, uterine abnormalities,\nmale factor), and with all types of fertility treatment including\nintrauterine insemination (IUI), in vitro fertilisation (IVF), and\nexpectant management.\nTypes of interventions\nWe included all studies in which weight loss was the main treatment\nintervention or weight loss interventions were part of a subfertility\nmanagement programme.\nEligible comparisons are pharmacological, non-pharmacological,\nand no intervention or placebo.\nWe considered the following comparisons.\n• Non-pharmacological versus pharmacological intervention (e.g.\nacupuncture versus SSRI).\n• Non-pharmacological versus non-pharmacological intervention\n(e.g. acupuncture versus exercise, one type of exercise versus\nanother).\n• Pharmacological versus pharmacological intervention (e.g. one\nSSRI versus one type of pharmacological intervention, one SSRI\nversus another).\n• Pharmacological intervention versus no intervention or\nplacebo.\n• Non-pharmacological intervention versus no intervention or\nplacebo.\nThe following interventions will be considered.\nNon–pharmacological interventions\n• Behaviour: behaviour modification, behaviour change, brief\nintervention, brief advice, nurse counselling, physician\ncounselling, psychological counselling, waiting list for\ntreatment with the promise of treatment upon achieving\na weight target, behavioural advice, behaviour therapy,\nInternet-based support, self-directed support, social support,\ngroup therapy, family therapy, psychotherapy, support group,\nrelaxation, health education, health promotion, motivation,\nmeditation, religious intervention.\n• Diet: diet modification, dietician-led dietary advice, self-\ndirected dietary instruction, low-carbohydrate diet, low-fat diet,\nhypocaloric diet.\n• Exercise: walking, jogging, running, swimming, aerobics,\nstructured exercise referral/interventions, weight-li/f_ting/\ntraining, gymnastics, resistance training, fitness training,\nendurance training, cycling, boxing, kick-boxing, pedometry,\nexercise therapy, sports therapy.\n• Complementary and traditional healthcare approaches:\nacupuncture; electro-therapy; physical therapy; aromatherapy;\nauricular stimulation; body therapy; acupuncture - Moxibustion;\nTai-chi; phytooestrogens; soy products; phytovitamins; dietary\nsupplements and herbal products including conjugated linoleic,\npyruvate, ephedra sinica (ma huang), chromium, hydroxy citric\nacid (Garcinia cambogia), and Chitosan.\nPharmacological interventions\n• Drugs acting on the GIT: lipase inhibitors (e.g. orlistat (Xenical),\ntetrahydrolipstatin), bulking agents (e.g. methylcellulose\n(Celevac), ispaghula husk, sterculia, bran, guar gum), insulin\nsensitisers, gastrointestinal peptides, glucagon-like peptide-1,\nenterostatin.\n• Centrally acting anti-obesity agents: catecholaminergic\nagents (e.g. phentermine, mazindol, diethylpropion,\nphenylpropanolamine), serotonergic agents (e.g. fenfluramine,\ndexfenfluramine, fluoxetine), combined catecholaminergic plus\nserotoninergic agents (e.g. phentermine plus fenfluramine).\n• Serotonin and noradrenaline reuptake inhibitors (e.g.\nsibutramine), selective serotonin reuptake inhibitors (SSRIs; e.g.\nsertraline).\n• Dopamine reuptake antagonists (e.g. bupropion), anti-\ndepressants (e.g. fluoxetine).\n• Exercise mimetics (e.g. ephedrine, caffeine, synephrine),\nbeta 3 adrenergic agonists, uncoupling proteins 2 and 3\n(Thermogenin).\n• Leptin-related agents (e.g. therapeutic leptin, leptin analogues,\nleptin receptor agonists).\nWe excluded surgical interventions.\nTypes of outcome measures\nPrimary outcomes\n• Live birth or ongoing pregnancy (when live birth is not available)\n/uni25E6Live birth is defined as delivery of a live fetus a/f_ter 20\ncompleted weeks of gestation\n/uni25E6Ongoing pregnancy is defined as evidence of a gestational sac\nwith fetal heart motion at 12 weeks, confirmed by ultrasound\n• Adverse events: miscarriage (loss of pregnancy during the\nfirst 20 weeks of gestation) or gastrointestinal symptoms (e.g.\nnausea, vomiting, diarrhoea)\nSecondary outcomes\n• Clinical pregnancy: defined as evidence of a gestational sac,\nconfirmed by ultrasound\n• Weight change (e.g. body mass index (BMI), waist to hip ratio\n(WHR), percentage of body fat or total body fat)\n• Change in endocrine parameters: total and free testosterone\n(ng/dL or nmol/L), sex hormone-binding globulin (SHBG; nmol/\nL), testosterone-to-SHBG ratio, diabetic tests such as glucose\ntolerance test (GTT; mmol/L), glycated haemoglobin (HbA1c;\nmmol/mol)\n• Quality of life or mental health outcome. If studies reported\nmore than one scale, preference will be given to the SF-36 (36-\nItem Short Form Health Survey), then to other validated generic\nscales, and finally, to condition-specific scales\nSearch methods for identification of studies\nIn consultation with the Cochrane Gynaecology and Fertility Group\n(CGF) Information Specialist, we formulated a comprehensive\nsearch strategy to identify all RCTs of pharmacological\nand non-pharmacological strategies for obese women with\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n12\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nsubfertility regardless of language or publication status (published,\nunpublished, in press, or in progress).\nElectronic searches\nWe searched the following electronic databases, trial registers, and\nwebsites:\n• Cochrane Gynaecology and Fertility Group (CGF) Specialised\nRegister of Controlled Trials, ProCite platform, searched on 18\nAugust 2020 (Appendix 1).\n• Cochrane Central Register of Controlled Trials (CENTRAL), via\nthe Cochrane Central Register of Studies Online (CRSO), Web\nplatform, searched on 18 August 2020 (Appendix 2).\n• MEDLINE, Ovid platform, searched from 1946 to 18 August 2020\n(Appendix 3).\n• Embase, Ovid platform, searched from 1980 to 18 August 2020\n(Appendix 4).\n• PsycINFO, Ovid platform, searched from 1806 to 18 August 2020\n(Appendix 5).\n• Allied and Complementary Medicine Database (AMED), Ovid\nplatform, searched from 1985 to 18 August 2020 (Appendix 6).\n• Cumulative Index to Nursing and Allied Health Literature\n(CINAHL), Ebsco platform, searched from 1961 to 26 September\n2019 ( Appendix 7 ). (CINAHL references are now included in\nCENTRAL; therefore the CENTRAL search on 18 August 2020\nincluded CINAHL references).\nThe MEDLINE search from inception to 18 August 2020\nwas combined with the Cochrane highly sensitive search\nstrategy for identifying randomised trials, which appears in\nthe Cochrane Handbook for Systematic Reviews of Interventions\n(Lefebvre 2020, Version 6.1, Chapters 4, 4.4.7; 4S1). Searches\nof Embase and CINAHL from inception to 18 August 2020\nwere combined with trial filters developed by the Scottish\nIntercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/what-\nwe-do/methodology/search-filters/).\nSearching other resources\nOther sources of trials below were searched on 18 August 2020:\n• Trial registers for ongoing and registered trials:\nwww.clinicaltrials.gov (a service of the US National Institutes\nof Health), the World Health Organization International Trials\nRegistry Platform search portal, at www.who.int/trialsearch/\nDefault.aspx.;\n• Database of Abstracts of Reviews of Effects (DARE), part of\nthe Cochrane Library, at onlinelibrary.wiley.com/o/cochrane/\ncochrane_cldare_articles_fs.html (for reference lists from\nrelevant non-Cochrane reviews);\n• Relevant non-Cochrane reviews;\n• Web of Science wokinfo.com/ (another source of trials and\nconference abstracts);\n• OpenGrey at www.opengrey.eu/ (for unpublished literature\nfrom Europe);\n• PubMed (for recent trials not yet indexed in MEDLINE);\n• ProQuest.\nWe checked the reference lists of relevant trials, reviews, and\ntextbooks. We contacted experts in the field for relevant trials and\nto obtain additional data. Output of all searches was managed with\nEndNote, which lists all studies and removes duplicates.\nData collection and analysis\nSelection of studies\nA/f_ter an initial screen of titles and abstracts retrieved by the search,\nconducted by two review authors (FB and ST), we retrieved the\nfull text of all potentially eligible studies. These review authors\nindependently examined these full-text articles for compliance\nwith the inclusion criteria and selected eligible studies. We\ncorresponded with study investigators, as required, to clarify study\neligibility. Any disagreement about whether to include or exclude a\nstudy was discussed with a third review author (SJ) until consensus\nwas achieved. We have listed excluded studies and reasons for\ntheir exclusion in the Characteristics of excluded studies tables.\nSee Figure 1 (PRISMA flow chart) for details of the screening and\nselection process.\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n13\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFigure 1. /uni00A0 Study flow diagram.\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n14\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nData extraction and management\nTwo review authors (FB and ST) independently extracted data\nfrom eligible studies using a data extraction form that had been\ndesigned and pilot-tested by review authors. Any disagreements\nwere resolved by discussion. Data extracted included study\ncharacteristics and outcome data. When studies had multiple\npublications, review authors collated multiple reports of the same\nunder a single study ID with multiple references. We corresponded\nwith study investigators to request further data on methods\nand/or results, as required. Data extracted included population\ncharacteristics (e.g. female age, BMI, waist-hip ratio, ethnicity),\nstudy characteristics, and outcome data.\nAssessment of risk of bias in included studies\nTwo review authors (FB and ST) assessed risk of bias using\nthe Cochrane 'Risk of bias' assessment tool to assess selection\nbias (random sequence generation, allocation concealment);\nperformance bias (blinding of women and personnel); detection\nbias (blinding of outcome assessors); attrition bias (incomplete\noutcome data); reporting bias (selective reporting); and other\nbiases (Higgins 2011). Disagreements were resolved by consensus\nor by discussion with a third review author (SJ).\nRandom sequence generation was scored at low risk of bias when\nan appropriate method of sequence generation was described\naccording to Cochrane methods (Higgins 2011).\nAllocation concealment was considered at low risk of bias if\nopaque and numbered envelopes or a centralised Internet-based\nrandomisation procedure was used. Lack of blinding is unlikely to\naffect live birth (scored at low risk of bias) but might affect adverse\nevents (scored at high risk of bias). Attrition bias was scored low\nwhen all or most (> 95%) of the women randomised were analysed.\nReporting bias was scored low when all relevant outcomes were\nreported as planned in the protocol, as described in published\nprotocols in journals or in trial registers. To score other forms of\nbias, we looked at differences in baseline values and treatment\ndetails. If these issues were unclear, we scored the risk of bias as\nunclear.\nWe corresponded with study authors to identify any within-trial\nselective reporting. We sought published protocols and compared\noutcomes between the protocol and the final published study. The\n'Risk of bias' table is presented with the table Characteristics of\nincluded studies. All judgements are fully described. Conclusions\nare presented in the ’Risk of bias’ table and are incorporated into\nthe interpretation of review findings through sensitivity analyses.\nWith respect to within-trial selective reporting, when identified\nstudies failed to report the primary outcome of live birth but did\nreport interim outcomes such as pregnancy, we assessed whether\nthe interim values were similar to those reported in studies that also\nreported live birth.\nMeasures of treatment effect\nWe performed a statistical analysis in accordance with statistical\nguidelines provided in the Cochrane Handbook for Systematic\nReviews of Interventions ( Higgins 2011 ). We used a fixed-effect\nmodel for all analyses.\nFor dichotomous data (e.g. live birth rates), we used numbers of\nevents in control and intervention groups of each study to calculate\nodds ratios (ORs). For reporting purposes, we translated primary\noutcomes to absolute risks.\nFor continuous data (e.g. weight loss), if all studies reported\nexactly the same outcomes, we planned to calculate mean\ndifferences (MDs) between treatment groups. If similar outcomes\nwere reported on different scales (e.g. change in weight, quality\nof life), we planned to calculate standardised mean differences\n(SMDs). We planned to reverse the direction of effect of individual\nstudies, if required, to ensure consistency across trials. We planned\nto treat ordinal data (e.g. quality of life scores) as continuous data.\nWe planned to present 95% confidence intervals for all outcomes.\nWhen data to calculate RRs or MDs were not available, we planned\nto utilise the most detailed numerical data available that may\nfacilitate similar analyses of included studies (e.g. test statistics,\nP values). We planned to assess whether estimates calculated in\nthe review for individual studies were compatible in each case with\nestimates reported in study publications.\nBecause cluster-RCTs are included in the review, we planned\nto first make an assessment as to whether the trial had been\nanalysed in such a way as to account for clustering, and if not, we\nplanned to make an adjustment to the trial results using one of\nseveral available approaches including a generic inverse-variance\nmethod via effect estimates and their standard errors extracted\nfrom cluster-RCTs.\nUnit of analysis issues\nThe primary analysis was planned to be per woman randomised;\nper pregnancy data may also be included for some outcomes (e.g.\nmiscarriage). Data that do not allow valid analysis (e.g. 'per cycle'\ndata) were planned to be briefly summarised in an additional table\nand not to be meta-analysed. Multiple births were planned to count\nas one live birth event. Only first-phase data from cross-over trials\nwere planned to be included.\nDealing with missing data\nWe planned to analyse data on an intention-to-treat basis as far as\npossible (i.e. including all randomised women in the analysis, in the\ngroups to which they were randomised). We planned to attempt\nto obtain missing data from the original study authors. When\nthese were unobtainable, we planned to undertake imputation\nof individual values for live birth only: live birth was planned to\nbe assumed not to have occurred in women without a reported\noutcome. For other outcomes, we planned to analyse only available\ndata. Any imputation undertaken was planned to be subjected to\nSensitivity analysis.\nIf studies reported sufficient detail to calculate mean differences\nbut no information on associated SD, we planned to assume the\noutcome to have an SD equal to the highest SD from other studies\nwithin the same analysis.\nAssessment of heterogeneity\nWe planned to consider whether the clinical and methodological\ncharacteristics of included studies were sufficiently similar for\nmeta-analysis to provide a clinically meaningful summary. We\nplanned to assess statistical heterogeneity by using the I/two.sups value.\nAn I/two.sups measurement greater than 50% was planned to be taken to\nindicate substantial heterogeneity (Higgins 2011).\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n15\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAssessment of reporting biases\nIn view of the difficulty of detecting publication bias and other\nbiases, review authors aimed to minimise their potential impact by\nensuring a comprehensive search for eligible studies, and by being\nalert for duplication of data. If 10 or more studies were included in\nan analysis, we planned to use a funnel plot to assess the potential\nfor publication bias.\nData synthesis\nIf studies were sufficiently similar, we planned to combine data\nusing a fixed-effect model for the following comparisons.\n• Non-pharmacological intervention versus no intervention/\nplacebo.\n• Non-pharmacological versus non-pharmacological\nintervention.\n• Pharmacological versus pharmacological intervention.\n• Pharmacological intervention versus no intervention/placebo.\n• Pharmacological versus non-pharmacological intervention.\nSee Types of interventions for the exact study interventions we\nplanned to investigate.\nAn increase in the risk of all outcomes was planned to be displayed\ngraphically in meta-analyses to the right of the centre-line, and a\ndecrease in the risk of an outcome to the le/f_t of the centre-line.\nSubgroup analysis and investigation of heterogeneity\nWhen sufficient data were available (at least five RCTs), we planned\nto perform the following subgroup analyses for primary outcomes\nonly.\n• Duration of intervention (short: 2 to 4 weeks, medium: 4 weeks\nto 6 months, long: longer than 6 months) (Lim 2019).\n• Cause of infertility: anovulatory versus unexplained versus other\ncauses.\n• Maternal age: ≤ 35 or ≥ 36 years.\n• Severity of obesity (BMI): 30.0 < BMI < 34.9 (class I obesity) versus\n35.0 < BMI < 39.9 (class II obesity) versus BMI ≥ 40.0 (class III\nobesity).\nSensitivity analysis\nWe planned to conduct the following sensitivity analyses\nfor primary outcomes, to examine stability regarding pooled\noutcomes.\n• Restriction to studies without high risk of bias.\n• Use of a random-effects model.\n• Use of risk ratio rather than odds ratio.\nSummary of findings and assessment of the certainty of the\nevidence\nWe prepared a 'Summary of findings' table using GRADEpro\n(GRADEpro GDT 2014) and Cochrane methods (Higgins 2011). This\ntable evaluates the overall quality of the body of evidence for\nthe primary review outcomes (live birth or ongoing pregnancy,\nadverse events, clinical pregnancy, miscarriage) for the main\nreview comparison (pharmacological versus non-pharmacological\nstrategies). Additional 'Summary of findings' tables were also\nprepared for the main review outcomes for other important\ncomparisons.\nWe assessed the quality of the evidence using GRADE criteria:\nrisk of bias, consistency of effect, imprecision, indirectness\nand publication bias. Judgements about evidence quality\n(high, moderate, low or very low) were made by two review\nauthors working independently, with disagreements resolved\nby discussion. Judgements were justified, documented, and\nincorporated into reporting of results for each outcome.\nWe extracted study data, formatted our comparisons in data tables\nand prepared a 'Summary of findings' table using the GRADEpro\nGuideline Development Tool (GDT) (GRADEpro GDT 2014) before\nwriting the results and conclusions of our review.\nR E S U L T S\nDescription of studies\nWe have reported the characteristics of included and\nexcluded studies in the Characteristics of included studies and\nCharacteristics of excluded studies tables. We did not identify any\nstudies from the reference lists.\nResults of the search\nOur search retrieved 5577 articles (910 duplicates were removed).\nOf these articles, 4667 studies were screened by title and abstract\nand 68 studies were assessed at full text for eligibility. Finally, we\nincluded 10 studies that met the inclusion criteria for the review\n(Figure 1). The 10 included trials varied in size from 11 to 564 women\n(Einarsson 2017; El 2019 ; Galletly 1996; Johnson 2010 ; Khorram\n2006; Mutsaerts 2016; Rothberg 2016; Salamun 2018 ; Sim 2014 ;\nTang 2006).\nIncluded studies\nStudy design\nOne study was a cross-over randomised clinical trial (Galletly\n1996) for which we tried to extract pre-cross-over data, and the\nothers were RCTs (Einarsson 2017; El 2019; Johnson 2010; Khorram\n2006; Mutsaerts 2016; Rothberg 2016; Salamun 2018 ; Sim 2014 ;\nTang 2006). Einarsson 2017, El 2019 , and Johnson 2010  used a\ncomputerised randomisation programme for the randomisation\nprocess, and Tang 2006 used a table of random numbers. Khorram\n2006 explained that randomisation was done by picking a card\nout of a box. A web-based randomisation program was adopted\nfor Mutsaerts 2016. It is not clear how randomisation was done in\nGalletly 1996, Sim 2014, Salamun 2018, and Rothberg 2016.\nSample size\nThe number of women included in the studies ranged from 11 to\n564.\nSetting\nAll studies except one were conducted in high-income countries\n(Egypt; El 2019). One study was undertaken in the UK (Tang 2006),\none in The Netherlands (Mutsaerts 2016), two in the USA (Khorram\n2006; Rothberg 2016), one in Sweden (Einarsson 2017), one in New\nZealand (Johnson 2010), one in Slovenia (Salamun 2018), and two\nin Australia (Galletly 1996; Sim 2014). All trials recruited women in\nhospital settings.\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n16\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nParticipants\nAll women in the included studies met our inclusion criteria.\nWe found 10 randomised trials including 1490 obese women\nwith subfertility. Einarsson 2017 included 305 participants, Sim\n2014 48 participants, Mutsaerts 2016 564 participants, Rothberg\n2016 11 participants, Salamun 2018  28 participants, El 2019\n274 participants, Galletly 1996 21 participants, Tang 2006 143\nparticipants, Khorram 2006 31 participants, and Johnson 2010 65\nparticipants.\nThe main inclusion criterion was:\n• age 18 to 37 (Sim 2014), 38 (Einarsson 2017), 39 (Mutsaerts 2016\nTang 2006 ), 40 (Rothberg 2016), or ≤ 38 years (Salamun 2018).\nThe main exclusion criteria were:\n• insulin-dependent diabetes mellitus (Einarsson 2017);\n• endocrinopathy (El 2019 ; Johnson 2010 ; Mutsaerts 2016\nRothberg 2016 Salamun 2018  Sim 2014  Tang 2006 Khorram\n2006);\n• binge eating disorder (Einarsson 2017);\n• current psychiatric condition (Sim 2014);\n• recent (within three months) participation in treatment known\nto affect diet or body weight (Sim 2014);\n• taking anti-obesity drugs or appetite suppressants within the\npast two months (Rothberg 2016);\n• previous bariatric surgery or gastrointestinal disease (Rothberg\n2016);\n• use of medications that affect reproductive or metabolic\nfunctions within the past six weeks (Tang 2006), or in the\npast two or three months (Rothberg 2016; Salamun 2018 ,\nrespectively);\n• smoker (El 2019); and\n• drug user (El 2019 Khorram 2006).\nThere were no significant differences between baseline\ncharacteristics in all studies (El 2019 Galletly 1996 Johnson 2010;\nKhorram 2006; Mutsaerts 2016; Rothberg 2016; Sim 2014 ; Tang\n2006), except termination of pregnancy in Einarsson 2017 and 120-\nminute overload of insulin levels in Salamun 2018.\nInterventions\nNon-pharmacological intervention versus no intervention or placebo\nOne study compared diet versus no intervention (IVF) (Einarsson\n2017). In the intervention group, weight reduction was done before\nIVF, starting with 12 weeks of a low-calorie liquid formula diet (LCD)\nof 880 kcal/d and therea/f_ter weight stabilisation for two to five\nweeks. In the control group, only IVF was done.\nOne study compared lifestyle versus no intervention (Mutsaerts\n2016). In Mutsaerts 2016, the lifestyle intervention consisted of a six-\nmonth structured programme aiming at a weight loss of 5% to 10%\nof original body weight. It included six structured outpatient visits\nand four telephone consultations with a pre-trained intervention\ncoach. Daily dietary energy intake was reduced by 600 kcal and\nwas maintained at a minimum of 1200 kcal/d. Physical activity\nwas stimulated to a level of 10,000 steps a day and at least 30\nminutes of exercise two to three times a week. Behavioural changes\nwere facilitated by motivational counselling. A/f_ter the six-month\nprogramme was completed, or when weight loss of 5% to 10%\nhad been achieved, women started with appropriate infertility\ntreatment if they were not yet pregnant. The control group received\nappropriate infertility treatment immediately a/f_ter randomisation.\nOne study compared diet versus no intervention in a 12-week\nintervention consisting of a very low-energy diet for the first six\nweeks followed by a hypocaloric diet, combined with a weekly\ngroup multi-disciplinary programme (Sim 2014). The control group\nreceived recommendations for weight loss and the same printed\nmaterial as the intervention group.\nNon-pharmacological versus non-pharmacological intervention\nOne study compared two different diet methods (Rothberg 2016):\nan intensive weight loss intervention (IWL) and standard of care\nnutrition counselling (SCN). IWL consisted of 12 weeks of a very\nlow-energy diet (800 kcal/d) and four weeks of a low-calorie\nconventional food-based diet (CFD) to promote 15% weight loss.\nSCN consisted of 16 weeks of CFD to promote 5% weight loss.\nPharmacological versus pharmacological intervention\nOne study compared metformin versus metformin combined with\nliraglutide (Salamun 2018). Metformin (MET) was initiated at a dose\nof 500 mg once per day and was increased by 500 mg every three\ndays up to 1000 mg twice daily. In the group given metformin\n1000 mg twice daily combined with 1.2 mg liraglutide once daily\nsubcutaneously (COMBI), there was a run-in period of 12 days\nto titrate metformin up to 1000 mg twice daily before liraglutide\nwas added. Liraglutide was initiated at a dose of 0.6 mg injected\nsubcutaneously once per day and was increased to 1.2 mg a/f_ter\nthree days. Medical treatment in both groups lasted 12 weeks.\nOne study compared dexfenfluramine/placebo versus placebo/\ndexfenfluramine (Galletly 1996). Dexfenfluramine and placebo\nwere given in a cross-over design. Dexfenfluramine dosage was 15\nmg twice daily, and the duration of each treatment condition was\n12 weeks.\nOne study compared L-carnitine versus placebo (El 2019). Group 1\n(clomiphene citrate (CC) plus metformin and L-carnitine) received\n150 mg/d CC from day 3 to day 7 of the menstrual cycle plus oral L-\ncarnitine (3 g) and metformin 850 mg (1 tablet daily); the dose was\ndoubled a/f_ter one week to 1700 mg/d (2 tablets daily). Metformin\nwas ingested before a meal once daily during the first week, and\ntherea/f_ter twice daily. L-carnitine and metformin were stopped only\nwhen pregnancy was documented. Group 2 (CC plus metformin\nand placebo) received 150 mg/d CC plus metformin (as above) and\nplacebo capsules that were designed to look exactly like L-carnitine\ncapsules.\nPharmacological intervention versus no intervention or placebo\nOne study compared diet combined with metformin versus diet\ncombined with placebo (Tang 2006). The intervention group took\nmetformin (850 mg) twice daily over six months. The control group\nreceived placebo over six months.\nOne study compared metformin versus no intervention (Khorram\n2006). All patients received CC 100 mg per day on cycle days 5\nthrough 9 only. In group 1 (CC + MET), participants received MET\n500 mg three times a day, given on cycle days 1 through 14, with\ncycle day 1 defined as the first day of menstrual flow. Group 2 (CC)\nreceived CC 100 mg per day on cycle days 5 through 9 only.\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n17\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOne study compared metformin versus placebo (Johnson 2010 ).\nWomen with BMI > 32 received no treatment other than advice\nand encouragement on a lifestyle intervention (which included\nadvice on calorie restriction and on increasing aerobic exercise\nto 30 minutes at least five times per week combined with an\nopportunity to see a dietician and an exercise therapist if required\n(i.e. standard care)). Women were then allocated to placebo\nor intervention groups. The intervention group (in addition to\nstandard care) received metformin 500 mg three times daily at a\ngradually increasing dose over two weeks for six months.\nPharmacological versus non-pharmacological intervention\nNo study was found for this comparison.\nExcluded studies\nWe excluded 58 studies from the review for the following reasons.\n• 49 of 58 included women not of interest to this review.\n• 4 of 58 reported outcomes not of interest to this review and\nunlikely to ever be measured, as the objectives were different\nfrom the objective of this review.\n• 1 of 58 reported interventions not of interest to this review.\n• 4 of 58 studies are awaiting classification.\nRisk of bias in included studies\nWe have summarised the risk of bias of included studies in Figure\n2 and Figure 3.\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n18\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFigure 2. /uni00A0 Risk of bias summary: review authors' judgements about each risk of bias item for each included study.\nRandom sequence generation (selection bias)\nAllocation concealment (selection bias)\nBlinding of participants and personnel (performance bias): All outcomes\nBlinding of outcome assessment (detection bias): All outcomes\nIncomplete outcome data (attrition bias): All outcomes\nSelective reporting (reporting bias)\nOther bias\nEinarsson 2017 + + - ? + + +\nEl 2019 + + + + + + +\nGalletly 1996 ? ? ? ? ? - +\nJohnson 2010 + + + + + + +\nKhorram 2006 + - ? ? ? - +\nMutsaerts 2016 + + - - + + +\nRothberg 2016 ? - - - + + +\nSalamun 2018 ? - - - + + +\nSim 2014 + + - ? - + +\nTang 2006 + + + + + - +\n/uni00A0\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n19\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFigure 3. /uni00A0 Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages\nacross all included studies.\nRandom sequence generation (selection bias)\nAllocation concealment (selection bias)\nBlinding of participants and personnel (performance bias): All outcomes\nBlinding of outcome assessment (detection bias): All outcomes\nIncomplete outcome data (attrition bias): All outcomes\nSelective reporting (reporting bias)\nOther bias\n0% 25% 50% 75% 100%\nLow risk of bias Unclear risk of bias High risk of bias\n/uni00A0\nAllocation\nRandom sequence generation\nThe method of random sequence generation was associated with\na low risk of bias in seven trials (Einarsson 2017, El 2019, Johnson\n2010, Khorram 2006, Mutsaerts 2016, Tang 2006 Sim 2014  ). The\nthree remaining trials were rated as unclear risk of bias as they did\nnot report the methods of randomisation (Rothberg 2016, Galletly\n1996, Salamun 2018).\nAllocation concealment\nFive studies were at low risk of selection bias, for allocation to\nintervention was Internet-based or sequentially opaque envelopes\nwere used (El 2019; Einarsson 2017; Johnson 2010; Mutsaerts 2016;\nTang 2006). One study was at high risk of selection bias related to\nallocation concealment through open random allocation (Khorram\n2006). Four studies were at unclear risk of selection bias, as they\nnot report adequate details to establish whether an appropriate\nmethod of allocation and/or concealment had been used (Galletly\n1996; Rothberg 2016; Salamun 2018; Sim 2014).\nBlinding\nThree studies described blinding of women and were at low risk of\nperformance bias (El 2019; Johnson 2010; Tang 2006). In five studies\n(Einarsson 2017; Mutsaerts 2016; Rothberg 2016; Salamun 2018 ;\nSim 2014), blinding of treatment assignments was not possible, and\nthe studies were at high risk of performance bias. Two studies did\nnot describe blinding; we judged them to be at unclear risk of bias\n(Galletly 1996; Khorram 2006).\nRelated to detection bias (outcome), three studies described\nblinding of both women and outcome assessors and were at low\nrisk of this bias ( El 2019 ; Johnson 2010 ; Tang 2006). Three study\nused no blinding, and we judged this trial to be at high risk\n(Mutsaerts 2016; Rothberg 2016; Salamun 2018). Four studies were\njudged to have unclear detection bias (Galletly 1996; Khorram 2006;\nSim 2014; Einarsson 2017).\nIncomplete outcome data\nEight studies mentioned dropouts or withdrawals, but the numbers\nwere balanced across groups with similar reasons for missing data;\ntherefore, we judged them as having low risk of attrition bias\n(Einarsson 2017; El 2019; Johnson 2010; Mutsaerts 2016; Rothberg\n2016; Salamun 2018; Tang 2006). One study was considered to have\nhigh risk of bias for incomplete outcome data in view of the high\n(20%) drop-out rate (Sim 2014 ). We judged two studies to be at\nunclear risk of attrition bias, as they did not mention dropouts or\nwithdrawals (Galletly 1996; Khorram 2006).\nSelective reporting\nSeven studies were at low risk of selective bias, as the protocols\nfor these articles were available and their aims were pre-specified\n(Einarsson 2017; El 2019; Johnson 2010; Mutsaerts 2016; Rothberg\n2016; Salamun 2018 ; Sim 2014 ). Three studies were at high risk\nof selective bias, as the protocols were unavailable (Galletly 1996;\nKhorram 2006; Tang 2006).\nOther potential sources of bias\nWe did not identify any other potential sources of bias in the\nincluded studies, and we judged each of the included studies to be\nat low risk of other potential sources of bias.\nPublication bias\nWe did not assess potential publication bias using a funnel plot or\nother corrective analytical methods in view of the small number\nof studies that could be included in the meta-analysis (maximally,\nthree RCTs) (Egger 1997).\nEffects of interventions\nSee: Summary of findings 1 Non-pharmacological intervention\ncompared to no intervention or placebo for obese women\nwith subfertility; Summary of findings 2 Non-pharmacological\nintervention compared to non-pharmacological intervention\nfor obese women with subfertility; Summary of findings\n3 Pharmacological intervention compared to pharmacological\nintervention for obese women with subfertility; Summary\nof findings 4 Pharmacological intervention compared to no\nintervention or placebo for obese women with subfertility\nNon-pharmacological intervention versus no intervention or\nplacebo\nThree studies compared diet or a lifestyle intervention with no\nintervention: One study compared diet versus no IVF intervention\n(Einarsson 2017); another study compared diet versus no\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n20\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nintervention (Sim 2014 ); and another study compared lifestyle\nversus no intervention (Mutsaerts 2016).\nPrimary outcomes\nLive birth rate or ongoing pregnancy\nAll three studies that compared diet or a lifestyle intervention\nalone versus no intervention provided data on live birth rates. We\nfound no conclusive evidence of a difference in live birth (odds\nratio (OR) 0.85, 95% confidence interval (CI) 0.65 to 1.11; 3 studies,\n917 women; I/two.sups = 78%; low-quality evidence; Analysis 1.1 ). The\ncorresponding relative risk was 0.91 (95% CI 0.78 to 1.06), and use\nof a random-effects model resulted in an OR of 1.17 (95% CI 0.55\nto 2.48). This suggests that if the chance of live birth following\nno intervention is assumed to be 43%, the chance following diet\nor lifestyle change would be 33% to 46%. This result needs to be\ninterpreted with caution in view of high statistical heterogeneity.\nHeterogeneity in results was caused mainly by the smallest study of\n48 women (Sim 2014); excluding this study resulted in an OR for live\nbirth of 0.87 (95% CI 0.75 to 1.02) and I/two.sups of 49%.\nIn a two-year follow-up study of the Einarsson 2017 trial, the\ncumulative live birth rate was 57% (87/152) and 54% (82/153) for\nthe weight loss/IVF group versus the IVF only group (OR 1.07, 95%\nCI 0.87 to 1.31).\nAdverse events\nWe are uncertain whether miscarriage may occur more o/f_ten\nfollowing diet or lifestyle change compared to no intervention (OR\n1.54, 95% CI 0.99 to 2.39; 3 studies, 917 women; I/two.sups = 0%; low-quality\nevidence; Analysis 1.3).\nSecondary outcomes\nClinical pregnancy\nFor diet alone versus no intervention, we found insufficient\nevidence of a difference for clinical pregnancy (OR 1.06, 95% CI 0.81\nto 1.40, 1.13; 3 studies, 917 women; I/two.sups = 73%; low-quality evidence;\nAnalysis 1.4 ). This result needs to be interpreted with caution in\nview of high statistical heterogeneity. Heterogeneity in results was\ncaused mainly by the smallest study of 48 women (Sim 2014 );\nexcluding this study resulted in an OR for live birth of 0.98 (95% CI\n0.74 to 1.29) and I/two.sups of 11%.\nWeight change\nAll three studies found lower BMI in the lifestyle intervention group.\nOne study reported BMI at three months following lifestyle change\ncompared with no intervention (mean difference (MD) -1.00, 95%\nCI -1.02 to -0.98; 1 study, 574 women) and at six months (MD -1.30,\n95% CI -1.32 to -1.28; 1 study, 574 women), but as a large proportion\nof pregnant women had to be excluded from the analysis, these\nresults are difficult to interpret (Mutsaerts 2016). Diet resulted in a\ndecrease in BMI in two studies (Einarsson 2017; Sim 2014), but data\nwere not pooled due to heterogeneity in effect (MD -3.70, 95% CI\n-4.10 to -3.36; 305 women, 1 study; low-quality evidence; and MD\n-1.80, 95% CI -2.67 to -0.93; 43 women, 1 study; very low-quality\nevidence).\nIn a two-year follow-up study of the Einarsson 2017 trial, women\nin the weight loss group had regained their pre-trial weight (mean\n(SD) BMI a/f_ter 2 years was 32.5 (3.5) and 33.1 (3.0) for the weight\nloss/IVF versus IVF only arm).\nChange in endocrine parameters\nThis outcome was not reported.\nQuality of life or mental health outcome\nThis outcome was not reported.\nNon-pharmacological versus non-pharmacological\nintervention\nOne study with 11 women compared two different diet methods\nincluding intensive weight loss intervention (IWL) versus standard\nof care nutrition counselling (SCN) (Rothberg 2016).\nPrimary outcomes\nLive birth rate or ongoing pregnancy\nThere was uncertainty about the effects of IWL versus SCN on live\nbirth (OR 11, 95% CI 0.43 to 284; 1 study, 11 women; very low-\nquality evidence; Analysis 2.1). An absolute translation could not be\ncalculated as there were no live births in the SCN group.\nAdverse events\nIn the trial with 11 women, no pregnancy loss occurred.\nSecondary outcomes\nClinical pregnancy\nEvidence of a difference in clinical pregnancy for IWL versus SCN\nwas insufficient (OR 11, 95% CI 0.43 to 284; 1 study, 11 women; very\nlow-quality evidence; Analysis 2.2).\nWeight change\nIn the single trial with 11 women, we found greater weight loss and a\nlarger decrease in BMI for IWL versus SCN (MD -9.00 kg, 95% CI -15.5\nto -2.5; and MD -3.00, 95% CI -5.37 to -0.63, respectively), but In view\nof the very low quality of the evidence, we are uncertain whether\nIWL reduces weight and BMI to a greater extent than SCN.\nChange in endocrine parameters\nNo data on endocrine parameters were available.\nQuality of life or mental health outcome\nEvidence of a difference between IWL and SCN in quality of life\n(MD 0.06, 95% CI -0.03 to 0.15; 1 study, 11 women; very low-\nquality evidence) and in mental health outcome (MD -7.00, 95% CI\n-13.92 to -0.08; 1 study, 11 women; very low-quality evidence) was\ninsufficient.\nPharmacological versus pharmacological intervention\nOne study compared metformin plus liraglutide versus metformin\n(Salamun 2018); one study compared a combination of metformin,\nclomiphene, and L-carnitine versus metformin, clomiphene, and\nplacebo (El 2019); and one study compared dexfenfluramine versus\nplacebo (Galletly 1996); for this last study, only weight loss as an\noutcome could be retrieved from the pre-cross-over data.\nPrimary outcomes\nLive birth rate or ongoing pregnancy\nNo comparison of live birth rate or ongoing pregnancy was\navailable.\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n21\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAdverse events\nFor metformin plus CC plus L-carnitine versus metformin plus\nCC plus placebo (El 2019 ), we found insufficient evidence of a\ndifference in miscarriage (OR 3.58, 95% CI 0.73 to 17.55; 243 women,\n1 study; very low-quality evidence; Analysis 3.1).\nFor metformin plus liraglutide versus metformin (Salamun 2018),\nwe found insufficient evidence of a difference for nausea (OR 7.22,\n95% CI 0.72 to 72.7; 28 women, 1 study; very low-quality evidence;\nAnalysis 3.2); diarrhoea (OR 0.31, 95% CI 0.01 to 8.29; 28 women,\n1 study; very low-quality evidence; Analysis 3.3 ) and headache\n(OR 5.80, 95% CI 0.25 to 133; 28 women, 1 study; very low-quality\nevidence; Analysis 3.4).\nSecondary outcomes\nClinical pregnancy\nFor metformin plus liraglutide versus metformin (Salamun 2018),\nwe found insufficient evidence of a difference in clinical pregnancy\n(OR 3.67, 95% CI 0.70 to 19.12; 28 women, 1 study; very low-quality\nevidence; Analysis 3.5).\nFor metformin plus clomiphene citrate (CC) plus L-carnitine versus\nmetformin plus CC plus placebo (El 2019 ), we found evidence\nof a difference in favour of L-carnitine for clinical pregnancy but\nconsidered this evidence to be of very low quality (OR 5.56, 95%\nCI 2.57 to 12.02; 274 women, 1 study; very low-quality evidence;\nAnalysis 3.5).\nWeight change\nFor metformin plus liraglutide versus metformin (Salamun 2018),\nwe found insufficient evidence of a difference in BMI (MD 2.10, 95%\nCI -0.42 to 4.62; 28 women, 1 study; very low-quality evidence).\nFor dexfenfluramine versus placebo (Galletly 1996), we are unsure\nwhether the data for weight loss presents pre-cross-over data. We\nfound insufficient evidence of a difference in mean weight loss (MD\n-0.10, 95% CI -2.77 to 2.57; 21 women, 1 study; very low-quality\nevidence). The mean weight loss ranged from 3 to 4 kg in the\nintervention group .\nOne study provided no evidence of a difference for metformin plus\nliraglutide versus metformin in percentage of body fat (MD -0.50,\n95% CI -4.65 to 3.65; 28 women, 1 study; very low-quality evidence)\n(Salamun 2018).\nChange in endocrine parameters\nFor metformin plus liraglutide versus metformin (Salamun 2018),\nwe found insufficient evidence of a difference in the oral glucose\ntolerance test (OGTT) (MD -0.30, 95% CI -1.92 to 1.3; 28 women, 1\nstudy; very low-quality evidence), free testosterone (MD 0.80, 95%\nCI -3.0 to 4.60; 28 women, 1 study; very low-quality evidence), total\ntestosterone (MD 0.20, 95% CI -0.21 to 0.61; 28 women, 1 study; very\nlow-quality evidence), and sex hormone-binding globulin (SHBG)\n(MD 0.30, 95% CI -12.22 to 12.82; 28 women, 1 study; very low-\nquality evidence).\nQuality of life or mental health outcome\nNo comparison of quality of life or mental health outcome was\navailable.\nPharmacological intervention versus no intervention or\nplacebo\nWe found three studies: one study compared diet combined with\nmetformin versus diet combined with placebo (Tang 2006); one\nstudy compared metformin versus no intervention (Khorram 2006);\nanother study compared metformin versus placebo (Johnson\n2010).\nPrimary outcomes\nLive birth rate or ongoing pregnancy\nOnly one study that compared metformin with placebo reported on\nlive birth, resulting in insufficient evidence of a difference (OR 1.57,\n95% CI 0.44 to 5.57; 1 study, 65 women; very low-quality evidence;\nAnalysis 4.1) (Johnson 2010). This suggests that if the chance of live\nbirth following placebo is assumed to be 15%, the chance following\nmetformin would be 7.3% to 50%.\nAdverse events\nOne study compared pharmacological intervention versus no\ntreatment or placebo, with no conclusive evidence of a difference\nfor miscarriage (OR 0.50, 95% CI 0.04 to 5.80; 65 women, 1 study;\nvery low-quality evidence; Analysis 4.2) (Johnson 2010).\nWe found insufficient evidence of a difference between metformin\nand placebo in gastrointestinal adverse events (OR 0.91, 95% CI 0.32\nto 2.57; 1 study, 65 women; very low-quality evidence; Analysis 4.3)\n(Johnson 2010).\nSecondary outcomes\nClinical pregnancy\nTwo studies compared metformin versus no treatment or placebo,\nwith no conclusive evidence of a difference for pregnancy (OR 2.67,\n95% CI 0.90 to 7.93; 96 women, 2 studies; I/two.sups = 48%; very low-quality\nevidence; Analysis 4.4) (Johnson 2010; Khorram 2006)\nWeight change\nOne study reported on weight change, with no conclusive evidence\nof a change in BMI (MD -0.30, 95% CI -2.16 to 1.56; 143 women, 1\nstudy; very low-quality evidence) or WHR (MD 2.00, 95% CI -2.21 to\n6.21; 1 study, 143 women; very low-quality evidence) for metformin\nversus placebo (Tang 2006).\nChange in endocrine parameters\nOne study reported on endocrine parameters (Khorram 2006).\nChanges in endocrine parameters were inconclusive for free\ntestosterone (MD 0.7 nmol/L, 95% CI -1.01 to 2.42; 31 women, 1\nstudy; very low-quality evidence). Total testosterone and SHBG\nwere higher following metformin versus placebo, but evidence was\nof very low quality (total testosterone: MD 6.20 nmol/L, 95% CI 0.46\nto 11.94; 1 study, 31 women; very low-quality evidence; SHBG: 5.50\nnmol/L, 95% CI 3.79 to 7.21; 1 study, 31 women; very low-quality\nevidence).\nQuality of life or mental health outcome\nNo comparison of quality of life or mental health outcome was\navailable.\nNon-pharmacological versus pharmacological intervention\nNo study reported this comparison.\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n22\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFor this review, we did not gather enough data to perform subgroup\nanalyses. Moreover, for this version of the review, we identified\ninsufficient studies to perform meaningful sensitivity analyses.\nD I S C U S S I O N\nSummary of main results\nBased on available data, we are uncertain about the effectiveness\nand safety of pharmaceutical and non-pharmaceutical\ninterventions for weight reduction in obese women with subfertility\ndue to evidence of very low to low quality. We included 10 trials\nthat varied in size from 11 to 564 women. The best evidence was\nfound for diet/lifestyle interventions (three randomised controlled\ntrials (RCTs)). Compared to no intervention or placebo, the lifestyle\nintervention did not appear to improve live birth or clinical\npregnancy; however, lifestyle intervention may lower body mass\nindex (BMI) among obese women. It is unclear whether intensive\nweight loss interventions compared to nutrition counselling had a\npositive or negative effect on any outcomes.\nFor pharmaceutical interventions, all outcomes were scored to\nhave evidence of very low quality. Whether pharmaceutical\ninterventions such as liraglutide, L-carnitine as addition to\nmetformin, and clomiphene result in improved fertility or weight\noutcomes is unclear. Similarly, we found no conclusive evidence for\nmetformin versus placebo or no intervention in terms of live birth,\nclinical pregnancy, or weight change outcomes.\nWe found no trials that compared pharmacological versus non-\npharmacological interventions.\nOverall completeness and applicability of evidence\nThere is a serious lack of evidence in the field of weight\nreduction in obese women with subfertility. The included studies\nonly partially addressed the objectives of this review. Outcome\ndata could not be retrieved for several of the comparisons and\noutcomes that we sought to investigate. The high heterogeneity of\npharmacological and non-pharmacological strategies in included\nstudies may limit the generalisability of trial results regarding\nthe effectiveness of pharmacological and non-pharmacological\nstrategies for obese women with subfertility. The included studies\nwere clinically heterogeneous and differed in factors such as\nduration of treatment, type of intervention, dosage, and length\nof follow-up. Given the very low quality of evidence for the\npharmaceutical interventions, the applicability of those findings is\nlimited and does not allow us to draw conclusions.\nIt was our intention to include studies with obese women with a\nBMI of at least 30. In two trials the minimal BMI was 29 (Khorram\n2006, Mutsaerts 2016) with medians or means above 36. The study\ngroups consider the effect of including a few women with a BMI of\n29 instead of 30 negligible.\nQuality of the evidence\nAlthough evidence generated in this review was based on 10\nRCTs, this evidence was of very low to low quality as determined\nby GRADE methods (see 'Summary of findings' for the main\ncomparison and 'Summary of findings 2'). The main limitations\nwere due to lack of studies and poor reporting of study methods.\nThe quality of individual studies was generally low, with over 40%\nfailing to describe adequate methods of blinding of participants\nand personnel, outcome assessment, and selective reporting (see\nFigure 2 and Figure 3).\nPotential biases in the review process\nTo minimise bias and issues related to subjectivity of judgement,\nany disagreements that occurred during the review process were\ndiscussed among all review authors until consensus was reached.\nTwo review authors independently carried out data extraction. The\naccuracy of data was further checked by a third review author.\nPotential risk of bias in each study and the overall quality of\nevidence for each outcome were assessed by two independent\nreview authors. We adopted a highly sensitive search strategy.\nHowever, the literature identified was predominantly written\nin English, and most studies were conducted in high-income\ncountries.\nAgreements and disagreements with other studies or\nreviews\nOne systematic review evaluated the effectiveness of non-\npharmacological interventions for overweight or obese infertile\nwomen (Kim 2020). On the basis of 21 RCTs, it was suggested that\nnon-pharmacological interventions could have a positive effect\non pregnancy and natural conception rates, whereas it remains\nunclear whether they improve the live birth rate. Not all women in\nthe included studies were overweight, and most were not obese,\nwhich may explain the medium to high heterogeneity of effect sizes\nfor pregnancy rates and live birth rates in all non-pharmacological\ninterventions.\nAn earlier systematic review evaluated first whether weight loss\ninterventions for infertile patients achieve their goal in reducing\nweight, and second whether they result in improved fertility\noutcomes (Best 2017). A total of 40 studies were included, of\nwhich 14 were RCTs. Results suggest that weight loss interventions,\nparticularly diet and exercise, may improve pregnancy rates and\novulatory status.\nIn a Cochrane Review aiming to assess the effectiveness of\nlifestyle treatment (diet, exercise, behavioural, or combined\ntreatments) for women with PCOS, lifestyle intervention improved\nbody composition, hyperandrogenism, and insulin resistance, but\nevidence for an effect of diet on reproductive outcomes was lacking\n(Lim 2019).\nOur review differs from previous reviews in that it is focused on\nobese women only. We conducted an extensive search until 2020\nand could include data from 10 studies. In contrast to previous\nreviews, we are uncertain whether pharmacological or non-\npharmacological strategies improve live birth, ongoing pregnancy,\nadverse events, clinical pregnancy, quality of life, or mental health\noutcomes. However, for obese women with subfertility, a lifestyle\nintervention may reduce BMI.\nA U T H O R S ' /uni00A0 C O N C L U S I O N S\nImplications for practice\nEvidence is yet insufficient to support the use of pharmacological\nand non-pharmacological strategies for weight reduction for obese\nwomen with subfertility. No data are available for the comparison\nof pharmacological versus non-pharmacological strategies. We\nare uncertain whether pharmacological or non-pharmacological\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n23\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nstrategies improve live birth, ongoing pregnancy, adverse events,\nclinical pregnancy, quality of life, or mental health outcomes. Our\nfindings were based on very low-quality evidence from studies that\nmay contribute to these outcomes. Thus, we are not able to draw\nfirm conclusions with regard to the impact of pharmacological and\nnon-pharmacological strategies for weight reduction. However,\nlimited information suggests that lifestyle intervention for obese\nwomen with subfertility may reduce BMI. Although obese women\nshould be counselled about the risk of obesity for fertility and\npregnancy outcomes, healthcare providers should caution women\nthat the existing research is of poor quality and of limited quantity.\nImplications for research\nIn view of the high prevalence of obesity-related subfertility and\nlack of good evidence, we need well-designed and well-conducted\nRCTs with double-blinding and adequately powered trials reporting\nmethods such as randomisation and allocation concealment in\ndetail and aiming to share data a/f_ter the trial. Future studies\nare advised to focus on lifestyle interventions with or without\npharmacological interventions for obese women with subfertility.\nFollow-up time needs to be long enough for these clinically\nrelevant outcome data to be obtained. The duration of follow-up\nfor assessing outcomes should be at least three months, but longer\nfollow-up is advised to enable reporting of natural pregnancies.\nFinally, the economic impact of different weight reduction methods\nshould be reported.\nA C K N O W L E D G E M E N T S\nWe thank Marian Showell (the Information Specialist of the\nCochrane Gynaecology and Fertility Group) for preparing the search\nstrategy, and Helen Nagels and Melissa Vercoe (Managing Editors of\nthe Cochrane Gynaecology and Fertility Group) for their continuous\nsupport. We thank the peer reviewers, Jack Wilkinson, Abha\nMaheshwari, Harry Siristatidis, for providing valuable clinical and\neditorial advice.\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n24\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nREFERENCES\n/uni00A0\nReferences to studies included in this review\nEinarsson 2017 {published data only}\n*/uni00A0 Einarsson/uni00A0S, Bergh/uni00A0C, Friberg/uni00A0B, Pinborg/uni00A0A, Klajnbard/uni00A0A,\nKarlström/uni00A0PO, et al. Weight reduction intervention for obese\ninfertile women prior to IVF: a randomised controlled trial.\nHuman Reproduction 2017;8(32):1621-30.\nKluge/uni00A0L, Bergh/uni00A0C, Einarsson/uni00A0S, Pinborg/uni00A0A, Mikkelsen Englund A-\nL, Thurin-Kjellberg/uni00A0A. Cumulative live birth rates a/f_ter weight\nreduction in obese women scheduled for IVF: follow-up of\na randomized controlled trial. Human Reproduction Open\n2019;2019:hoz030.\nEl 2019 {published data only}\nEl Sharkwy/uni00A0I, Sharaf El-Din/uni00A0M. l-Carnitine plus metformin in\nclomiphene-resistant obese PCOS women, reproductive and\nmetabolic effects: a randomized clinical trial. Gynecological\nEndocrinology 2019;35:701-5.\nGalletly 1996 {published data only}\nGalletly/uni00A0C, Clark/uni00A0A, Tomlinson/uni00A0L. Evaluation of dexfenfluramine\nin a weight loss program for obese infertile women.\nInternational Journal of Eating Disorders 1996;2(19):209-12.\nJohnson 2010 {published data only}\nJohnson/uni00A0NP, Stewart/uni00A0AW, Falkiner/uni00A0J, Farquhar/uni00A0CM, Milsom/uni00A0S,\nSingh/uni00A0VP, et al, REACT-NZ (REproduction And Collaborative\nTrials in New Zealand), a Multi-centre Fertility Trials Group.\nPCOSMIC: a multi-centre randomised trial in women with\npolycystic ovary syndrome evaluating metformin for infertility\nwith clomiphene. Human Reproduction 2010;7(25):1675-83.\nKhorram 2006 {published data only}\nKhorram/uni00A0O, Helliwell/uni00A0JP, Katz/uni00A0S, Bonpane/uni00A0CM, Jaramillo/uni00A0L. Two\nweeks of metformin improves clomiphene citrate-induced\novulation and metabolic profiles in women with polycystic\novary syndrome. Fertility and Sterility 2006;5(85):1448-51.\nMutsaerts 2016 {published data only}\n*/uni00A0 Mutsaerts/uni00A0MA, Van Oers/uni00A0AM, Groen/uni00A0H, Burggraaff/uni00A0JM,\nKuchenbecker/uni00A0WK, Perquin/uni00A0DA, et al. Randomized trial of\na lifestyle program in obese infertile women. New England\nJournal of Medicine 2016;374(20):1942-1953.\nRothberg 2016 {published data only}\nRothberg/uni00A0A, Lanham/uni00A0M, Randolph/uni00A0J, Fowler/uni00A0C, Miller/uni00A0N, Smith/uni00A0Y.\nFeasibility of a brief, intensive weight loss intervention to\nimprove reproductive outcomes in obese, subfertile women: a\npilot study. Fertility and Sterility 2016;5(106):1212-20.\nSalamun 2018 {published data only}\nSalamun/uni00A0V, Jensterle/uni00A0M, Janez/uni00A0A, Bokal/uni00A0EV. Liraglutide increases\nIVF pregnancy rates in obese PCOS women with poor response\nto first-line reproductive treatments: a pilot randomized study.\nEuropean Journal of Endocrinology 2018;179(1):1-11.\nSim 2014 {published data only}\nSim/uni00A0KA, Dezarnaulds/uni00A0GM, Denyer/uni00A0GS, Skilton/uni00A0MR, Caterson/uni00A0ID.\nWeight loss improves reproductive outcomes in obese women\nundergoing fertility treatment: a randomized controlled trial.\nClinical Obesity 2014;2(4):61-8.\nTang 2006 {published data only}\nTang/uni00A0T, Glanville/uni00A0J, Hayden/uni00A0CJ, White/uni00A0D, Barth/uni00A0JH, Balen/uni00A0AH.\nCombined lifestyle modification and metformin in obese\npatients with polycystic ovary syndrome. A randomized,\nplacebo-controlled, double-blind multicentre study. Human\nReproduction 2005;1(21):80-9.\n/uni00A0\nReferences to studies excluded from this review\nAsemi 2014 {published data only}\nAsemi/uni00A0Z, Esmaillzadeh/uni00A0A. DASH diet, insulin resistance, and\nserum hs-CRP in polycystic ovary syndrome: a randomized\ncontrolled clinical trial. Hormone and Metabolic Research\n2015;47(03):232-8.\nAsemi 2014a {published data only}\nAsemi/uni00A0Z, Samimi/uni00A0M, Tabassi/uni00A0Z, Shakeri/uni00A0H, Sabihi/uni00A0SS,\nEsmaillzadeh/uni00A0A. Effects of DASH diet on lipid profiles and\nbiomarkers of oxidative stress in overweight and obese women\nwith polycystic ovary syndrome: a randomized clinical trial.\nNutrition 2014;30(11-12):1287-93.\nAsemi 2015 {published data only}\nAsemi/uni00A0Z, Foroozanfard/uni00A0F, Hashemi/uni00A0T, Bahmani/uni00A0F, Jamilian/uni00A0M,\nEsmaillzadeh/uni00A0A. Calcium plus vitamin D supplementation\naffects glucose metabolism and lipid concentrations in\noverweight and obese vitamin D deficient women with\npolycystic ovary syndrome. Clinical Nutrition 2015;34(4):586-92.\nAshoush 2016 {published data only}\nAshoush/uni00A0S, Abou-Gamrah/uni00A0A, Bayoumy/uni00A0H, Othman/uni00A0N. Chromium\npicolinate reduces insulin resistance in polycystic ovary\nsyndrome: randomized controlled trial. Journal of Obstetrics\nand Gynaecology Research 2016;42(3):279-85.\nAttarzadeh 2012 {published data only}\nAttarzadeh Hosseini/uni00A0R, Sardar/uni00A0M, Taghavi/uni00A0M, Ayaz Khosh\nHava/uni00A0F. The effects of an aerobic exercise program on LH, FSH,\nTST and DHEA levels in obese women with polycystic ovary\nsyndrome. Iranian Journal of Endocrinology and Metabolism\n2012;14(1):39-94.\nBaillargeon 2004 {published data only}\nBaillargeon/uni00A0JP, Iuorno/uni00A0MJ, Jakubowicz/uni00A0DJ, Apridonidze/uni00A0T, He/uni00A0N,\nNestler/uni00A0JE. Metformin therapy increases insulin-stimulated\nrelease of D-chiro-inositol-containing inositol phosphoglycan\nmediator in women with polycystic ovary syndrome. Journal of\nClinical Endocrinology and Metabolism 2004;89(1):242-9.\nBecker 2015 {published data only}\nBecker/uni00A0GF, Passos/uni00A0EP, Moulin/uni00A0CC. Short-term effects of a\nhypocaloric diet with low glycemic index and low glycemic\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n25\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nload on body adiposity, metabolic variables, ghrelin, leptin,\nand pregnancy rate in overweight and obese infertile women:\na randomized controlled trial. American Journal of Clinical\nNutrition 2015;102(6):1365-72.\nCheraghi 2014 {published data only}\nCheraghi/uni00A0E, Mehranjani/uni00A0MS, Shariatzadeh/uni00A0MA, Esfahani/uni00A0MH,\nEbrahimi/uni00A0Z. Co-administration of metformin and N-acetyl\ncysteine fails to improve clinical manifestations in PCOS\nindividual undergoing ICSI. International Journal of Fertility and\nSterility 2014;8(2):119-28.\nGambineri 2004 {published data only}\nGambineri/uni00A0A, Pelusi/uni00A0C, Genghini/uni00A0S, Morselli-Labate/uni00A0AM,\nCacciari/uni00A0M, Pagotto/uni00A0U, et al. Effect of flutamide and metformin\nadministered alone or in combination in dieting obese women\nwith polycystic ovary syndrome. Clinical Endocrinology\n2004;60(2):241-9.\nHanjalic-Beck 2010 {published data only}\nHanjalic-Beck/uni00A0A, Gabriel/uni00A0B, Schaefer/uni00A0W, Zahradnik/uni00A0HP,\nSchories/uni00A0M, Tempfer/uni00A0C, et al. Metformin versus acarbose\ntherapy in patients with polycystic ovary syndrome (PCOS):\na prospective randomised double-blind study. Gynecological\nEndocrinology 2010;26(9):690-7.\nJanez 2017 {published data only}\nJanez/uni00A0A, Salamun/uni00A0V, Jensterle/uni00A0M, Bokal/uni00A0EV. Short-term\nintervention with liraglutide and metformin increased\nfertility potential in a subset of obese PCOS preceding in vitro\nsterilisation. Diabetes 2017;66(Suppl 1):A561.\nJanez 2018 {published data only}\nJanez/uni00A0A, Jensterle/uni00A0M. GLP-1 receptor agonist liraglutide\nincreased IVF pregnancy rates in obese women with PCOS and\nprevious poor response to first-line reproductive treatments.\nDiabetes 2018;67(Suppl 1):A392-3.\nJensterle 2017 {published data only}\nJensterle/uni00A0M, Kravos/uni00A0NA, Goričar/uni00A0K, Janez/uni00A0A. Short-term\neffectiveness of low dose liraglutide in combination with\nmetformin versus high dose liraglutide alone in treatment\nof obese PCOS: randomized trial. BMC Endocrine Disorders\n2017;17(1):5.\nKarsten 2018 {published data only}\nKarsten/uni00A0MDA, van/uni00A0Oers/uni00A0AM, Groen/uni00A0H, Mutsaerts/uni00A0MAQ,\nvan/uni00A0Poppel/uni00A0MNM, Geelen/uni00A0A, et al. Determinants of successful\nlifestyle change during a 6-month preconception lifestyle\nintervention in women with obesity and infertility. European\nJournal of Nutrition 2019;58(6):2463-75.\nKocak 2002 {published data only}\nKocak/uni00A0M, Caliskan/uni00A0E, Simsir/uni00A0C, Haberal/uni00A0A. Metformin therapy\nimproves ovulatory rates, cervical scores, and pregnancy rates\nin clomiphene citrate-resistant women with polycystic ovary\nsyndrome. Fertility and Sterility 2002;77(1):101-6.\nLegro 2007 {published data only}\nLegro/uni00A0RS, Zaino/uni00A0RJ, Demers/uni00A0LM, Kunselman/uni00A0AR, Gnatuk/uni00A0CL,\nWilliams/uni00A0NI, et al. The effects of metformin and rosiglitazone,\nalone and in combination, on the ovary and endometrium in\npolycystic ovary syndrome. American Journal of Obstetrics and\nGynecology 2007;196(4):402.e1-402.e11.\nLiao 2011 {published data only}\nLiao/uni00A0L, Tian/uni00A0YJ, Zhao/uni00A0JJ, Xin/uni00A0Y, Xing/uni00A0HY, Dong/uni00A0JJ. Metformin\nversus metformin plus rosiglitazone in women with polycystic\novary syndrome. Chinese Medical Journal 2011;124(5):714-8.\nMa 2007 {published data only}\nMa/uni00A0LK, Jin/uni00A0LN, Yu/uni00A0Q, Xu/uni00A0L. Effect of lifestyle adjustment,\nmetformin and rosiglitazone in polycystic ovary syndrome.\n[Chinese]. Zhonghua Fu Chan Ke Za Zhi 2007;42(5):294-7.\nMoran 2006 {published data only}\nMoran/uni00A0LJ, Noakes/uni00A0M, Cli/f_ton/uni00A0PM, Wittert/uni00A0GA, Williams/uni00A0G,\nNorman/uni00A0RJ. Short-term meal replacements followed by dietary\nmacronutrient restriction enhance weight loss in polycystic\novary syndrome. American Journal of Clinical Nutrition\n2006;84(1):77-87.\nMorin-Papunen 1998 {published data only}\nMorin-Papunen/uni00A0LC, Koivunen/uni00A0RM, Tomas/uni00A0C, Ruokonen/uni00A0A,\nMartikainen/uni00A0HK. Decreased serum leptin concentrations during\nmetformin therapy in obese women with polycystic ovary\nsyndrome. Journal of Clinical Endocrinology and Metabolism\n1998;83(7):2566-8.\nMorin-Papunen 2000 {published data only}\nMorin-Papunen/uni00A0LC, Vauhkonen/uni00A0I, Koivunen/uni00A0RM, Ruokonen/uni00A0A,\nMartikainen/uni00A0HK, Tapanainen/uni00A0JS. Endocrine and metabolic\neffects of metformin versus ethinyl estradiol-cyproterone\nacetate in obese women with polycystic ovary syndrome:\na randomized study. Journal of Clinical Endocrinology and\nMetabolism 2000;85(9):3161-8.\nMorin-Papunen 2012 {published data only}\nMorin-Papunen/uni00A0L, Rantala/uni00A0AS, Unkila-Kallio/uni00A0L, Tiitinen/uni00A0A,\nHippeläinen/uni00A0M, Perheentupa/uni00A0A, et al. Metformin improves\npregnancy and live-birth rates in women with polycystic\novary syndrome (PCOS): a multicenter, double-blind, placebo-\ncontrolled randomized trial. Journal of Clinical Endocrinology\n2012;97(5):1492-500.\nPasquali 1986 {published data only}\nPasquali/uni00A0R, Fabbri/uni00A0R, Venturoli/uni00A0S, Paradisi/uni00A0R, Antenucci/uni00A0D,\nMelchionda/uni00A0N. Effect of weight loss and antiandrogenic therapy\non sex hormone blood levels and insulin resistance in obese\npatients with polycystic ovaries. American Journal of Obstetrics\nand Gynecology 1986;154(1):139-44.\nPasquali 2000 {published data only}\nPasquali/uni00A0R, Gambineri/uni00A0A, Biscotti/uni00A0D, Vicennati/uni00A0V, Gagliardi/uni00A0L,\nColitta/uni00A0D, et al. Effect of long-term treatment with metformin\nadded to hypocaloric diet on body composition, fat\ndistribution, and androgen and insulin levels in abdominally\nobese women with and without the polycystic ovary\nsyndrome. Journal of Clinical Endocrinology and Metabolism\n2000;85(8):2767-74.\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n26\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nPastore 2011 {published data only}\nPastore/uni00A0LM, Williams/uni00A0CD, Jenkins/uni00A0J, Patrie/uni00A0JT. True and sham\nacupuncture produced similar frequency of ovulation and\nimproved LH to FSH ratios in women with polycystic ovary\nsyndrome. Journal of Clinical Endocrinology and Metabolism\n2011;96(10):3143-50.\nPenna 2005 {published data only}\nPenna/uni00A0IA, Canella/uni00A0PR, Reis/uni00A0RM, Silva de Sa/uni00A0MF, Ferriani/uni00A0RA.\nAcarbose in obese patients with polycystic ovarian syndrome:\na double-blind, randomized, placebo-controlled study. Human\nReproduction 2005;20(9):2396-401.\nPetranyi 2011 {published data only}\nPetranyi/uni00A0G, Zaoura-Petranyi/uni00A0M. Metformin treatment with or\nwithout life style changes in patients with polycystic ovary\nsyndrome. [Hungarian]. Orvosi Hetilap 2011;152(16):628-32.\nPourmatroud 2015 {published data only}\nPourmatroud/uni00A0E, Mohammadjafari/uni00A0R, Roozitalab/uni00A0M. Comparison\nof metformin and simvastatin administration in women with\npolycystic ovary syndrome before intra-cytoplasmic sperm\ninjection cycle: a prospective, randomized, clinical trial study.\nIranian Red Crescent Medical Journal 2015;17(12):e20082.\nPremawardhana 1994 {published data only}\nPremawardhana/uni00A0LD, Ismail/uni00A0IS, Riad Fahmy/uni00A0D, Miell/uni00A0JP,\nPeters/uni00A0JR, Scanlon/uni00A0MF. Acute cholinergic blockade with low\ndose pirenzepine reduces the insulin and glucose responses\nto a mixed meal in obese women with the polycystic ovary\nsyndrome. Clinical Endocrinology 1994;40(5):617-21.\nQin 2016 {published data only}\nQin/uni00A0W, Zhao/uni00A0K, Yang/uni00A0H. Effect of acupoint catgut embedding\ntherapy combined with Chinese medicine for nourishing the\nkidneys and promoting blood circulation and improving blood\nglucose and lipid levels as well as the pregnancy rate in obese\nPCOS patients with infertility. Experimental and Therapeutic\nMedicine 2016;12(5):2909-14.\nQublan 2007 {published data only}\nQublan/uni00A0HS, Yannakoula/uni00A0EK, Al-Qudad/uni00A0MA, El-Uri/uni00A0FI. Dietary\nintervention versus metformin to improve the reproductive\noutcome in women with polycystic ovary syndrome. A\nprospective comparative study. Saudi Medical Journal\n2007;28(11):1694-8.\nSeibel 2008 {published data only}\nSeibel/uni00A0SA, Chou/uni00A0KH, Capp/uni00A0E, Spritzer/uni00A0PM, von/uni00A0Eye Corleta/uni00A0H.\nEffect of metformin on IGF-1 and IGFBP-1 levels in obese\npatients with polycystic ovary syndrome. European Journal\nof Obstetrics and Gynecology and Reproductive Biology\n2008;138(1):122-4.\nShahebrahimi 2016 {published data only}\nShahebrahimi/uni00A0K, Jalilian/uni00A0N, Bazgir/uni00A0N, Rezaei/uni00A0M. Comparison\nclinical and metabolic effects of metformin and pioglitazone in\npolycystic ovary syndrome. Indian Journal of Endocrinology and\nMetabolism 2016;20(6):805-9.\nSiebert 2009 {published data only}\nSiebert/uni00A0T, Kruger/uni00A0T, Lombard/uni00A0C. Evaluating the equivalence of\nclomiphene citrate with and without metformin in ovulation\ninduction in PCOS patients. Journal of Assisted Reproduction\nand Genetics 2009;26(4):165-71.\nSonmez 2005 {published data only}\nSönmez/uni00A0AS, Yasar/uni00A0L, Savan/uni00A0K, Koç/uni00A0S, Ozcan/uni00A0J, Toklar/uni00A0A, et al.\nComparison of the effects of acarbose and metformin use on\novulation rates in clomiphene citrate-resistant polycystic ovary\nsyndrome. Human Reproduction 2005;20(1):175-9.\nSordia-Hernandez 2016 {published data only}\nSordia-Hernández/uni00A0LH, Ancer Rodríguez/uni00A0P, Saldivar Rodriguez/uni00A0D,\nTrejo Guzman/uni00A0S, Servín Zenteno/uni00A0ES, Guerrero González/uni00A0G, et\nal. Effect of a low glycemic diet in patients with polycystic\novary syndrome and anovulation: a randomized controlled\ntrial. Clinical and Experimental Obstetrics and Gynecology\n2016;43(4):555-9.\nSorensen 2012 {published data only}\nSorensen/uni00A0LB, Soe/uni00A0M, Halkier/uni00A0KH, Stigsby/uni00A0B, Astrup/uni00A0A. Effects\nof increased dietary protein-to-carbohydrate ratios in women\nwith polycystic ovary syndrome. American Journal of Clinical\nNutrition 2012;95(1):39-48.\nStamets 2004 {published data only}\nStamets/uni00A0K, Taylor/uni00A0DS, Kunselman/uni00A0A, Demers/uni00A0LM, Pelkman/uni00A0CL,\nLegro/uni00A0RS. A randomized trial of the effects of two types of short-\nterm hypocaloric diets on weight loss in women with polycystic\novary syndrome. Fertility and Sterility 2004;81(3):630-7.\nSwora-Cwynar 2016 {published data only}\nSwora-Cwynar/uni00A0E, Kujawska-Łuczak/uni00A0M, Suliburska/uni00A0J, Reguła/uni00A0J,\nKargulewicz/uni00A0A, Kręgielska-Narożna/uni00A0M, et al. The effects\nof a low-calorie diet or an isocaloric diet combined with\nmetformin on sex hormones In obese women of child-bearing\nage. Acta Scientiarum Polonorum Technologia Alimentaria\n2016;15(2):213-20.\nTang 2006a {published data only}\nTang/uni00A0T, Glanville/uni00A0J, Orsi/uni00A0N, Barth/uni00A0JH, Balen/uni00A0AH. The use of\nmetformin for women with PCOS undergoing IVF treatment.\nHuman Reproduction 2006;21(6):1416-25.\nToscani 2011 {published data only}\nToscani/uni00A0MK, Mario/uni00A0FM, Radavelli-Bagatini/uni00A0S, Wiltgen/uni00A0D,\nMatos/uni00A0MC, Spritzer/uni00A0PM. Effect of high-protein or normal-protein\ndiet on weight loss, body composition, hormone, and metabolic\nprofile in southern Brazilian women with polycystic ovary\nsyndrome: a randomized study. Gynecological Endocrinology\n2011;27(11):925-30.\nTsagareli 2006 {published data only}\nTsagareli/uni00A0V, Noakes/uni00A0M, Norman/uni00A0RJ. Effect of a very-low-calorie\ndiet on in vitro fertilization outcomes. Fertility and Sterility\n2006;86(1):227-9.\nTurner-McGrievy 2014 {published data only}\nTurner-McGrievy/uni00A0GM, Davidson/uni00A0CR, Wingard/uni00A0EE, Billings/uni00A0DL. Low\nglycemic index vegan or low-calorie weight loss diets for women\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n27\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nwith polycystic ovary syndrome: a randomized controlled\nfeasibility study. Nutrition Research 2014;34(6):552-8.\nVandermolen 2001 {published data only}\nVandermolen/uni00A0DT, Ratts/uni00A0VS, Evans/uni00A0WS, Stovall/uni00A0DW, Kauma/uni00A0SW,\nNestler/uni00A0JE. Metformin increases the ovulatory rate and\npregnancy rate from clomiphene citrate in patients with\npolycystic ovary syndrome who are resistant to clomiphene\ncitrate alone. Fertility and Sterility 2001;75(2):310-5. [PMID:\n11172832]\nVanky 2004 {published data only}\nVanky/uni00A0E, Salvesen/uni00A0KA, Carlsen/uni00A0SM. Six-month treatment\nwith low-dose dexamethasone further reduces androgen\nlevels in PCOS women treated with diet and lifestyle advice,\nand metformin. Human Reproduction (Oxford, England)\n2004;19(3):529-33. [PMID: 14998946]\nVan Oers 2016a {published data only}\nvan/uni00A0Oers/uni00A0AM, Groen/uni00A0H, Mutsaerts/uni00A0MA, Burggraaff/uni00A0JM,\nKuchenbecker/uni00A0WK, Perquin/uni00A0DA, et al, LIFEstyle Study Group.\nEffectiveness of lifestyle intervention in subgroups of obese\ninfertile women: a subgroup analysis of an RCT. Human\nReproduction 2016;31(12):2704-13.\nVan Oers 2017 {published data only}\nvan/uni00A0Oers/uni00A0AM, Mutsaerts/uni00A0MAQ, Burggraaff/uni00A0JM,\nKuchenbecker/uni00A0WKH, Perquin/uni00A0DAM, Koks/uni00A0CAM, et al, LIFEstyle\nStudy Group. Cost-effectiveness analysis of lifestyle\nintervention in obese infertile women. Human Reproduction\n2017;32(7):1418-26.\nvan Oers 2018 {published data only}\nvan/uni00A0Oers/uni00A0AM, Mutsaerts/uni00A0MAQ, Burggraaff/uni00A0JM,\nKuchenbecker/uni00A0WKH, Perquin/uni00A0DAM, Koks/uni00A0CAM, et al, LIFEstyle\nStudy Group. Association between periconceptional weight loss\nand maternal and neonatal outcomes in obese infertile women.\nPloS One 2018;13(3).\nvan Santbrink 2005 {published data only}\nvan/uni00A0Santbrink/uni00A0EJ, Hohmann/uni00A0FP, Eijkemans/uni00A0MJ,\nLaven/uni00A0JS, Fauser/uni00A0BC. Does metformin modify ovarian\nresponsiveness during exogenous FSH ovulation induction\nin normogonadotrophic anovulation? A placebo-controlled\ndouble-blind assessment. European Journal of Endocrinology\n2005;152(4):611-7.\nVigerust 2012 {published data only}\nVigerust/uni00A0NF, Bohov/uni00A0P, Bjørndal/uni00A0B, Seifert/uni00A0R, Nygård/uni00A0O, Svardal/uni00A0A,\net al. Free carnitine and acylcarnitines in obese patients\nwith polycystic ovary syndrome and effects of pioglitazone\ntreatment. Fertility and Sterility 2012;98(6):1620-6.\nVosnakis 2013 {published data only}\nVosnakis/uni00A0C, Georgopoulos/uni00A0NA, Rousso/uni00A0D, Mavromatidis/uni00A0G,\nKatsikis/uni00A0I, Roupas/uni00A0ND, et al. Diet, physical exercise and orlistat\nadministration increase serum anti-Mullerian hormone (AMH)\nlevels in women with polycystic ovary syndrome (PCOS).\nGynecological Endocrinology 2013;29(3):242-5.\nWiweko 2017 {published data only}\nWiweko/uni00A0B, Susanto/uni00A0CA. The effect of metformin and cinnamon\non serum anti-Mullerian hormone in women having PCOS: a\ndouble-blind, randomized, controlled trial. Journal of Human\nReproductive Sciences 2017;10(1):31.\nYang 2005 {published data only}\nYang/uni00A0YS, Zhang/uni00A0YL. Clinical study of ganshao capsule in treating\nclomiphene-resistant polycystic ovarian syndrome. Chinese\nJournal of Integrated Traditional and Western Medicine\n2005;25(8):704-6.\nYang 2017 {published data only}\nYang/uni00A0D, Zhao/uni00A0M, Tan/uni00A0J. Effect of polycystic ovary syndrome\ntreated with the periodic therapy of acupuncture. Chinese\nAcupuncture & Moxibustion 2017;37(8):825-9.\nYin 2018 {published data only}\nYin/uni00A0Y, Zhang/uni00A0Y, Zhang/uni00A0H, Jiang/uni00A0D, Guo/uni00A0G. Clinical therapeutic\neffects of acupuncture combined with Chinese herbal medicine\non infertility of polycystic ovary syndrome in the patients with\novulation induction with letrozole. Chinese Acupuncture and\nMoxibustion 2018;38(1):27-32.\nZhang 2015 {published data only}\nZhang/uni00A0T. Effect of qingre yangyin recipe on endocrine and\nmetabolism of polycystic ovary syndrome patients. Chinese\nJournal of Integrated Traditional and Western Medicine\n2015;35(10):1175-80.\nZhang 2017 {published data only}\nZhang/uni00A0J, Si/uni00A0Q, Li/uni00A0J. Therapeutic effects of metformin and\nclomiphene in combination with lifestyle intervention on\ninfertility in women with obese polycystic ovary syndrome.\nPakistan Journal of Medical Sciences 2017;33(1):8.\nZheng 2013 {published data only}\nZheng/uni00A0YH, Wang/uni00A0XH, Lai/uni00A0MH, Yao/uni00A0H, Liu/uni00A0H, Ma/uni00A0HX. Effectiveness\nof abdominal acupuncture for patients with obesity-type\npolycystic ovary syndrome: a randomized controlled\ntrial. Journal of Alternative and Complementary Medicine\n2013;19(9):740-5.\n/uni00A0\nReferences to studies awaiting assessment\nDuval 2015 {published data only}\nDuval/uni00A0K, Belan/uni00A0M, Jean-Denis/uni00A0F, Carranza-Mamane/uni00A0B, Pesant/uni00A0MH,\nLanglois/uni00A0MF, et al. An interdisciplinary lifestyle intervention\nimproves clinically relevant fertility outcomes in obese infertile\nwomen: preliminary results of a randomized controlled trial.\nCanadian Journal of Diabetes 2015;39:529-47.\nEgbase 2001 {published data only}\nEgbase/uni00A0P, Al Sharhan/uni00A0M, Buzaber/uni00A0M, Grudzinskas/uni00A0J. Prospective\nrandomised study of metformin in IVF and embryo transfer\ntreatment cycles in obese patients with polycystic ovarian\nsyndrome. Human Reproduction 2001;16(Suppl 1):202.\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n28\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nLi 2015 {published data only}\nLi/uni00A0SS. Metformin and auxiliary acupuncture in the treatment\nof obese women infertility with polycystic ovary syndrome\nfor 75 cases. Chinese Medicine Modern Distance Education of\nChina [zhong guo zhong yi yao xian dai yuan cheng jiao yu]\n2015;13(6):78-9.\nPfüller 2004 {published data only}\nPfüller/uni00A0B, Ibragimova/uni00A0E, Klaua/uni00A0S, Machlitt/uni00A0A, Rohde/uni00A0W, Voigt/uni00A0K.\nEffect of metformin treatment combined with lifestyle\nmodification on reproductive features, endocrine and\nmetabolic profiles in obese infertile women with PCOS. Human\nReproduction 2004;19:i176.\n/uni00A0\nAdditional references\nAbdallah 2011\nAbdallah Ismail/uni00A0N, Ragab/uni00A0SH, Abd Elbaky/uni00A0A, Shoeib/uni00A0AR,\nAlhosary/uni00A0Y, Fekry/uni00A0D. Frequency of firmicutes and bacteroidetes\nin gut microbiota in obese and normal weight Egyptian children\nand adults. Archives of Medical Science 2011;7(3):501-7.\nASRM 2015\nPractice Committee of the American Society for Reproductive\nMedicine. Obesity and reproduction: a committee opinion.\nFertility and Sterility 2015;104:1116-26.\nBerkel 2005\nBerkel/uni00A0LA, Poston/uni00A0WS, Reeves/uni00A0RS, Foreyt/uni00A0JP. Behavioral\ninterventions for obesity. Journal of the American Dietetic\nAssociation 2005;105(5 Suppl 1):S35-43.\nBest 2017\nBest/uni00A0D, Avenell/uni00A0A, Bhattacharya/uni00A0S. How effective are weight-loss\ninterventions for improving fertility in women and men who are\noverweight or obese? A systematic review and meta-analysis of\nthe evidence. Human Reproduction Update 2017;23(6):681-705.\nBoots 2011\nBoots/uni00A0C, Stephenson/uni00A0MD. Does obesity increase the risk of\nmiscarriage in spontaneous conception: a systematic review.\nSeminars in Reproductive Medicine 2011;29(6):507-13.\nBrauer 2015\nBrauer/uni00A0P, Gorber/uni00A0SC, Shaw/uni00A0E, Singh/uni00A0H, Bell/uni00A0N, Shane/uni00A0AR,\net al. Canadian Task Force on Preventive Health Care.\nRecommendations for prevention of weight gain and use of\nbehavioural and pharmacologic interventions to manage\noverweight and obesity in adults in primary care. Canadian\nMedical Association Journal 2015;187:184–95.\nBrown 2009\nBrown/uni00A0AJ, Setji/uni00A0TL, Sanders/uni00A0LL, Lowry/uni00A0KP, Otvos/uni00A0JD, Kraus/uni00A0WE,\net al. Effects of exercise on lipoprotein particles in women with\npolycystic ovary syndrome. Medicine and Science in Sports and\nExercise 2009;41:497.\nCabioglu 2006\nCabioglu/uni00A0MT, Ergene/uni00A0N. Changes in serum leptin and beta\nendorphin levels with weight loss by electroacupuncture\nand diet restriction in obesity treatment. American Journal of\nChinese Medicine 2006;34(1):1-11.\nCho 2009\nCho/uni00A0SH, Lee/uni00A0JS, Thabane/uni00A0L, Lee/uni00A0J. Acupuncture for obesity: a\nsystematic review and meta-analysis. International Journal of\nObesity 2009;33(2):183-96.\nChong 1986\nChong/uni00A0AP, Rafael/uni00A0RW, Forte/uni00A0CC. Influence of weight in the\ninduction of ovulation with human menopausal gonadotropin\nand human chorionic gonadotropin. Fertility and Sterility\n1986;46:599-603.\nClark 1998\nClark/uni00A0AM, Thornley/uni00A0B, Tomlinson/uni00A0L, Galletley/uni00A0C, Norman/uni00A0RJ.\nWeight loss in obese infertile women results in improvement in\nreproductive outcome for all forms of fertility treatment. Human\nReproduction 1998;13(6):1502-5.\nCrosignani 1994\nCrosignani/uni00A0PG, Ragni/uni00A0G, Parazzini/uni00A0F, Wyssling/uni00A0H, Lombroso/uni00A0G,\nPerotti/uni00A0L. Anthropometric indicators and response to\ngonadotrophin for ovulation induction. Human Reproduction\n1994;9:420-3.\nCrosignani 2003\nCrosignani/uni00A0PG, Colombo/uni00A0M, Vegetti/uni00A0W, Somigliana/uni00A0E, Gessati/uni00A0A,\nRagni/uni00A0G. Overweight and obese anovulatory patients with\npolycystic ovaries: parallel improvements in anthropometric\nindices, ovarian physiology and fertility rate induced by diet.\nHuman Reproduction 2003;18:1928–32.\nEdwards 1996\nEdwards/uni00A0LE, Hellerstedt/uni00A0WL, Alton/uni00A0IR, Story/uni00A0M, Himes/uni00A0JH.\nPregnancy complications and birth outcomes in obese and\nnormal-weight women: effects of gestational weight change.\nObstetrics & Gynecology 1996;87:389-94.\nEgger 1997\nEgger/uni00A0M, Smith/uni00A0GD, Schneider/uni00A0M, Minder/uni00A0C. Bias in meta-analysis\ndetected by a simple, graphical test. BMJ 1997;315(7109):629–\n34.\nFalsetti 1992\nFalsetti/uni00A0L, Pasinetti/uni00A0E, Mazzani/uni00A0MD, Gastaldi/uni00A0A. Weight loss and\nmenstrual cycle: clinical and endocrinological evaluation.\nGynecological Endocrinology 1992;6(1):49-56.\nFedorcsák 2004\nFedorcsák/uni00A0P, Dale/uni00A0PO, Storeng/uni00A0R, Ertzeid/uni00A0G, Bjercke/uni00A0S,\nOldereid/uni00A0N, et al. Impact of overweight and underweight\non assisted reproduction treatment. Human Reproduction\n2004;19:2523-8.\nFlegal 2010\nFlegal/uni00A0KM, Carroll/uni00A0MD, Ogden/uni00A0CL, Curtin/uni00A0LR. Prevalence\nand trends in obesity among US adults, 1999-2008. JAMA\n2010;303(3):235-41.\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n29\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nGarbaciak 1985\nGarbaciak/uni00A0JA, Richter/uni00A0M, Miller/uni00A0S, Barton/uni00A0JJ. Maternal weight\nand pregnancy complications. American Journal of Obstetrics\nand Gynecology 1985;152:238-45.\nGarvey 2013\nGarvey/uni00A0WT. New tools for weight-loss therapy enable a\nmore robust medical model for obesity treatment: rationale\nfor a complications-centric approach. Endocrine Practice\n2013;19(5):864-74.\nGRADEpro GDT 2014 [Computer program]\nGRADEpro GDT. Version accessed 10 August 2015. Hamilton\n(ON): GRADE Working Group, McMaster University, 2014.\nGucel 2012\nGucel/uni00A0F, Bahar/uni00A0B, Demirtas/uni00A0C, Mit/uni00A0S, Cevik/uni00A0C. Influence of\nacupuncture on leptin, ghrelin, insulin and cholecystokinin in\nobese women: a randomised, sham-controlled preliminary trial.\nAcupuncture in Medicine 2012;30(3):203-7.\nHamilton-Fairley 1992\nHamilton-Fairley/uni00A0D, Kiddy/uni00A0D, Watson/uni00A0H, Paterson/uni00A0C, Franks/uni00A0S.\nAssociation of moderate obesity with a poor pregnancy\noutcome in women with polycystic ovary syndrome treated\nwith low dose gonadotrophin. BJOG 1992;99:128-31.\nHamilton-Fairley 1993\nHamilton-Fairley/uni00A0D, Kiddy/uni00A0D, Anyaoku/uni00A0V, Koistinen/uni00A0R, Seppala/uni00A0M,\nFranks/uni00A0S. Response of sex hormone binding globulin and\ninsulin-like growth factor binding protein-1 to an oral glucose\ntolerance test in obese women with polycystic ovary syndrome\nbefore and a/f_ter calorie restriction. Clinical Endocrinology\n1993;39(3):363-7.\nHiggins 2011\nHiggins/uni00A0JPT, Green S (editors). Cochrane Handbook for\nSystematic Reviews of Interventions Version 5.1.0 (updated\nMarch 2011). The Cochrane Collaboration, 2011. Available from\nhandbook.cochrane.org.\nHollmann 1996\nHollmann/uni00A0M, Runnebaum/uni00A0B, Gerhard/uni00A0I. Effects of weight loss\non the hormonal profile in obese, infertile women. Human\nReproduction 1996;11(9):1884-91.\nHossain 2007\nHossain/uni00A0P, Kawar/uni00A0B, El Nahas/uni00A0M. Obesity and diabetes in the\ndeveloping world - a growing challenge. New England Journal of\nMedicine 2007;356(3):213-5.\nHuber-Buchholz 1999\nHuber-Buchholz/uni00A0MM, Carey/uni00A0DG, Norman/uni00A0RJ. Restoration of\nreproductive potential by lifestyle modification in obese\npolycystic ovary syndrome: role of insulin sensitivity and\nluteinizing hormone. Journal of Clinical Endocrinology and\nMetabolism 1999;84(4):1470-4.\nJohansson 2015\nJohansson/uni00A0K, Cnattingius/uni00A0S, Näslund/uni00A0I, Roos/uni00A0N, Trolle Lagerros/uni00A0Y,\nGranath/uni00A0F, et al. Outcomes of pregnancy a/f_ter bariatric surgery.\nNew England Journal of Medicine 2015;372:814–82.\nKaptchuk 2001\nKaptchuk/uni00A0TJ, Eisenberg/uni00A0DM. Varieties of healing. 2: a taxonomy\nof unconventional healing practices. Annals of Internal Medicine\n2001;135(3):196-204.\nKhaskheli 2013\nKhaskheli/uni00A0MN, Baloch/uni00A0S, Baloch/uni00A0AS. Infertility and weight\nreduction: influence and outcome. Journal of the College of\nPhysicians and Surgeons Pakistan 2013;23(10):798-801.\nKim 2020\nKim/uni00A0SY, Park/uni00A0ES, Kim/uni00A0HW. Effectiveness of non-pharmacological\ninterventions for overweight or obese infertile women: a\nsystematic review and meta-analysis. International Journal of\nEnvironmental Research and Public Health 2020;17(20):7438.\nKoloszar 2002\nKoloszar/uni00A0S, Daru/uni00A0J, Kereszturi/uni00A0A, Zavaczki/uni00A0Z, Szöllosi/uni00A0J, Pal/uni00A0A.\nEffect of female body weight on efficiency of donor AI. Systems\nBiology in Reproductive Medicine 2002;48:323-7.\nKominiarek 2017\nKominiarek/uni00A0MA, Jungheim/uni00A0ES, Hoeger/uni00A0KM, Rogers/uni00A0AM, Kahan/uni00A0S,\nKim/uni00A0JJ. American Society for Metabolic and Bariatric Surgery\nposition statement on the impact of obesity and obesity\ntreatment on fertility and fertility therapy Endorsed by the\nAmerican College of Obstetricians and Gynecologists and\nthe Obesity Society. Surgery for Obesity and Related Diseases\n2017;13:750–7.\nKoning 2012\nKoning/uni00A0A, Mutsaerts/uni00A0M, Kuchenbecher/uni00A0W, Broekmans/uni00A0F,\nLand/uni00A0J, Mol/uni00A0B, et al. Complications and outcome of assisted\nreproduction technologies in overweight and obese women.\nHuman Reproduction 2012;27:457–67.\nKumar 1993\nKumar/uni00A0A, Mittal/uni00A0S, Buckshee/uni00A0K, Farooq/uni00A0A. Reproductive\nfunctions in obese women. Progress in Food & Nutrition Science\n1993;17(2):89-98.\nKupta 2014\nKupka/uni00A0MS, Ferraretti/uni00A0AP, De Mouzon/uni00A0J, Erb/uni00A0K, D’Hooghe/uni00A0T,\nCastilla/uni00A0JA, et al. Assisted reproductive technology in Europe,\n2010: results generated from European registers by ESHRE.\nHuman Reproduction 2014;29:2099–113.\nLang 2006\nLang/uni00A0A, Froelicher/uni00A0ES. Management of overweight and obesity\nin adults: behavioral intervention for long-term weight loss\nand maintenance. European Journal of Cardiovascular Nursing\n2006;5(2):102-14.\nLefebvre 2020\nLefebvre/uni00A0C, Glanville/uni00A0J, Briscoe/uni00A0S, Littlewood/uni00A0A, Marshall/uni00A0C,\nMetzendorf M-I, et al. Chapter 4. Searching for and selecting\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n30\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nstudies. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li\nT, Page MJ, et al (editors). Cochrane Handbook for Systematic\nReviews of Interventions Version 6.1 (updated September 2020).\nAvailable from www.training.cochrane.org/handbook.\nLi 2005\nLi/uni00A0Z, Maglione/uni00A0M, Tu/uni00A0W, Mojica/uni00A0W, Arterburn/uni00A0D, Shugarman/uni00A0LR, et\nal. Meta-analysis: pharmacologic treatment of obesity. Annals of\nInternal Medicine 2005;142(7):532-46.\nLim 2019\nLim/uni00A0SS, Hutchison/uni00A0SK, Van Ryswyk/uni00A0E, Norman/uni00A0RJ, Teede/uni00A0HJ,\nMoran/uni00A0LJ. Lifestyle changes in women with polycystic ovary\nsyndrome. Cochrane Database of Systematic Reviews 2019, Issue\n3. Art. No: CD007506. [DOI: 10.1002/14651858.CD007506.pub4]\nMetwally 2007\nMetwally/uni00A0M, Li/uni00A0T, Ledger/uni00A0W. The impact of obesity on female\nreproductive function. Obesity Reviews 2007;8(6):515-23.\nMoran 2005\nMoran/uni00A0LJ, Luscombe-Marsh/uni00A0ND, Noakes/uni00A0M, Wittert/uni00A0GA, Keogh/uni00A0JB,\nCli/f_ton/uni00A0PM. The satiating effect of dietary protein is unrelated to\npostprandial ghrelin secretion. Journal of Clinical Endocrinology\nand Metabolism 2005;90(9):5205-11.\nOgden 2006\nOgden/uni00A0CL, Carroll/uni00A0MD, Curtin/uni00A0LR, McDowell/uni00A0MA, Tabak/uni00A0CJ,\nFlegal/uni00A0KM. Prevalence of overweight and obesity in the United\nStates,1999-2004. JAMA 2006;295(13):1549-55.\nPandey 2010\nPandey/uni00A0S, Pandey/uni00A0S, Maheshwari/uni00A0A, Bhattacharya/uni00A0S. The impact\nof female obesity on the outcome of fertility treatment. Journal\nof Human Reproductive Sciences 2010;3:62-7.\nRandeva 2002\nRandeva/uni00A0HS, Lewandowski/uni00A0KC, Drzewoski/uni00A0J, Brooke-Wavell/uni00A0K,\nO'Callaghan/uni00A0C, Czupryniak/uni00A0L, et al. Exercise decreases plasma\ntotal homocysteine in overweight young women with polycystic\novary syndrome. Journal of Clinical Endocrinology & Metabolism\n2002;87:4496-501.\nRittenberg 2011\nRittenberg/uni00A0V, Seshadri/uni00A0S, Sunkara/uni00A0SK, Sobaleva/uni00A0S, Oteng\nNtim/uni00A0E, El-Toukhy/uni00A0T. Effect of body mass index on IVF treatment\noutcome: an updated systematic review and meta-analysis.\nReproductive BioMedicine Online 2011;23:421–39.\nScott 2009\nScott/uni00A0MM, Lachey/uni00A0JL, Sternson/uni00A0SM, Lee/uni00A0CE, Elias/uni00A0CF,\nFriedman/uni00A0JM, et al. Leptin targets in the mouse brain. Journal of\nComparative Neurology 2009;514(5):518-32.\nSermonade 2019\nSermondade/uni00A0N, Huberlant/uni00A0S, Bourhis-Lefebvre/uni00A0V, Arbo/uni00A0E,\nGallot/uni00A0V, Colombani/uni00A0M, Fréour/uni00A0T. Female obesity is negatively\nassociated with live birth rate following IVF: a systematic\nreview and meta-analysis. Human Reproduction Update\n2019;25(4):439-451.\nSmith 2002\nSmith/uni00A0GD, Jackson/uni00A0LM, Foster/uni00A0DL. Leptin regulation\nof reproductive function and fertility. Theriogenology\n2002;57(1):73-86.\nStraus 2004\nStraus/uni00A0SE. Complementary and alternative medicine. In:\nGoldman L, Ausiello D, editors(s). Cecil Textbook of Medicine.\n22nd edition. Philadelphia (PA): Saunders, 2004.\nSwinburn 2009\nSwinburn/uni00A0BA, Sacks/uni00A0G, Lo/uni00A0SK, Westerterp/uni00A0KR, Rush/uni00A0EC,\nRosenbaum/uni00A0M, et al. Estimating the changes in energy flux that\ncharacterize the rise in obesity prevalence. American Journal of\nClinical Nutrition 2009;89(6):1723-8.\nThessaloniki 2008\nThessaloniki ESHRE/ASRM-Sponsored PCOS Consensus\nWorkshop Group. Consensus on infertility treatment\nrelated to polycystic ovary syndrome. Human Reproduction\n2008;23(3):462-77.\nThomson 2010\nThomson/uni00A0RL, Buckley/uni00A0JD, Lim/uni00A0SS, Noakes/uni00A0M, Cli/f_ton/uni00A0PM,\nNorman/uni00A0RJ, et al. Lifestyle management improves quality of life\nand depression in overweight and obese women with polycystic\novary syndrome. Fertility and Sterility 2010;94:1812-6.\nvan der Steeg 2008\nvan der/uni00A0Steeg/uni00A0JW, Steures/uni00A0P, Eijkemans/uni00A0MJ, Habbema/uni00A0JD,\nHompes/uni00A0PG, Burggraaff/uni00A0JM, et al. Obesity affects spontaneous\npregnancy chances in subfertile, ovulatory women. Human\nReproduction 2008;23(2):324-8.\nWadden 2005\nWadden/uni00A0TA, Berkowitz/uni00A0RI, Womble/uni00A0LG, Sarwer/uni00A0DB, Phelan/uni00A0S,\nCato/uni00A0RK, et al. Randomized trial of lifestyle modification and\npharmacotherapy for obesity. New England Journal of Medicine\n2005;353(20):2111-20.\nWahrenberg 1999\nWahrenberg/uni00A0H, Ek/uni00A0I, Reynisdottir/uni00A0S, Carlstrom/uni00A0K, Bergqvist/uni00A0A,\nArner/uni00A0P. Divergent effects of weight reduction and oral\nanticonception treatment on adrenergic lipolysis regulation in\nobese women with the polycystic ovary syndrome. Journal of\nClinical Endocrinology and Metabolism 1999;84(6):2182-7.\nWaller 1994\nWaller/uni00A0DK, Mills/uni00A0JL, Simpson/uni00A0JL, Cunningham/uni00A0GC, Conley/uni00A0MR,\nLassman/uni00A0MR, et al. Are obese women at higher risk for\nproducing malformed offspring? American Journal of Obstetrics\nand Gynecology 1994;170:541-8.\nWang 2002\nWang/uni00A0JX, Davies/uni00A0MJ, Norman/uni00A0RJ. Obesity increases the risk\nof spontaneous abortion during infertility treatment. Obesity\nResearch 2002;10:551-4.\nWeiss 2004\nWeiss/uni00A0JL, Malone/uni00A0FD, Emig/uni00A0D, Ball/uni00A0RH, Nyberg/uni00A0DA, Comstock/uni00A0CH,\net al, FASTER Research Consortium. Obesity, obstetric\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n31\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\ncomplications and cesarean delivery rate: a population-based\nscreening study. American Journal of Obstetrics and Gynecology\n2004;190:1091-7.\nYin 2005\nYin/uni00A0S, Lin-shan/uni00A0Z. Therapeutic idea and approaches to obesity\nwith acupuncture. Journal of Acupuncture and Tuina Science\n2005;3(4):54-7.\n/uni00A0\n* Indicates the major publication for the study\n/uni00A0\nC 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\nCharacteristics of included studies [ordered by study ID]\n/uni00A0\nStudy characteristics\nMethods Multi-centre, multi-disciplinary, prospective, randomised controlled trial\nParticipants • Setting: 9 infertility clinics in Sweden, Denmark, and Iceland\n• Inclusion: infertile women between 18 and 38 years of age with indications for IVF and planning to\nstart their first, second, or third IVF treatment and with BMI ≥ 30 and < 35 kg/m/two.sups\n• Exclusion: women were excluded from the trial if they had insulin-dependent diabetes mellitus and\nother exclusion factors such as planned oocyte donation, planned pre-implantation genetic diagno-\nsis, husband with azoospermia known at randomisation, less than adequate knowledge of the local\nlanguage, binge eating disorder, or previous study participation\nInterventions Comparison\n• Intervention group: weight reduction before IVF, starting with 12 weeks of a low-calorie liquid formula\ndiet (LCD) of 880 kcal/d and thereafter weight stabilisation for 2 to 5 weeks\n• Control group: IVF only\nOutcomes Live birth rate\nWeight reduction (change in BMI)\nClinical pregnancy\nOngoing pregnancy\nMiscarriage\nNotes Conflicts of interest: some issues are presented in the article\nFunding: Sahlgrenska University Hospital (ALFGBG-70 940), Merck AB Solna Sweden (an affiliate of\nMerck KGaA, Darmstadt, Germany), Impolin AB, Hjalmar Svensson Foundation, and Jane and Dan Ols-\nson Foundation for Science. Funders had no role in the design of the study, statistical analysis, or inter-\npretation of study results, nor in writing the article or deciding to submit it for publication\nDate study was conducted: 10 May 2010\nClinical trial registration number: NCT01566929\nTrial authors contacted: Ann Thurin-Kjellberg\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Computerised randomisation programme\nAllocation concealment\n(selection bias)\nLow risk Online concealed allocation of patients in the proportion of 1:1. Optimal allo-\ncation was applied according to Pocock’s minimisation technique for sequen-\ntial randomisation, taking account of the number of previously performed\nEinarsson 2017/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n32\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nfresh IVF cycles and age of the woman, as well as parity, polycystic ovarian\nsyndrome (PCOS), fertilisation method planned, tubal factor, smoking, BMI,\nand waist circumference\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nHigh risk Blinding was not possible for patients or physicians\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk Embryologists and statisticians were unaware as to which group participants\nwere allocated but as the women and investigators were aware we can't rule\nout detection bias\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Missing outcome data were balanced in numbers across intervention groups,\nwith similar reasons for missing data across groups\n• In the weight reduction and IVF group, 1 patient did not receive the allocat-\ned intervention and 7 discontinued the intervention. In the IVF only group,\n2 patients did not receive the allocated intervention and 2 discontinued the\nintervention. No patients were lost to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol is available, and all of the study's pre-specified outcomes\nhave been reported in the results\nhttps://clinicaltrials.gov/ct2/show/NCT01566929\nOther bias Low risk We did not identify any other potential sources of bias in the study, and we\njudged low risk for other potential sources of bias\nEinarsson 2017/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Double-blinded randomised controlled clinical trial\nParticipants • Setting: Department of Obstetrics and Gynecology, Faculty of Medicine, Zagazig University, Zagazig,\nEgypt\n• Inclusion:obesity, infertility\n• Exclusion: smokers, drug users, those with other causes of infertility such as male factor or tubal fac-\ntor, those with endocrine disorders such as thyroid dysfunction or hyperprolactinaemia\nInterventions Group 1 (CC plus metformin and L-carnitine): received 150 mg/d CC from day 3 till day 7 of menstrual\ncycle plus oral L-carnitine 3 g and metformin 850 mg (1 tablet daily), then the dose was doubled after\n1 week to 1700 mg/d (2 tablets daily). Metformin was ingested before a meal once daily during the first\nweek and thereafter twice daily. L-carnitine and metformin were stopped only when pregnancy was\ndocumented.\nGroup 2 (CC plus metformin and placebo): received 150 mg/d CC plus metformin (as above) and place-\nbo capsules that were designed to look exactly like L-carnitine capsules.\nOutcomes Pregnancy rate\nMiscarriage rate\nBMI\nFree testosterone\nEl 2019/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n33\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nNotes Conflicts of interest: no\nFunding: Zagazig University\nDate study was conducted: January 2017\nClinical trial registration number: NCT03108963\nTrial authors contacted: El Sharkwy I.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Computerised randomisation programme\nAllocation concealment\n(selection bias)\nLow risk Allocation was concealed in opaque, sealed, serially numbered envelopes\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Women, treating physicians, and investigators were blinded to treatment allo-\ncation\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Women, treating physicians, and investigators were blinded to treatment allo-\ncation\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Missing outcome data were balanced in numbers across intervention groups,\nwith similar reasons for missing data across groups\n• A total of 375 women were assessed for eligibility. Of them, 95 were exclud-\ned (60 did not meet the inclusion criteria and 35 refused to participate). The\nconsenting 280 women were randomly allocated to group 1 (n = 140) or group\n2 (n = 140). Six women were excluded from analysis due to loss to follow-up:\n2 women in group 1 and 4 women in group 2\nSelective reporting (re-\nporting bias)\nLow risk The study protocol is available, and all of the study's pre-specified outcomes\nhave been reported in the results\nOther bias Low risk We did not identify any other potential sources of bias in the study, and we\njudged low risk for other potential sources of bias\nEl 2019/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Double-blind, cross-over design\nParticipants • Setting: reproductive medicine clinic, Australia\n• Inclusion: obese infertile women\n• Exclusion: not mentioned\nInterventions Comparison: dexfenfluramine and placebo were given in a double-blind cross-over design\n• Dexfenfluramine dosage was 15 mg twice daily, and the duration of each treatment condition was 12\nweeks for placebo/dexfenfluramine (n = 11) and dexfenfluramine/placebo (n = 10). We tried to extract\nonly the pre-cross-over data\nGalletly 1996/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n34\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcomes Weight loss, this was the only useable outcome but not sure whether truly pre-cross-over data\nSelf-esteem score\nDepression score\nAnxiety score\nNotes Data regarding self-esteem, depression, and BMI are not presented separately for each group.\nConflicts of interest: not mentioned\nFunding: not mentioned\nDate study was conducted: not mentioned\nClinical trial registration number: not mentioned\nTrial authors contacted: Cherrie Galletly\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk Insufficient information about sequence generation\nAllocation concealment\n(selection bias)\nUnclear risk Method of concealment not described\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk Insufficient information to permit judgement\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk Insufficient information to permit judgement\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nUnclear risk The study did not address this outcome\nSelective reporting (re-\nporting bias)\nHigh risk The study protocol is unavailable, and all of the study's pre-specified out-\ncomes have not been reported in the results\n• At the beginning, midpoint, and end of the study, patients completed the\nRosenberg Self-Esteem Scale and the Hospital Anxiety and Depression Scale.\nWeight patients were weighed weekly throughout the study\nBMI is not an outcome measure but it was evaluated\nOther bias Low risk We did not identify any other potential sources of bias in the study, and we\njudged low risk for other potential sources of bias\nGalletly 1996/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Double-blinded multi-centre randomised trial\nJohnson 2010/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n35\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nParticipants • Setting: multi-centre, New Zealand\n• Inclusion: anovulatory or oligo-ovulatory women with PCOS\n• Exclusion: couples who had undergone previous fertility treatment involving more than 5 months of\ntreatment with CC or metformin; with any other important infertility factor known to be present, in-\ncluding known tubal factor in which at least 1 fallopian tube was blocked (although a tubal potency\ntest was not a prerequisite for trial entry); with important medical disorders in women\nInterventions Comparison\n• Women with BMI > 32 received no treatment other than advice and encouragement on lifestyle inter-\nvention (which included advice on calorie restriction and on increasing aerobic exercise to 30 minutes\nat least 5 times per week with an opportunity to see a dietician and an exercise therapist if required\n(i.e. standard care)):\n• Placebo\n• Intervention: metformin (in addition to standard care) for 6 months; metformin 500 mg 3 times\ndaily at a gradually increasing dose over 2 weeks was given; for CC, 50 mg was the initial dose and\n150 mg the highest dose used\nOutcomes Clinical pregnancy\nLive birth\nSpontaneous abortion\nAdverse events\nIn this study, patients were divided according to BMI < 32 and BMI ≥ 32. We included only data from BMI\n≥ 32 in this review\nNotes Conflicts of interest: NPJ reports receiving travel support from Serono, Organon, Bayer-Schering, and\nDevice Technologies New Zealand, and funding for a research meeting from Serono. VPS reports receiv-\ning travel support from Serono\nFunding: Auckland Medical Research Foundation, Mercia Barnes Trust, and University of Auckland Re-\nsearch Committee. Funders played no role in the design, the conduct of the research, or the decision to\npublish\nDate study was conducted: August 2003\nClinical trial registration number: NCT00795808\nTrial authors contacted: NP Johnson\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk In this study, it was mentioned that complete description of patients is provid-\ned\nRandomisation was done through a computer-generated randomisation\nprocess\nAllocation concealment\n(selection bias)\nLow risk Concealment was strictly maintained by a telephone call from the recruiting\nresearch nurse to the pharmacy\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Blinding (masking) of all parties (women and personnel) was maintained in\nall cases by placebo control until the end of the course of treatment or, in the\nevent of pregnancy, until after the pregnancy\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk The research pharmacist executed the assignment by dispensing pre-prepared\ndrugs by true third party randomisation. Blinding (masking) of all parties was\nJohnson 2010/uni00A0/uni00A0(Continued)\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n36\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nmaintained in all cases by placebo control until the end of the course of treat-\nment or, in the event of pregnancy, until after the pregnancy\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk • Of 33 women with BMI ≥ 32 kg/m/two.sups receiving placebo, 30 completed treatment\nand follow-up (2 of whom were not fully adherent to treatment - 1 experi-\nenced side effects so took a reduced dose; 1 misunderstood the gradual in-\ncrease in dose and did this every month)\n• 3 breached the protocol by stopping trial medications; 25 women who had\nnot had confirmed ovulation 3 months into the trial received CC thereafter.\nAmong 32 women with BMI ≥ 32 kg/m/two.sups receiving metformin, 29 completed\ntreatment and follow-up (all of whom were fully adherent to treatment) - 2\nwomen were lost to follow-up, 1 of whom was pregnant at the time of emi-\ngration to Australia, and 1 who stopped trial medication; 22 women who had\nnot had confirmed ovulation 3 months into the trial received CC thereafter\nSelective reporting (re-\nporting bias)\nLow risk The study protocol is available, but all of the study's pre-specified outcomes\nhave been reported in the results\nhttps://clinicaltrials.gov/ct2/show/NCT00795808\nOther bias Low risk We did not identify any other potential sources of bias in the study, and we\njudged low risk for other potential sources of bias\nJohnson 2010/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods A randomised prospective trial\nParticipants • Setting: university-based medical centre, California\n• Inclusion: anovulatory or oligo-ovulatory cycles (35 days or 8 cycles/year), polycystic ovaries on a\nbaseline ultrasound, hyperandrogenism (hirsutism, acne, alopecia, or elevated testosterone), BMI >\n29 kg/m/two.sups, desire for fertility\n• Exclusion: pregnancy, hepatic disease, renal disease, heart disease, alcoholism, pulmonary disease,\nthyroid disease, prolactinoma, congenital adrenal hyperplasia, androgen-secreting tumour\nInterventions Comparison\n• Group 1 (CC + met): participants received MET 500 mg 3 times a day, given on cycle days 1 through\n14, with cycle day 1 defined as the first day of menstrual flow after a 10-day course of medroxyproges-\nterone acetate (10 mg daily) challenge in combination with CC 100 mg per day taken on days 5 through\n9 of the cycle. In the group receiving MET, the entire dose of the medication (1500 mg/d) was taken\nfrom the start of treatment (n = 16)\n• Group 2 (CC): participants received CC 100 mg per day on cycle days 5 through 9 only. The dose of CC\nchosen (100 mg/d) was based on significant obesity in the population and the known ineffectiveness\nof lower doses of CC in these patients (n = 15)\nOutcomes Free glucose\nTotal and free Testosterone\nSHBG\nPregnancy rate\nNotes Conflicts of interest: not mentioned\nFunding: not mentioned\nKhorram 2006/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n37\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nDate study was conducted: not found\nClinical trial registration number: not found, at https://clinicaltrials.gov/\nTrial authors contacted: Khorram O\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Randomisation was done by picking a card out of a box, which had 1 or the\nother treatment written on it; the participant was assigned to that group\nAllocation concealment\n(selection bias)\nHigh risk Randomisation was done by picking a card out of a box, which had 1 or the\nother treatment written on it; the participant was assigned to that group\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk Probably not blinded\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk Probably not blinded\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nUnclear risk The study lacks details of dropout rates\nSelective reporting (re-\nporting bias)\nHigh risk The study protocol is unavailable\nOther bias Low risk We did not identify any other potential sources of bias in the study, and we\njudged low risk for other potential sources of bias\nKhorram 2006/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Secondary analysis of a multi-centre RCT (randomised controlled trial)\nParticipants • Setting: 6 university medical centres and 17 general hospitals in The Netherlands\n• Inclusion: infertile women between 18 and 39 years of age with BMI ≥ 29\n• Exclusion: women with severe endometriosis, premature ovarian failure, or endocrinopathy (e.g.\nwomen with type 1 diabetes, women with Cushing’s syndrome). Those who were eligible for donor\ninsemination because of azoospermia were excluded, as were women with untreated preexisting hy-\npertension and those with hypertension-related complications in a previous pregnancy\nInterventions Comparison\n• Intervention: lifestyle intervention consisted of a 6-month structured programme aiming at weight\nloss of 5% to 10% of original body weight. It included 6 structured outpatient visits and 4 telephone\nconsultations with a pre-trained intervention coach. Daily dietary energy intake was reduced by 600\nkcal and was maintained at a minimum of 1200 kcal/d\n• Physical activity was stimulated to a level of 10,000 steps a day and at least 30 minutes of exercise\n2 to 3 times a week. Behavioural changes were facilitated by motivational counselling. After com-\npletion of the 6-month programme, or when weight loss of 5% to 10% had been achieved, women\nstarted to receive appropriate infertility treatment if they were not yet pregnant\nMutsaerts 2016/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n38\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Control: appropriate infertility treatment immediately after randomisation.\nOutcomes Live birth\nOngoing pregnancy\nClinical pregnancy\nMiscarriage\nNotes This lifestyle project and some data are presented in the papers below\n• Mutsaerts MA, Groen H, ter Bogt NC, Bolster JH, Land JA, Bemelmans WJ, Kuchenbecker WK, Hompes\nPG, Macklon NS, Stolk RP, et al. The LIFESTYLE study: costs and effects of a structured lifestyle program\nin overweight and obese subfertile women to reduce the need for fertility treatment and improve re-\nproductive outcome. A randomised controlled trial. BMC Womens Health 2010;10:22-6874-10-22\n• Mutsaerts MA, van Oers AM, Groen H, Burggraaff JM, Kuchenbecker WK, Perquin DA, Koks CA, van Golde\nR, Kaaijk EM, Schierbeek JM, et al. Randomized trial of a lifestyle program in obese infertile women.\nN Engl J Med 2016;374:1942–1953\n• Karsten MDA, van Oers AM, Groen H, Mutsaerts MAQ, van Poppel MNM, Geelen A, van de Beek C, Painter\nRC, Mol BWJ, Roseboom TJ , Hoek A; LIFEstyle study group.Determinants of successful lifestyle change\nduring a 6-month preconception lifestyle intervention in women with obesity and infertility. Eur J Nutr\n• van Oers AM, Mutsaerts MAQ, Burggraaff JM, Kuchenbecker WKH, Perquin DAM, Koks CAM, van Golde\nR, Kaaijk EM, Schierbeek JM, Klijn NF, van Kasteren YM, Land JA, Mol BWJ, Hoek A, Groen H; LIFEstyle\nStudy Group. Cost-effectiveness analysis of lifestyle intervention in obese infertile women. Hum Re-\nprod 2017;32(7):1418-1426. doi: 10.1093/humrep/dex092\n• van Oers AM , Mutsaerts MAQ. Association between periconceptional weight loss and maternal\nand neonatal outcomes in obese infertile women. PLoS One 2018;13(3):e0192670. doi: 0.1371/jour-\nnal.pone.0192670\nConflicts of interest: the Department of Obstetrics and Gynaecology of the UMCG received an unre-\nstricted educational grant from Ferring Pharmaceuticals BV, The Netherlands. BWJM is a consultant for\nObsEva, Geneva\nFunding: Netherlands Organization for Health Research and Development\nDate study was conducted: 1 April 2009\nClinical trial registration number: NTR1530\nTrial authors contacted: Zon MW\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Randomisation was performed through a web-based randomisation pro-\ngramme and was stratified according to trial centre and ovulatory status\nAllocation concealment\n(selection bias)\nLow risk Web-based randomisation programme\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nHigh risk Blinding to treatment assignments was not possible\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nHigh risk Blinding to treatment assignments was not possible\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Missing outcome data were balanced in numbers across intervention groups,\nwith similar reasons for missing data across groups\nMutsaerts 2016/uni00A0/uni00A0(Continued)\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n39\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• We randomised 577 women, of whom 290 were randomised to the lifestyle in-\ntervention preceding infertility treatment arm (9 were lost to follow-up and 1\nwithdrew informed consent) and 287 to the prompt infertility treatment arm\n(1 was lost to follow-up and 2 withdrew informed consent). So, in total, data\nfor 280 women in the intervention group and for 284 women in the control\ngroup were available for analysis\nSelective reporting (re-\nporting bias)\nLow risk The study protocol is available, and all of the study's pre-specified outcomes\nhave been reported in the results\nOther bias Low risk We did not identify any other potential sources of bias in the study, and we\njudged low risk for other potential sources of bias\nMutsaerts 2016/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Open-label, single-site, pilot study\nParticipants • Setting: single-site, academic institution, Michigan\n• Inclusion: 18 to 35 years old. Obesity (BMI ≥ 35 and ≤ 45 kg/m/two.sups). Infertility. Evidence of normal uterine\nanatomy and at least 1 patent tube documented by hysterosalpingogram or saline infusion sonogram.\nPolycystic ovary syndrome. Ovulatory dysfunction (amenorrhoea, irregular cycles, or progesterone\nlevel < 10 ng/mL in the luteal phase). Partner with semen analysis demonstrating ≥ 20 million sperm/\nmL, 50% motility, and normal morphology by Kruger criteria of 8%\n• Exclusion: women who were using donor sperm, had FSH > 10 mIU/mL, or had endometriosis Ameri-\ncan Fertility Society class III or IV; were taking anti-obesity drugs or appetite suppressants within the\npast 2 months; had previous bariatric surgery or gastrointestinal disease; used hormone medications\nwithin the past 2 months; had elevated prolactin, type 1 diabetes, uncorrected thyroid disease, or evi-\ndence of adrenal disease; had evidence of conditions that would complicate pregnancy (liver disease,\nkidney disease, autoimmune disorders such as systemic lupus erythematosus, significant anaemia,\nhistory of clotting disorder, uncontrolled hypertension, heart disease, or cancer)\nInterventions Comparison\n• Intensive weight loss intervention (IWL): IWL consisted of 12 weeks of very low-energy diet (800 kcal/\nd) and 4 weeks of a low-calorie conventional food-based diet (CFD) to promote 15% weight loss (n = 6)\n• Standard of care nutrition counselling (SCN): SCN consisted of 16 weeks of CFD to promote 5% weight\nloss (n = 5)\nOutcomes Live birth\nWeight loss (BMI)\nFasting glucose\nConfirmed pregnancy\nDepression (IDS-SR)\nQuality of life (EQ-5D health score)\nAdverse events\nNotes Thirty-nine women were screened; 25 (64%) were eligible to participate, and 14 of those eligible (56%)\nagreed to be randomised, 7 to each group. One withdrew from the IWL group and 2 from the SCN group\nConflicts of interest: not mentioned\nRothberg 2016/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n40\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFunding: supported by a grant from the Michigan Institute for Clinical Research (grant U040012 PI to\nA.R.); core services of the Michigan Nutrition Obesity Research Center (grant DK089503); and the Michi-\ngan Center for Diabetes Research (grant P30DK020572)\nDate study was conducted: October 2013\nClinical trial registration number: NCT01894074\nTrial authors contacted: Rothberg A\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk Information insufficient to permit judgement\nAllocation concealment\n(selection bias)\nHigh risk Open-label trial, not concealed\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nHigh risk Open-label trial, not blinded\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nHigh risk Open-label trial, not blinded\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk • We screened 39 women, of whom 25 were found to be eligible and 14 agreed\nto participate. Our inability to achieve a target sample size of 32 was due\nto the extremely restrictive eligibility criteria and the reluctance of eligible\nwomen to delay ovulation induction. After the baseline oral glucose toler-\nance test, participants were randomly allocated to treatment. Seven partic-\nipants were randomised to each group. One participant withdrew from the\nIWL group (did not tolerate diet) after 1 week of starting the dietary interven-\ntion and 2 participants withdrew (decided not to pursue pregnancy and were\ndissatisfied with the randomisation arm) from the SCN group before the di-\netary intervention\nSelective reporting (re-\nporting bias)\nLow risk The study protocol is available, but all of the study's pre-specified outcomes\nhave been reported in the results\nhttps://clinicaltrials.gov/ct2/show/NCT01894074\nOther bias Low risk We did not identify any other potential sources of bias in the study, and we\njudged low risk for other potential sources of bias\nRothberg 2016/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods A prospective, randomised, open-label study\nParticipants • Setting: Slovenia\n• Inclusion: PCOS diagnosed according to revised Rotterdam criteria, body mass index (BMI) ≥ 30 kg/\nm/two.sups, age ≤ 38, first or second IVF attempt; no severe male infertility\n• Exclusion: type 1 or type 2 diabetes mellitus; history of carcinoma; personal or family history of MEN2;\nsignificant cardiovascular, kidney, or liver disease; use of medications other than metformin known or\nSalamun 2018/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n41\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nsuspected to affect reproductive or metabolic functions or statins within 90 days before study entry;\nno coexisting ovarian pathology\nInterventions Comparison\n• Metformin (MET) 1000 mg twice daily: metformin was initiated at a dose of 500 mg once per day and\nwas increased by 500 mg every 3 days up to 1000 mg twice daily\n• Metformin 1000 mg twice daily combined with 1.2 mg liraglutide every day subcutaneously (COMBI):\nin the COMBI arm, there was a run-in period of 12 days to titrate metformin up to 1000 mg twice daily\nbefore liraglutide was added. Liraglutide was initiated at a dose of 0.6 mg injected subcutaneously\nonce per day and increased to 1.2 mg after 3 days. Medical treatment in both groups lasted 12 weeks\nOutcomes Clinical pregnancy\nWeight loss (BMI)\nTotal body fat (%)\nGlu OGTT\nFree T\nTotal T\nSHBG\nAdverse events\nNotes Conflicts of interest: no\nFunding: grant number 20140031 of the University Medical Center, Ljubljana, Slovenia\nDate study was conducted: 1 September 2014\nClinical trial registration number: NCT03353948\nTrial authors contacted: Vesna Salamun\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk This is not described in sufficient detail to allow a definitive judgement\nAllocation concealment\n(selection bias)\nHigh risk Open-label trial, not concealed\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nHigh risk Open-label trial, not blinded\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nHigh risk Open-label trial, not blinded\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Missing outcome data were balanced in numbers across intervention groups,\nwith similar reasons for missing data across groups\n• 28 patients started the study, and 27 (14 on MET, 13 on COMBI) completed\ntreatment according to the protocol and were included in the analysis (Fig.\n1). 1 patient in the COMBI group discontinued the study because of proto-\ncol violation, 2 patients in the MET group refused IVF. 1 patient in the COMBI\ngroup and 1 in the MET group conceived spontaneously immediately after\nSalamun 2018/uni00A0/uni00A0(Continued)\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n42\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\ntreatment completion. The remaining 23 patients (11 in the MET group and\n12 in the COMBI group) attended an IVF after treatment completion\nSelective reporting (re-\nporting bias)\nLow risk The study protocol is available, and all of the study's pre-specified outcomes\nhave been reported in the results\nhttps://clinicaltrials.gov/ct2/show/NCT03353948\nOther bias Low risk We did not identify any other potential sources of bias in the study, and we\njudged low risk for other potential sources of bias\nSalamun 2018/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Evaluator-blinded, randomised controlled trial\nParticipants • Setting: Australian\n• Inclusion: obese (BMI ≥ 30 kg/m/two.sups) female patients aged 18 to 37 years, intending to commence their\nIVF, ICSI, or cryo-stored embryo transfer treatment at RPAH Fertility Unit\n• Exclusion: current psychiatric condition (i.e. bulimia nervosa, overt psychosis, severe depression, drug\nor alcohol abuse); significant physical condition (i.e. acute cerebrovascular or cardiovascular disease,\nmalignancy, significant hepatic or renal dysfunction, musculoskeletal disease); endocrine condition\nother than polycystic ovarian syndrome (PCOS) (i.e. type 1 diabetes, uncontrolled thyroid disease,\nCushing’s syndrome, hyperprolactinaemia (> 450 IU L –1)); pancreatitis; porphyria; recent (within 3\nmonths) participation in treatment known to affect diet or body weight; unable to follow both verbal\nand written English instructions; unwilling to suspend fertility treatment for up to 3 months\nInterventions Comparison\n• Intervention (n = 27): 12-week intervention consisting of a very low-energy diet for the first 6 weeks\nfollowed by a hypocaloric diet, combined with a weekly group multi-disciplinary programme\n• Control (n = 22): received recommendations for weight loss and the same printed material as the in-\ntervention group\nOutcomes Clinical pregnancy rate\nLive birth\nChanges in anthropometric measures (weight, BMI, and waist circumference (WC))\nMiscarriage rate\nNotes Conflicts of interest: no\nFunding: not mentioned.\nDate study was conducted: February 2007\nClinical trial registration number: 12606000448549\nTrial authors contacted: KA Sim\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk The code was prepared before study start, as the allocation was performed us-\ning sealed envelopes\nSim 2014/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n43\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAllocation concealment\n(selection bias)\nLow risk Randomisation was done by the sequentially numbered, opaque-sealed enve-\nlope method\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nHigh risk The dietician, midwives, counsellor, fertility fellow, and participants were\naware of randomisation, but fertility specialists were not\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk The fertility fellow who was aware of randomisation was not involved with cy-\ncle management and did not perform any assisted conception procedures for\nthese patients. The dietician, midwives, counsellor, fertility fellow, and partici-\npants were aware of randomisation, but fertility specialists and patients were\nnot. This may have affected detection bias\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nHigh risk Very small study (26 versus 22). Missing outcome data problematic, especially\nfor weight loss data as a 20% loss can have a lot of impact on the outcomes./uni00A0\n• An estimated 86 patients were identified in consultation at the fertility unit\nand were approached by the research leader for discussion of participation\nin the study. Forty-nine were screened for eligibility, and 37 chose not to\nparticipate. The physicians identifying patients referred only 86 for an ini-\ntial discussion; it was estimated that more were eligible. All of the 49 partic-\nipants who entered the trial completed a baseline assessment. 6 separate\nweight loss intervention programmes were run, with groups of participants\nvarying in number between 3 and 8. At 12 weeks, 10 (20%) participants had\nwithdrawn or dropped out of the trial. No participants reported any serious\nadverse events during the dietary intervention. There were no statistically\nsignificant differences between completers and dropouts in both groups in\nterms of pregnancy rates, fertility treatment outcomes, or maternal and fetal\ncomplications (results not shown)\nSelective reporting (re-\nporting bias)\nLow risk The study protocol is available, and all of the study's pre-specified outcomes\nhave been reported in the results\nhttps://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=81639\nOther bias Low risk We did not identify any other potential sources of bias in the study, and we\njudged low risk for other potential sources of bias\nSim 2014/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods A randomised, placebo-controlled, double-blind study\nParticipants • Setting: England\n• Inclusion: anovulatory PCOS and BMI ≥ 30 kg/m/two.sups, between 18 and 39 years of age inclusive, a desire to\nconceive, presence of ≥ 1 patent fallopian tube and normal semen analysis from male partner. All par-\nticipants had normal serum prolactin concentrations; thyroid, renal, and liver function; and haema-\ntological indices, including serum B12 concentrations\n• Exclusion: concurrent hormone therapy within the previous 6 weeks; any chronic disease that could\ninterfere with absorption, distribution, metabolism, or excretion of metformin; renal or liver disease.\nPatients with significant systemic disease or diabetes (type 1 or 2) were excluded. Patients with irreg-\nular menstrual bleeding were thoroughly assessed to exclude pathology of the genital tract other than\nPCOS, and a negative pregnancy test was a prerequisite for commencing treatment\nInterventions Comparison\nTang 2006/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n44\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Intervention: metformin (850 mg) twice daily over 6 months (n = 69)\n• Control: placebo over 6 months (n = 74)\nAll received the same advice from a dietician\nOutcomes Change in anthropometric measurements (BMI, WHR)\nTestosterone\nSHBG\nPregnancy rate\nNotes Randomised: 143 patients: 69 metformin (56 completed) and 74 placebo (66 completed)\nConflicts of interest: not mentioned\nFunding: not mentioned\nDate study was conducted: 1999\nClinical trial registration number: not found\nTrial authors contacted: Adam H. Balen\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk A block-of-four randomisation technique was performed using random tables\nAllocation concealment\n(selection bias)\nLow risk Double-blind, placebo tablets for metformin were identical in appearance (size\nand colour) to metformin.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk The randomisation process was carried out by the clinical trials office in the\npharmacy department and blinded to patients and investigators.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk The randomisation process was carried out by the clinical trials office in the\npharmacy department and blinded to patients and investigators.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk • A total of 8 centres took part in the recruitment process. A total of 183 women\nwere screened for inclusion in the study. Of these, 40 women were exclud-\ned due to previously undiagnosed tubal disease or coexisting male factor in-\nfertility. As a result, a total of 143 subjects were randomised to receive met-\nformin (n = 69) or to receive placebo (n = 74) (Fig. 1). In the metformin arm,\n13 participants withdrew within the first 4 months of the trial (11 due to side\neffects and 2 due to spontaneous pregnancies). 8 women withdrew from the\nplacebo arm (6 due to ‘side effects’ and 2 due to spontaneous pregnancies)\nwithin the first 2 months of the study. The difference in dropout rates, exclud-\ning those due to pregnancy (metformin 15.9% versus placebo 8.0%) was not\nsignificant (P = 0.229; 95% CI –2.69 to 18.5). At the end of the study, the num-\nbers of participants who completed the trial in the metformin and placebo\narms were 56 and 66, respectively. Compliance was high and the dropout rate\nrelatively low, as these patients were motivated by a desire to conceive and\nthe knowledge that they needed to attain BMI < 30 kg/m/two.sups to qualify for ovu-\nlation induction\nSelective reporting (re-\nporting bias)\nHigh risk The study protocol is unavailable. It is not described in sufficient detail to al-\nlow a definitive judgement\nTang 2006/uni00A0/uni00A0(Continued)\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n45\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOther bias Low risk We did not identify any other potential sources of bias in the study, and we\njudged low risk for other potential sources of bias\nTang 2006/uni00A0/uni00A0(Continued)\nBMI: body mass index.\nCC: clomiphene citrate.\nCFD: conventional food-based diet.\nEQ-5D: EuroQoL Group Quality of Life Questionnaire based on 5 dimensions.\nFSH: follicle-stimulating hormone.\nICSI: intracytoplasmic sperm injection.\nIDS-SR: Inventory of Depressive Symptomatology-Self-Report.\nIVF: in vitro fertilisation.\nIWL: intensive weight loss intervention.\nMEN2: multiple endocrine neoplasia type 2.\nMET: metformin.\nOGTT: oral glucose tolerance test.\nPCOS: polycystic ovarian syndrome.\nRCT: randomised controlled trial.\nSCN: standard of care nutrition counselling.\nSD: standard deviation.\nSHBG: sex hormone-blinding globulin.\nWC: waist circumference.\n/uni00A0\nCharacteristics of excluded studies [ordered by study ID]\n/uni00A0\nStudy Reason for exclusion\nAsemi 2014 Wrong patient population\nAsemi 2014a Wrong patient population\nAsemi 2015 Wrong patient population\nAshoush 2016 Wrong patient population\nAttarzadeh 2012 Wrong patient population\nBaillargeon 2004 Wrong patient population\nBecker 2015 Wrong patient population\nCheraghi 2014 Wrong patient population\nGambineri 2004 Wrong patient population\nHanjalic-Beck 2010 Wrong patient population\nJanez 2017 Wrong patient population\nJanez 2018 Wrong patient population\nJensterle 2017 Wrong patient population\nKarsten 2018 Wrong outcome\nKocak 2002 Wrong patient population\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n46\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nStudy Reason for exclusion\nLegro 2007 Wrong patient population\nLiao 2011 Wrong patient population\nMa 2007 Wrong patient population\nMoran 2006 Wrong patient population\nMorin-Papunen 1998 Wrong patient population\nMorin-Papunen 2000 Wrong patient population\nMorin-Papunen 2012 Wrong patient population\nPasquali 1986 Wrong patient population\nPasquali 2000 Wrong patient population\nPastore 2011 Wrong patient population\nPenna 2005 Wrong patient population\nPetranyi 2011 Wrong patient population\nPourmatroud 2015 Wrong patient population\nPremawardhana 1994 Wrong patient population\nQin 2016 Wrong patient population\nQublan 2007 Wrong patient population\nSeibel 2008 Wrong patient population\nShahebrahimi 2016 Wrong patient population\nSiebert 2009 Wrong patient population\nSonmez 2005 Wrong patient population\nSordia-Hernandez 2016 Wrong patient population\nSorensen 2012 Wrong patient population\nStamets 2004 Wrong patient population\nSwora-Cwynar 2016 Wrong patient population\nTang 2006a Wrong patient population\nToscani 2011 Wrong patient population\nTsagareli 2006 Wrong patient population\nTurner-McGrievy 2014 Wrong patient population\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n47\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nStudy Reason for exclusion\nVandermolen 2001 Wrong patient population\nVanky 2004 Wrong patient population\nVan Oers 2016a Wrong outcome\nVan Oers 2017 Wrong outcome\nvan Oers 2018 Wrong outcome\nvan Santbrink 2005 Wrong patient population\nVigerust 2012 Wrong patient population\nVosnakis 2013 Wrong patient population\nWiweko 2017 Wrong patient population\nYang 2005 Wrong patient population\nYang 2017 Wrong patient population\nYin 2018 Wrong patient population\nZhang 2015 Wrong patient population\nZhang 2017 Wrong study design\nZheng 2013 Wrong patient population\n/uni00A0\nCharacteristics of studies awaiting classification [ordered by study ID]\n/uni00A0\nMethods RCT\nParticipants Obese infertile women\nInterventions Comparison\n• Intervention: lifestyle intervention without fertility treatment for the first 6 months\n• Control: standard fertility treatment\nParticipants were followed for 18 months or until the end of pregnancy\nOutcomes Pregnancy rate\nSpontaneous pregnancy rate\nLive birth\nWeight loss\nNotes This study did not report the number of participants\nDuval 2015/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n48\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\n/uni00A0\nMethods RCT\nParticipants 68 obese infertile PCOS patients\nInterventions Group 1: patients received metformin (500 mg tds) from day 2 of same index treatment menstrual\ncycle and continued until the day of administration of trigger dose of HCG\nGroup 2: control (no drug)\nOutcomes Serum levels of T\nDHAS\nSHBG\nFBS/FBI ratio\nFertilization and cleavage rates\nClinical pregnancy rate\nImplantation rate\nMiscarriage rate\nNotes Metformin reduced insulin resistance in obese PCOS patients with a statistically significant positive\neffect on folliculogenesis (follicular synchrony) and embryo quality (good quality embryos and im-\nplantation rates)\nEgbase 2001/uni00A0\n/uni00A0\n/uni00A0\nMethods RCT\nParticipants Obese women with infertility with polycystic ovary syndrome\nInterventions Control group: metformin\nObservation group: auxiliary acupuncture\n75 cases in each group\nOutcomes Cycle ovulation rate\nPregnancy rate\nNotes Cycle ovulation rate and pregnancy rate of the observation (auxiliary acupuncture) group were sig-\nnificantly better than those of the control (metformin) group\nLi 2015/uni00A0\n/uni00A0\n/uni00A0\nMethods RCT\nParticipants 46 infertile women with PCOS, between 22 and 39 years of age; mean BMI 38.1, range 28.1 to 49.0\nkg/m/two.sups\nPfüller 2004/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n49\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nInterventions Group 1: M and lifestyle modification\nGroup 2: Lifestyle modification only; patients received placebo\nOutcomes In the metformin group, mean BMI decreased significantly (-5.6 kg vs.-2.2 kg). Neither metformin\nnor placebo modified levels of testosterone (T), free T, FAI (free androgen index), LH/FSH ratio. After\ntreatment, SHBG concentrations were significantly increased in the metformin-taking group (+7.5\nvs. +3.2). Cholesterol, LDL, and triglycerides have not revealed any changes in either group. Serum\nHDL levels were significantly higher in the drug-treated group (+3.7 vs –1.7)\nNotes /uni00A0\nPfüller 2004/uni00A0/uni00A0(Continued)\nBMI: body mass index.\nDHAS: dehydroepiandrosterone sulphate.\nFBS/FBI: fasting blood sugar/fasting blood insulin.\nFSH: follicle-stimulating hormone.\nHCG: human chorionic gonadotropin.\nHDL: high-density lipoprotein.\nLDL: low-density lipoprotein.\nLH: luteinising hormone.\nPCOS: polycystic ovarian syndrome.\nRCT: randomised controlled trial.\nSHBG: sex hormone-binding globulin.\n/uni00A0\n/uni00A0\nD A T A /uni00A0 A N D /uni00A0 A N A L Y S E S\n/uni00A0\nComparison 1. /uni00A0 Non-pharmacological intervention versus no intervention or placebo\nOutcome or subgroup\ntitle\nNo. of studies No. of partici-\npants\nStatistical method Effect size\n1.1 Live birth 3 918 Odds Ratio (M-H, Fixed, 95% CI) 0.85 [0.65, 1.11]\n1.2 Ongoing pregnancy 1 564 Odds Ratio (M-H, Fixed, 95% CI) 0.81 [0.58, 1.13]\n1.3 Miscarriage 3 917 Odds Ratio (M-H, Fixed, 95% CI) 1.54 [0.99, 2.39]\n1.4 Clinical pregnancy 3 917 Odds Ratio (M-H, Fixed, 95% CI) 1.06 [0.81, 1.40]\n1.5 BMI change 2 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only\n/uni00A0\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n50\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 1.1. /uni00A0 Comparison 1: Non-pharmacological intervention\nversus no intervention or placebo, Outcome 1: Live birth\nStudy or Subgroup\nEinarsson 2017Mutsaerts 2016Sim 2014\nTotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 9.02, df = 2 (P = 0.01); I² = 78%\nTest for overall effect: Z = 1.18 (P = 0.24)\nTest for subgroup differences: Not applicable\nnon-pharmacological interventionEvents\n4512312\n180\nTotal\n15228027\n459\nNo interventionEvents\n421533\n198\nTotal\n15328422\n459\nWeight\n25.3%73.1%1.6%\n100.0%\nOdds RatioM-H, Fixed, 95% CI\n1.11 [0.68 , 1.83]0.67 [0.48 , 0.93]5.07 [1.21 , 21.28]\n0.85 [0.65 , 1.11]\nOdds RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Increased with no interventionIncreased with non-pharmacological intervention\nRisk of BiasA\n+++\nB\n+++\nC\n---\nD\n?-?\nE\n++-\nF\n+++\nG\n+++\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nAnalysis 1.2. /uni00A0 Comparison 1: Non-pharmacological intervention\nversus no intervention or placebo, Outcome 2: Ongoing pregnancy\nStudy or Subgroup\nMutsaerts 2016\nTotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.25 (P = 0.21)\nTest for subgroup differences: Not applicable\nnon-pharmacological interventionEvents\n150\n150\nTotal\n280\n280\nNo interventionEvents\n167\n167\nTotal\n284\n284\nWeight\n100.0%\n100.0%\nOdds RatioM-H, Fixed, 95% CI\n0.81 [0.58 , 1.13]\n0.81 [0.58 , 1.13]\nOdds RatioM-H, Fixed, 95% CI\n0.2 0.51 2 5Increased with no interventionIncreased with non-pharmacological intervention\nRisk of BiasA\n+\nB\n+\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nAnalysis 1.3. /uni00A0 Comparison 1: Non-pharmacological intervention\nversus no intervention or placebo, Outcome 3: Miscarriage\nStudy or Subgroup\nEinarsson 2017Mutsaerts 2016Sim 2014\nTotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 0.54, df = 2 (P = 0.76); I² = 0%\nTest for overall effect: Z = 1.92 (P = 0.06)\nTest for subgroup differences: Not applicable\nnon-pharmacological interventionEvents\n8417\n56\nTotal\n15228026\n458\nNo interventionEvents\n5276\n38\nTotal\n15328422\n459\nWeight\n14.6%70.7%14.7%\n100.0%\nOdds RatioM-H, Fixed, 95% CI\n1.64 [0.53 , 5.15]1.63 [0.97 , 2.74]0.98 [0.27 , 3.52]\n1.54 [0.99 , 2.39]\nOdds RatioM-H, Fixed, 95% CI\n0.020.1 1 10 50Increased with no interventionIncreased with non-pharmacological intervention\nRisk of BiasA\n+++\nB\n+++\nC\n---\nD\n?-?\nE\n++-\nF\n+++\nG\n+++\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n51\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\n/uni00A0\nAnalysis 1.4. /uni00A0 Comparison 1: Non-pharmacological intervention\nversus no intervention or placebo, Outcome 4: Clinical pregnancy\nStudy or Subgroup\nEinarsson 2017Mutsaerts 2016Sim 2014\nTotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 7.36, df = 2 (P = 0.03); I² = 73%\nTest for overall effect: Z = 0.45 (P = 0.65)\nTest for subgroup differences: Not applicable\nnon-pharmacological interventionEvents\n5317513\n241\nTotal\n15228026\n458\nNo interventionEvents\n471863\n236\nTotal\n15328422\n459\nWeight\n30.1%68.3%1.6%\n100.0%\nOdds RatioM-H, Fixed, 95% CI\n1.21 [0.75 , 1.95]0.88 [0.62 , 1.24]6.33 [1.50 , 26.73]\n1.06 [0.81 , 1.40]\nOdds RatioM-H, Fixed, 95% CI\n0.10.20.51 2 510Increased with no interventionIncreased with non-pharmacological intervention\nRisk of BiasA\n+++\nB\n+++\nC\n---\nD\n?-?\nE\n++-\nF\n+++\nG\n+++\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nAnalysis 1.5. /uni00A0 Comparison 1: Non-pharmacological intervention\nversus no intervention or placebo, Outcome 5: BMI change\nStudy or Subgroup\nEinarsson 2017Sim 2014\nTest for subgroup differences: Not applicable\nnon-pharmacological interventionMean\n-3.25-2.4\nSD\n2.421.6\nTotal\n15226\nNo interventionMean\n0.45-0.6\nSD\n0.721.3\nTotal\n15317\nMean Difference\nIV, Fixed, 95% CI\n-3.70 [-4.10 , -3.30]-1.80 [-2.67 , -0.93]\nMean Difference\nIV, Fixed, 95% CI\n-10-5 0 5 10Increased with no interventionIncreased with non-pharmacological intervention\nRisk of BiasA\n++\nB\n++\nC\n--\nD\n??\nE\n+-\nF\n++\nG\n++\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nComparison 2. /uni00A0 Non-pharmacological intervention versus non-pharmacological intervention\nOutcome or subgroup\ntitle\nNo. of studies No. of partici-\npants\nStatistical method Effect size\n2.1 Live birth 1 11 Odds Ratio (M-H, Fixed, 95% CI) 11.00 [0.43, 284.30]\n2.2 Clinical pregnancy 1 11 Odds Ratio (M-H, Fixed, 95% CI) 11.00 [0.43, 284.30]\n2.3 BMI change 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only\n2.4 Weight change 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only\n2.5 Mental health 1 11 Mean Difference (IV, Fixed, 95% CI) -7.00 [-13.92, -0.08]\n2.6 Quality of life 1 11 Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.03, 0.15]\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n52\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 2.1. /uni00A0 Comparison 2: Non-pharmacological intervention\nversus non-pharmacological intervention, Outcome 1: Live birth\nStudy or Subgroup\nRothberg 2016\nTotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 1.45 (P = 0.15)Test for subgroup differences: Not applicable\nIntensive weight loss intervention (IWL)Events\n3\n3\nTotal\n6\n6\nStandard-of-care nutrition counseling (SCN)Events\n0\n0\nTotal\n5\n5\nWeight\n100.0%\n100.0%\nOdds RatioM-H, Fixed, 95% CI\n11.00 [0.43 , 284.30]\n11.00 [0.43 , 284.30]\nOdds RatioM-H, Fixed, 95% CI\n0.0010.11 10 1000Increased with SCNIncreased with IWL\nRisk of BiasA\n?\nB\n-\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk 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\n/uni00A0\n/uni00A0\nAnalysis 2.2. /uni00A0 Comparison 2: Non-pharmacological intervention versus\nnon-pharmacological intervention, Outcome 2: Clinical pregnancy\nStudy or Subgroup\nRothberg 2016\nTotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 1.45 (P = 0.15)Test for subgroup differences: Not applicable\nIntensive weight loss intervention (IWL)Events\n3\n3\nTotal\n6\n6\nStandard-of-care nutrition counselling (SCN)Events\n0\n0\nTotal\n5\n5\nWeight\n100.0%\n100.0%\nOdds RatioM-H, Fixed, 95% CI\n11.00 [0.43 , 284.30]\n11.00 [0.43 , 284.30]\nOdds RatioM-H, Fixed, 95% CI\n0.0010.11 10 1000Increased with SCNIncreased with IWL\nRisk of BiasA\n?\nB\n-\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk 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\n/uni00A0\n/uni00A0\nAnalysis 2.3. /uni00A0 Comparison 2: Non-pharmacological intervention\nversus non-pharmacological intervention, Outcome 3: BMI change\nStudy or Subgroup\nRothberg 2016\nIntensive weight loss intervention (IWL)Mean\n-5\nSD\n2\nTotal\n6\nStandard-of-care nutrition counselling (SCN).Mean\n-2\nSD\n2\nTotal\n5\nMean DifferenceIV, Fixed, 95% CI\n-3.00 [-5.37 , -0.63]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Increased with SCNIncreased with IWL\nRisk of BiasA\n?\nB\n-\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk 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\n/uni00A0\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n53\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 2.4. /uni00A0 Comparison 2: Non-pharmacological intervention\nversus non-pharmacological intervention, Outcome 4: Weight change\nStudy or Subgroup\nRothberg 2016\nIntensive weight loss intervention (IWL)Mean\n-14\nSD\n6\nTotal\n6\nStandard-of-care nutrition counselling (SCN)Mean\n-5\nSD\n5\nTotal\n5\nMean DifferenceIV, Fixed, 95% CI\n-9.00 [-15.50 , -2.50]\nMean DifferenceIV, Fixed, 95% CI\n-10-50 5 10Increased with SCNIncreased with IWL\nRisk of BiasA\n?\nB\n-\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk 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\n/uni00A0\n/uni00A0\nAnalysis 2.5. /uni00A0 Comparison 2: Non-pharmacological intervention\nversus non-pharmacological intervention, Outcome 5: Mental health\nStudy or Subgroup\nRothberg 2016\nTotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.98 (P = 0.05)Test for subgroup differences: Not applicable\nIntensive weight loss intervention (IWL)Mean\n-5\nSD\n4\nTotal\n6\n6\nStandard-of-care nutrition counselling (SCN)Mean\n2\nSD\n7\nTotal\n5\n5\nWeight\n100.0%\n100.0%\nMean DifferenceIV, Fixed, 95% CI\n-7.00 [-13.92 , -0.08]\n-7.00 [-13.92 , -0.08]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Increased with IWLIncreased with SCN\nRisk of BiasA\n?\nB\n-\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk 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\n/uni00A0\n/uni00A0\nAnalysis 2.6. /uni00A0 Comparison 2: Non-pharmacological intervention\nversus non-pharmacological intervention, Outcome 6: Quality of life\nStudy or Subgroup\nRothberg 2016\nTotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.33 (P = 0.18)Test for subgroup differences: Not applicable\nIntensive weight loss intervention (IWL)Mean\n0.05\nSD\n0.08\nTotal\n6\n6\nStandard-of-care nutrition counselling (SCN)Mean\n-0.01\nSD\n0.07\nTotal\n5\n5\nWeight\n100.0%\n100.0%\nMean DifferenceIV, Fixed, 95% CI\n0.06 [-0.03 , 0.15]\n0.06 [-0.03 , 0.15]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Increased with SCNIncreased with IWL\nRisk of BiasA\n?\nB\n-\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk 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\n/uni00A0\n/uni00A0\nComparison 3. /uni00A0 Pharmacological intervention versus pharmacological intervention\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n3.1 Miscarriage 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only\n3.2 Adverse event ( nausea) 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only\n3.3 Adverse event (diarrhoea) 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n54\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n3.4 Adverse event (headache) 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only\n3.5 Clinical pregnancy 2 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only\n3.5.1 Metformin plus liraglutide vs\nmetformin\n1 28 Odds Ratio (M-H, Fixed, 95% CI) 3.67 [0.70, 19.12]\n3.5.2 Metformin + CC + L-carnitine\nvs metformin + CC + placebo\n1 274 Odds Ratio (M-H, Fixed, 95% CI) 5.56 [2.57, 12.02]\n3.6 BMI change 2 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n3.6.1 Metformin + CC + L-carnitine\nvs metformin + CC + placebo\n1 274 Mean Difference (IV, Fixed, 95%\nCI)\n-0.30 [-1.17, 0.57]\n3.6.2 Metformin plus liraglutide vs\nmetformin\n1 28 Mean Difference (IV, Fixed, 95%\nCI)\n2.10 [-0.42, 4.62]\n3.7 Weight loss 1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n3.7.1 Dexfenfluramine vs placebo 1 21 Mean Difference (IV, Fixed, 95%\nCI)\n-0.10 [-2.77, 2.57]\n3.8 Percent of total body fat 1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n3.8.1 Metformin plus liraglutide vs\nmetformin\n1 28 Mean Difference (IV, Fixed, 95%\nCI)\n-0.50 [-4.65, 3.65]\n3.9 Glucose test (OGTT) 1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n3.9.1 Metformin plus liraglutide vs\nmetformin\n1 28 Mean Difference (IV, Fixed, 95%\nCI)\n-0.30 [-1.90, 1.30]\n3.10 Free testosterone 2 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n3.10.1 Metformin plus liraglutide vs\nmetformin\n1 28 Mean Difference (IV, Fixed, 95%\nCI)\n0.80 [-3.00, 4.60]\n3.10.2 Metformin + CC + L-carnitine\nvs metformin + CC + placebo\n1 274 Mean Difference (IV, Fixed, 95%\nCI)\n-1.76 [-2.06, -1.46]\n3.11 Total testosterone 1 28 Mean Difference (IV, Fixed, 95%\nCI)\n0.20 [-0.21, 0.61]\n3.11.1 Metformin plus liraglutide vs\nmetformin\n1 28 Mean Difference (IV, Fixed, 95%\nCI)\n0.20 [-0.21, 0.61]\n3.12 SHBG 1 28 Mean Difference (IV, Fixed, 95%\nCI)\n0.30 [-12.22, 12.82]\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n55\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n3.12.1 Metformin plus liraglutide vs\nmetformin\n1 28 Mean Difference (IV, Fixed, 95%\nCI)\n0.30 [-12.22, 12.82]\n/uni00A0\n/uni00A0\nAnalysis 3.1. /uni00A0 Comparison 3: Pharmacological intervention\nversus pharmacological intervention, Outcome 1: Miscarriage\nStudy or Subgroup\nEl 2019\nTest for subgroup differences: Not applicable\nMetformin combined with CC + L-carnitineEvents\n7\nTotal\n138\nMetformin combined with CCEvents\n2\nTotal\n136\nOdds RatioM-H, Fixed, 95% CI\n3.58 [0.73 , 17.55]\nOdds RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Increased with met+CCIncreased with met+CC+L-carnitine\nRisk of BiasA\n+\nB\n+\nC\n+\nD\n+\nE\n+\nF\n+\nG\n+\nRisk 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\n/uni00A0\n/uni00A0\nAnalysis 3.2. /uni00A0 Comparison 3: Pharmacological intervention versus\npharmacological intervention, Outcome 2: Adverse event ( nausea)\nStudy or Subgroup\nSalamun 2018\nTest for subgroup differences: Not applicable\nMetformin combined with LiragutideEvents\n5\nTotal\n14\nMetforminEvents\n1\nTotal\n14\nOdds RatioM-H, Fixed, 95% CI\n7.22 [0.72 , 72.70]\nOdds RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Increased with metforminIncreased with metformin + liragutide\nRisk of BiasA\n?\nB\n-\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nAnalysis 3.3. /uni00A0 Comparison 3: Pharmacological intervention versus\npharmacological intervention, Outcome 3: Adverse event (diarrhoea)\nStudy or Subgroup\nSalamun 2018\nTest for subgroup differences: Not applicable\nMetformin combined with LiragutideEvents\n0\nTotal\n14\nMetforminEvents\n1\nTotal\n14\nOdds RatioM-H, Fixed, 95% CI\n0.31 [0.01 , 8.29]\nOdds RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Increased with metformin + LiragutideIncreased with metformin\nRisk of BiasA\n?\nB\n-\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n56\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\n/uni00A0\nAnalysis 3.4. /uni00A0 Comparison 3: Pharmacological intervention versus\npharmacological intervention, Outcome 4: Adverse event (headache)\nStudy or Subgroup\nSalamun 2018\nTest for subgroup differences: Not applicable\nMetformin combined with LiragutideEvents\n2\nTotal\n14\nMetforminEvents\n0\nTotal\n14\nOdds RatioM-H, Fixed, 95% CI\n5.80 [0.25 , 132.56]\nOdds RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Increased with metforminIncreased with metformin + liragutide\nRisk of BiasA\n?\nB\n-\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nAnalysis 3.5. /uni00A0 Comparison 3: Pharmacological intervention versus\npharmacological intervention, Outcome 5: Clinical pregnancy\nStudy or Subgroup\n3.5.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 1.54 (P = 0.12)\n3.5.2 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)\nTest for subgroup differences: Chi² = 0.20, df = 1 (P = 0.65), I² = 0%\nMetformin with co-interventionsEvents\n7\n7\n39\n39\nTotal\n1414\n138138\nMetformin/metformin with CC + placeboEvents\n3\n3\n9\n9\nTotal\n1414\n136136\nWeight\n100.0%100.0%\n100.0%100.0%\nOdds RatioM-H, Fixed, 95% CI\n3.67 [0.70 , 19.12]3.67 [0.70 , 19.12]\n5.56 [2.57 , 12.02]5.56 [2.57 , 12.02]\nOdds RatioM-H, Fixed, 95% CI\n0.0010.11 10 1000Increased with metformin/metformin + CC + placeboIncreased with metformin + co-interventions\nRisk of BiasA\n?\n+\nB\n-\n+\nC\n-\n+\nD\n-\n+\nE\n+\n+\nF\n+\n+\nG\n+\n+\nRisk 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\n/uni00A0\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n57\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 3.6. /uni00A0 Comparison 3: Pharmacological intervention\nversus pharmacological intervention, Outcome 6: BMI change\nStudy or Subgroup\n3.6.1 Metformin + CC + L-carnitine vs metformin + CC + placeboEl 2019Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.68 (P = 0.50)\n3.6.2 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.63 (P = 0.10)\nTest for subgroup differences: Chi² = 3.11, df = 1 (P = 0.08), I² = 67.9%\nMetformin combined with co-medicationMean\n32.2\n35.1\nSD\n4.1\n3.5\nTotal\n138138\n1414\nMetformin/Metformin combined with co-medicationMean\n32.5\n33\nSD\n3.2\n3.3\nTotal\n136136\n1414\nWeight\n100.0%100.0%\n100.0%100.0%\nMean DifferenceIV, Fixed, 95% CI\n-0.30 [-1.17 , 0.57]-0.30 [-1.17 , 0.57]\n2.10 [-0.42 , 4.62]2.10 [-0.42 , 4.62]\nMean DifferenceIV, Fixed, 95% CI\n-100-500 50 100Increased with metformin/metformin+co-medicationIncreased with metformin+co-medication\nRisk of BiasA\n+\n?\nB\n+\n-\nC\n+\n-\nD\n+\n-\nE\n+\n+\nF\n+\n+\nG\n+\n+\nRisk 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\n/uni00A0\n/uni00A0\nAnalysis 3.7. /uni00A0 Comparison 3: Pharmacological intervention\nversus pharmacological intervention, Outcome 7: Weight loss\nStudy or Subgroup\n3.7.1 Dexfenfluramine vs placeboGalletly 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.07 (P = 0.94)\nTest for subgroup differences: Not applicable\nDexfenfluramineMean\n3.21\nSD\n3.09\nTotal\n1010\nPlaceboMean\n3.31\nSD\n3.15\nTotal\n11\n11\nWeight\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-0.10 [-2.77 , 2.57]-0.10 [-2.77 , 2.57]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Increased with dexfenfluramine + placeboIncreased with placebo + dexfenfluramine\nRisk of BiasA\n?\nB\n?\nC\n?\nD\n?\nE\n?\nF\n-\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nAnalysis 3.8. /uni00A0 Comparison 3: Pharmacological intervention versus\npharmacological intervention, Outcome 8: Percent of total body fat\nStudy or Subgroup\n3.8.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.24 (P = 0.81)\nMetformin combined with LiragutideMean\n43\nSD\n5.5\nTotal\n1414\nMetforminMean\n43.5\nSD\n5.7\nTotal\n1414\nWeight\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-0.50 [-4.65 , 3.65]-0.50 [-4.65 , 3.65]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Increased with metformin + LiragutideIncreased with metformin\n/uni00A0\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n58\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 3.9. /uni00A0 Comparison 3: Pharmacological intervention versus\npharmacological intervention, Outcome 9: Glucose test (OGTT)\nStudy or Subgroup\n3.9.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.37 (P = 0.71)\nTest for subgroup differences: Not applicable\nMetformin combined with LiragutideMean\n6.3\nSD\n2\nTotal\n1414\nMetforminMean\n6.6\nSD\n2.3\nTotal\n1414\nWeight\n100.0%100.0%\nMean DifferenceIV, Fixed, 95% CI\n-0.30 [-1.90 , 1.30]-0.30 [-1.90 , 1.30]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Increased with metformin + LiragutideIncreased with metformin\nRisk of BiasA\n?\nB\n-\nC\n-\nD\n-\nE\n+\nF\n+\nG\n+\nRisk 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\n/uni00A0\n/uni00A0\nAnalysis 3.10. /uni00A0 Comparison 3: Pharmacological intervention versus\npharmacological intervention, Outcome 10: Free testosterone\nStudy or Subgroup\n3.10.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.41 (P = 0.68)\n3.10.2 Metformin + CC + L-carnitine vs metformin + CC + placeboEl 2019Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 11.52 (P < 0.00001)\nTest for subgroup differences: Chi² = 1.73, df = 1 (P = 0.19), I² = 42.3%\nMetformin combined with LiragutideMean\n8.9\n1.45\nSD\n6.3\n1.11\nTotal\n1414\n138138\nMetforminMean\n8.1\n3.21\nSD\n3.6\n1.4\nTotal\n1414\n136136\nWeight\n100.0%100.0%\n100.0%100.0%\nMean DifferenceIV, Fixed, 95% CI\n0.80 [-3.00 , 4.60]0.80 [-3.00 , 4.60]\n-1.76 [-2.06 , -1.46]-1.76 [-2.06 , -1.46]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Increased with metformin + co-medicationsIncreased with metformin/metformin+CC+placebo\nRisk of BiasA\n?\n+\nB\n-\n+\nC\n-\n+\nD\n-\n+\nE\n+\n+\nF\n+\n+\nG\n+\n+\nRisk 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\n/uni00A0\n/uni00A0\nAnalysis 3.11. /uni00A0 Comparison 3: Pharmacological intervention versus\npharmacological intervention, Outcome 11: Total testosterone\nStudy or Subgroup\n3.11.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.96 (P = 0.34)\nTotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.96 (P = 0.34)\nTest for subgroup differences: Not applicable\nMetformin combined with LiragutideMean\n1.5\nSD\n0.6\nTotal\n1414\n14\nMetforminMean\n1.3\nSD\n0.5\nTotal\n1414\n14\nWeight\n100.0%100.0%\n100.0%\nMean Difference\nIV, Fixed, 95% CI\n0.20 [-0.21 , 0.61]0.20 [-0.21 , 0.61]\n0.20 [-0.21 , 0.61]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Increased with metformin + LiragutideIncreased with metformin\n/uni00A0\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n59\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 3.12. /uni00A0 Comparison 3: Pharmacological intervention\nversus pharmacological intervention, Outcome 12: SHBG\nStudy or Subgroup\n3.12.1 Metformin plus liraglutide vs metforminSalamun 2018Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.05 (P = 0.96)\nTotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.05 (P = 0.96)\nTest for subgroup differences: Not applicable\nMetformin combined with LiragutideMean\n36\nSD\n13.4\nTotal\n1414\n14\nMetforminMean\n35.7\nSD\n19.8\nTotal\n1414\n14\nWeight\n100.0%100.0%\n100.0%\nMean Difference\nIV, Fixed, 95% CI\n0.30 [-12.22 , 12.82]0.30 [-12.22 , 12.82]\n0.30 [-12.22 , 12.82]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Increased with metformin + LiragutideIncreased with metformin\n/uni00A0\n/uni00A0\nComparison 4. /uni00A0 Pharmacological intervention versus no intervention/placebo\nOutcome or subgroup\ntitle\nNo. of studies No. of partici-\npants\nStatistical method Effect size\n4.1 Live birth 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only\n4.2 Miscarriage 1 /uni00A0 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only\n4.3 Adverse event (GI) 1 65 Odds Ratio (M-H, Fixed, 95% CI) 0.91 [0.32, 2.57]\n4.4 Clinical pregnancy 2 96 Odds Ratio (M-H, Fixed, 95% CI) 2.67 [0.90, 7.93]\n4.5 BMI change 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only\n4.6 WHR 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only\n4.7 Total testosterone 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only\n4.8 Free testosterone 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only\n4.9 SHBG 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only\n/uni00A0\n/uni00A0\nAnalysis 4.1. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 1: Live birth\nStudy or Subgroup\nJohnson 2010\nMetforminEvents\n7\nTotal\n32\nPlaceboEvents\n5\nTotal\n33\nOdds RatioM-H, Fixed, 95% CI\n1.57 [0.44 , 5.57]\nOdds RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Increased with placeboIncreased with metformin\nRisk of BiasA\n+\nB\n+\nC\n+\nD\n+\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n60\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.2. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 2: Miscarriage\nStudy or Subgroup\nJohnson 2010\nMetformin/L-carnitineEvents\n1\nTotal\n32\nPlaceboEvents\n2\nTotal\n33\nOdds RatioM-H, Fixed, 95% CI\n0.50 [0.04 , 5.80]\nOdds RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Increased with placeboIncreased with metformin/L-carnitine\nRisk of BiasA\n+\nB\n+\nC\n+\nD\n+\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nAnalysis 4.3. /uni00A0 Comparison 4: Pharmacological intervention\nversus no intervention/placebo, Outcome 3: Adverse event (GI)\nStudy or Subgroup\nJohnson 2010\nTotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.18 (P = 0.86)\nTest for subgroup differences: Not applicable\nmetforminEvents\n10\n10\nTotal\n32\n32\nplaceboEvents\n11\n11\nTotal\n33\n33\nWeight\n100.0%\n100.0%\nOdds RatioM-H, Fixed, 95% CI\n0.91 [0.32 , 2.57]\n0.91 [0.32 , 2.57]\nOdds RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Increased with placeboIncreased with metformin\n/uni00A0\n/uni00A0\nAnalysis 4.4. /uni00A0 Comparison 4: Pharmacological intervention\nversus no intervention/placebo, Outcome 4: Clinical pregnancy\nStudy or Subgroup\nJohnson 2010Khorram 2006\nTotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 1.94, df = 1 (P = 0.16); I² = 48%\nTest for overall effect: Z = 1.77 (P = 0.08)\nTest for subgroup differences: Not applicable\nMetforminEvents\n75\n12\nTotal\n3216\n48\nNo intervention/placeboEvents\n50\n5\nTotal\n3315\n48\nWeight\n91.7%8.3%\n100.0%\nOdds RatioM-H, Fixed, 95% CI\n1.57 [0.44 , 5.57]14.83 [0.74 , 295.97]\n2.67 [0.90 , 7.93]\nOdds RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Increased with no intervention/placeboIncreased with metformin\nRisk of BiasA\n++\nB\n+-\nC\n+?\nD\n+?\nE\n+?\nF\n+-\nG\n++\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n61\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.5. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 5: BMI change\nStudy or Subgroup\nTang 2006\nDiet combined metforminMean\n37.1\nSD\n5.04\nTotal\n69\nDiet combined placeboMean\n37.4\nSD\n6.3\nTotal\n74\nMean Difference\nIV, Fixed, 95% CI\n-0.30 [-2.16 , 1.56]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Increased with diet + metforminIncreased with diet + placebo\nRisk of BiasA\n+\nB\n+\nC\n+\nD\n+\nE\n+\nF\n-\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nAnalysis 4.6. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 6: WHR\nStudy or Subgroup\nTang 2006\nDiet combined with metforminMean\n111.1\nSD\n12.3\nTotal\n69\nDiet combined with placeboMean\n109.1\nSD\n13.4\nTotal\n74\nMean Difference\nIV, Fixed, 95% CI\n2.00 [-2.21 , 6.21]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Increased with diet+metforminIncreased with diet+placebo\nRisk of BiasA\n+\nB\n+\nC\n+\nD\n+\nE\n+\nF\n-\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nAnalysis 4.7. /uni00A0 Comparison 4: Pharmacological intervention\nversus no intervention/placebo, Outcome 7: Total testosterone\nStudy or Subgroup\nKhorram 2006\nMetformin plus clomiphene citrateMean\n51.8\nSD\n10\nTotal\n16\nClomiphene citrate onlyMean\n45.6\nSD\n5.9\nTotal\n15\nMean Difference\nIV, Fixed, 95% CI\n6.20 [0.46 , 11.94]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Increased with metformin + ccIncreased with cc only\nRisk of BiasA\n+\nB\n-\nC\n?\nD\n?\nE\n?\nF\n-\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n62\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.8. /uni00A0 Comparison 4: Pharmacological intervention\nversus no intervention/placebo, Outcome 8: Free testosterone\nStudy or Subgroup\nKhorram 2006\nMetformin plus clomiphene citrate/L-carnitineMean\n12.4\nSD\n2\nTotal\n16\nClomiphene citrate only/placeboMean\n11.7\nSD\n2.8\nTotal\n15\nMean DifferenceIV, Fixed, 95% CI\n0.70 [-1.02 , 2.42]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Increased with metformin + cc/L-carnitineIncreased with cc/placebo\nRisk of BiasA\n+\nB\n-\nC\n?\nD\n?\nE\n?\nF\n-\nG\n+\nRisk 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\n/uni00A0\n/uni00A0\nAnalysis 4.9. /uni00A0 Comparison 4: Pharmacological intervention versus no intervention/placebo, Outcome 9: SHBG\nStudy or Subgroup\nKhorram 2006\nMetformin plus clomiphene citrateMean\n25.4\nSD\n1.8\nTotal\n16\nClomiphene citrate onlyMean\n19.9\nSD\n2.9\nTotal\n15\nMean Difference\nIV, Fixed, 95% CI\n5.50 [3.79 , 7.21]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Increased with metformin + ccIncreased with cc only\nRisk of BiasA\n+\nB\n-\nC\n?\nD\n?\nE\n?\nF\n-\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(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\n/uni00A0\n/uni00A0\nA P P E N D I C E S\nAppendix 1. Cochrane Gynaecology and Fertility Specialised Register search strategy\nProCite platform\nSearched on 18 August 2020\nKeywords CONTAINS \"IVF\" or \"ICSI\" or \"in-vitro fertilisation \" or \"in-vitro fertilisation procedure\" or \"in vitro fertilization\"\nor \"intracytoplasmic sperm injection\" or \"intracytoplasmic morphologically selected sperm injection\" or \"superovulation\" or\n\"superovulation induction\" or \"IUI\" or \"insemination, intrauterine \" or \"Intrauterine Insemination\" or \"ART\" or \"artificial insemination\"\nor \"assisted reproduction techniques\" or \"subfertility-Female\" or \"pregnancy\" or \"live birth\" or\"unexplained and endometriosis\nrelated infertility\" or\"unexplained infertility\" or \"unexplained subfertility\" or \"anovulation\" or \"infertile\"or \"infertility\" or \"ovulation\" or\n\"subfertility\" or \"ovarian hyperstimulation\"or \"ovarian stimulation\"or\"controlled ovarian \"or \"timed intercourse\" or \"in vivo maturation\"\nor\"in vitro maturation\" or \"IMSI\" or \"implantation\" or \"oocyte\"or\"oocytes\"or\"embryo\" or \"polycystic ovary syndrome\" or \"PCOS\" or\n\"assisted reproduction\" or \"assisted reproductive technology\" or Title CONTAINS \"infertile\"\nAND\nKeywords CONTAINS \"*Obesity\" or \"obese women\" or \"obese\" or \"overweight\" or \"overweight-to-obese\" or \"fat body mass\" or \"fat\ndistribution\" or \"BMI\" or \"body mass index\" or \"body composition\" or \"body fat distribution\" or \"body fat mass\" or \"Body Mass\" or\n\"Body Mass Index\" or\"Body weight\"or \"Weight Loss\"or \"Diet\" or\"diet therapy\"or \"dietary intervention\"or\"Weight \"or\"Weight Gain\" or Title\nCONTAINS \"*Obesity\" or \"obese women\" or \"obese\" or\"overweight\"\nor \"overweight-to-obese\" or \"fat body mass\" or \"fat distribution\" or \"BMI\" or \"body mass index\" or \"body composition\" or \"body fat\ndistribution\" or \"body fat mass\" or \"Body Mass\" or \"Body Mass Index\" or \"Body weight\" or \"Weight Loss\" or \"Diet\" or \"diet therapy\" or\n\"dietary intervention\" or \"Weight\" or\"Weight Gain\"\n1167 records\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n63\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAppendix 2. CENTRAL via the Cochrane Central Register of Studies Online (CRSO) search strategy\nWeb platform\nSearched on 18 August 2020\n#1 MESH DESCRIPTOR Obesity EXPLODE ALL TREES 13487\n#2 MESH DESCRIPTOR Overweight EXPLODE ALL TREES 16016\n#3 (Obesity or obese or overweight):TI,AB,KY 43053\n#4 MESH DESCRIPTOR Obesity, Morbid EXPLODE ALL TREES 1165\n#5 MESH DESCRIPTOR Body Mass Index EXPLODE ALL TREES 9957\n#6 (High BMI or BMI above or BMI greater):TI,AB,KY 562\n#7 (High body mass index or body mass index above or body mass index greater):TI,AB,KY 348\n#8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 48495\n#9 MESH DESCRIPTOR Infertility, Female EXPLODE ALL TREES 1390\n#10 MESH DESCRIPTOR Polycystic Ovary Syndrome EXPLODE ALL TREES 1482\n#11 MESH DESCRIPTOR Fertilization in Vitro EXPLODE ALL TREES 2050\n#12 (infertil* or subfertil*):TI,AB,KY 8830\n#13 (Polycystic Ovar*):TI,AB,KY 3520\n#14 PCOS:TI,AB,KY 2823\n#15 (ivf or icsi):TI,AB,KY 6480\n#16 (intrauterine insemination*):TI,AB,KY 981\n#17 iui:TI,AB,KY 881\n#18 MESH DESCRIPTOR Ovulation Induction EXPLODE ALL TREES 1340\n#19 (Ovulation Induction):TI,AB,KY 2571\n#20 (ovar* hyperstimulation):TI,AB,KY 1625\n#21 (ovar* adj2 stimulation):TI,AB,KY 2263\n#22 MESH DESCRIPTOR Reproductive Techniques, Assisted EXPLODE ALL TREES 3136\n#23 (assisted reproduct*):TI,AB,KY 1401\n#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\n#25 #8 AND #24 1098\nAppendix 3. MEDLINE search strategy\nOvid platform\nSearched from 1946 to 18 August 2020\n1 (Obesity or obese or overweight).tw. (315125)\n2 exp Obesity/ or exp Overweight/ or exp Body Weight/ (466482)\n3 exp Body Composition/ or exp Body Fat Distribution/ (54864)\n4 exp Body Mass Index/ (126990)\n5 exp Obesity, Morbid/ or exp Waist-Hip Ratio/ (23856)\n6 (High BMI or BMI above).tw. (4009)\n7 (BMI adj3 over).tw. (1563)\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n64\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n8 Body Mass Index.tw. (183850)\n9 or/1-8 (743472)\n10 exp Infertility, Female/ (28492)\n11 exp Polycystic Ovary Syndrome/ (14478)\n12 exp Fertilization in Vitro/ (35811)\n13 (infertil$ adj5 female$).tw. (3518)\n14 (infertil$ adj5 wom?n).tw. (9574)\n15 (subfertil$ adj5 wom?n).tw. (635)\n16 (subfertil$ adj5 female$).tw. (253)\n17 Polycystic Ovar$.tw. (16819)\n18 PCOS.tw. (11371)\n19 exp Amenorrhea/ (9855)\n20 amenorrh?ea.tw. (13347)\n21 oligomenorrh$.tw. (1437)\n22 exp Oligomenorrhea/ (720)\n23 exp Hyperandrogenism/ (2019)\n24 hyperandrogenism.tw. (3816)\n25 (ivf or icsi).tw. (27791)\n26 intrauterine insemination$.tw. (2524)\n27 iui.tw. (1785)\n28 exp Ovarian Hyperstimulation Syndrome/ (2262)\n29 exp Ovulation Induction/ (13151)\n30 ovar$ hyperstimulation.tw. (5118)\n31 ovar$ stimulation.tw. (6023)\n32 exp Reproductive Techniques, Assisted/ (69677)\n33 assisted reproduct$.tw. (15166)\n34 or/10-33 (139274)\n35 randomized controlled trial.pt. (511179)\n36 controlled clinical trial.pt. (93800)\n37 randomized.ab. (489167)\n38 randomised.ab. (97651)\n39 placebo.tw. (215911)\n40 clinical trials as topic.sh. (192520)\n41 randomly.ab. (338981)\n42 trial.ti. (223326)\n43 (crossover or cross-over or cross over).tw. (85722)\n44 or/35-43 (1373935)\n45 exp animals/ not humans.sh. (4725508)\n46 44 not 45 (1265255)\n47 9 and 34 and 46 (1266)\nAppendix 4. Embase search strategy\nOvid platform\nSearched from 1980 to 18 August 2020\n1 exp obesity/ (512611)\n2 (obesity or obese or overweight).tw. (457990)\n3 exp body weight/ or exp body mass/ (832100)\n4 waist hip ratio/ (14604)\n5 body mass index.tw. (268127)\n6 (High BMI or BMI above).tw. (7500)\n7 (BMI adj3 over).tw. (3104)\n8 (weight adj3 above).tw. (1994)\n9 (weight adj3 over).tw. (10556)\n10 or/1-9 (1244347)\n11 exp female infertility/ or exp ovary polycystic disease/ or exp fertilization in vitro/ (122255)\n12 (infertil$ adj5 female$).tw. (5121)\n13 (infertil$ adj5 wom?n).tw. (14133)\n14 (subfertil$ adj5 wom?n).tw. (1029)\n15 (subfertil$ adj5 female$).tw. (369)\n16 Polycystic Ovar$.tw. (23277)\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n65\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n17 PCOS.tw. (17262)\n18 exp amenorrhea/ (17330)\n19 amenorrh?ea.tw. (15407)\n20 oligomenorrh$.tw. (1973)\n21 exp oligomenorrhea/ or exp \"amenorrhea and oligomenorrhea\"/ (27942)\n22 exp hyperandrogenism/ (7408)\n23 hyperandrogenism.tw. (5559)\n24 (ivf or icsi).tw. (47745)\n25 intrauterine insemination$.tw. (3780)\n26 iui.tw. (3278)\n27 exp ovary hyperstimulation/ or exp ovulation induction/ (22001)\n28 ovar$ hyperstimulation.tw. (7484)\n29 ovar$ stimulation.tw. (9753)\n30 or/11-29 (177709)\n31 exp Diet Therapy/ (340480)\n32 diet$.tw. (681613)\n33 (weight adj3 reduc$).tw. (48577)\n34 (body mass index adj2 loss).tw. (677)\n35 (body mass index adj2 reduc$).tw. (1197)\n36 (body mass index adj2 decreas$).tw. (1359)\n37 (BMI adj2 loss).tw. (1727)\n38 (BMI adj2 redu$).tw. (4064)\n39 (BMI adj2 decreas$).tw. (4800)\n40 exercise$.tw. (376424)\n41 exp sport/ (160081)\n42 (run$ or jog$).tw. (253096)\n43 (sport$ or walk$).tw. (255446)\n44 (swim$ or cycl$).tw. (1430222)\n45 (train or training).tw. (553768)\n46 exp cognitive therapy/ or exp psychotherapy/ (235459)\n47 (cognitive adj2 therap$).tw. (29865)\n48 Psychotherapy.tw. (40737)\n49 exp behavior therapy/ (42495)\n50 exp lifestyle/ (129810)\n51 (lifestyle adj2 change$).tw. (15252)\n52 (lifestyle adj2 intervention$).tw. (11337)\n53 exp social support/ (91720)\n54 (social adj2 support).tw. (49798)\n55 weight loss.tw. (138913)\n56 (weight adj2 control).tw. (12071)\n57 dynamic exercise/ or isotonic exercise/ or exercise/ or aquatic exercise/ or leg exercise/ or anaerobic exercise/ or stretching exercise/\nor aerobic exercise/ or isometric exercise/ (289306)\n58 behavio?r modif$.tw. (3258)\n59 exp weight control/ or exp weight reduction/ (39254)\n60 behavio?r therap$.tw. (9492)\n61 low calorie$.tw. (4447)\n62 fitness.tw. (81610)\n63 exp health behavior/ (409721)\n64 (decrease adj2 weight).tw. (3343)\n65 hypnosis.tw. (7140)\n66 group therap$.tw. (5887)\n67 or/31-66 (4363927)\n68 exp antiobesity agent/ (4884)\n69 antiobesity.tw. (2254)\n70 lipase inhibitor$.tw. (1255)\n71 (xenical or tetrahydrolipstatin or orlistat).tw. (3754)\n72 exp tetrahydrolipstatin/ (6440)\n73 exp metformin/ or exp pioglitazone/ or exp insulin sensitizing agent/ (75303)\n74 insulin sensitizer$.tw. (2157)\n75 exp antidiabetic agent/ (461406)\n76 exp 2,4 thiazolidinedione derivative/ (12894)\n77 exp thiazole derivative/ (168176)\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n66\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n78 metformin.tw. (35181)\n79 (Appetite adj3 (suppress$ or depress$)).tw. (2798)\n80 exp serotonin uptake inhibitor/ (256753)\n81 exp serotonin antagonist/ (221959)\n82 exp antidepressant agent/ (419880)\n83 exp noradrenalin uptake inhibitor/ (216863)\n84 (Reductil or sibutramine or fenfluramine).tw. (4271)\n85 fenfluramine/ (5653)\n86 exp dexfenfluramine/ (2264)\n87 exp phentermine/ (2547)\n88 exp phenylpropanolamine/ (3042)\n89 exp fluoxetine/ (46337)\n90 antidepressant$.tw. (89208)\n91 anti depressant$.tw. (3456)\n92 exp mazindol/ (1611)\n93 exp amfepramone/ (1320)\n94 antiandrogen/ (11465)\n95 androgen$ antagonist$.tw. (323)\n96 bulking agent$.tw. (1853)\n97 fluoxetine.tw. (16185)\n98 (methylcellulose or celevac).tw. (7244)\n99 guar gum.tw. (2212)\n100 anti obesity.tw. (4963)\n101 exp Ephedra/ (1143)\n102 ephedra.tw. (1024)\n103 bupropion.tw. (6245)\n104 exp amfebutamone/ (18316)\n105 (Wellbutrin or Zyban or Amfebutamone).tw. (2481)\n106 zonisamide.tw. (2062)\n107 (Excegran or Zonegran).tw. (379)\n108 sertraline.tw. (6775)\n109 exp sertraline/ (25989)\n110 (Serad or Serlain or Tresleen or Zolo/f_t).tw. (2616)\n111 leptin/ae, dt [Adverse Drug Reaction, Drug Therapy] (853)\n112 topiramate.tw. (7652)\n113 or/68-112 (1157634)\n114 (lap band$ or lapband$).tw. (629)\n115 roux-en-y.tw. (19567)\n116 bariatric surger$.tw. (30089)\n117 exp gastroplasty/ or exp bariatric surgery/ (46918)\n118 exp gastrectomy/ (52328)\n119 (GASTROPLASTY or Gastrectomy or gastric surgery or Gastric Bypass or gastric band$).tw. (60946)\n120 (Biliopancreatic Diversion$ or biliopancreatic bypass$ or gastro$gastrostomy or restrictive surgery).tw. (2030)\n121 (obesity adj3 surg$).tw. (6397)\n122 (obese adj3 surg$).tw. (3076)\n123 (jejunoileal bypass$ or jejuno ileal bypass$).tw. (789)\n124 exp gastric banding/ (7411)\n125 or/114-124 (106478)\n126 67 or 113 or 125 (5321490)\n127 Clinical Trial/ (970755)\n128 Randomized Controlled Trial/ (611928)\n129 exp randomization/ (87710)\n130 Single Blind Procedure/ (39825)\n131 Double Blind Procedure/ (172019)\n132 Crossover Procedure/ (63930)\n133 Placebo/ (339738)\n134 Randomi?ed controlled trial$.tw. (234558)\n135 Rct.tw. (38031)\n136 random allocation.tw. (2043)\n137 randomly allocated.tw. (35686)\n138 allocated randomly.tw. (2562)\n139 (allocated adj2 random).tw. (822)\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n67\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n140 Single blind$.tw. (25054)\n141 Double blind$.tw. (204347)\n142 ((treble or triple) adj blind$).tw. (1172)\n143 placebo$.tw. (305406)\n144 prospective study/ (618991)\n145 or/127-144 (2217034)\n146 case study/ (71157)\n147 case report.tw. (408717)\n148 abstract report/ or letter/ (1110703)\n149 or/146-148 (1579736)\n150 145 not 149 (2163027)\n151 10 and 30 and 126 and 150 (3462)\nAppendix 5. PsycINFO search strategy\nOvid platform\nSearched from 1806 to 18 August 2020\n1 exp Obesity/ (24601)\n2 (obesity or obese or overweight).tw. (44923)\n3 exp Body Weight/ or exp Body Mass Index/ (56375)\n4 Body Mass Index.tw. (20444)\n5 Body Weight.tw. (16156)\n6 BMI.tw. (17893)\n7 or/1-6 (88421)\n8 exp Infertility/ (2185)\n9 (infertil$ adj5 female$).tw. (357)\n10 (infertil$ adj5 wom?n).tw. (742)\n11 (subfertil$ adj5 wom?n).tw. (16)\n12 (subfertil$ adj5 female$).tw. (6)\n13 Polycystic Ovar$.tw. (426)\n14 PCOS.tw. (290)\n15 exp Amenorrhea/ (264)\n16 amenorrh?ea.tw. (830)\n17 oligomenorrh$.tw. (52)\n18 exp Menstrual Disorders/ (1270)\n19 hyperandrogenism.tw. (97)\n20 (ivf or icsi).tw. (604)\n21 intrauterine insemination$.tw. (32)\n22 iui.tw. (41)\n23 exp Reproductive Technology/ (1847)\n24 ovar$ hyperstimulation.tw. (13)\n25 ovar$ stimulation.tw. (26)\n26 or/8-25 (6184)\n27 7 and 26 (572)\n28 random.tw. (59084)\n29 control.tw. (448804)\n30 double-blind.tw. (23062)\n31 clinical trials/ (11727)\n32 placebo/ (5682)\n33 exp Treatment/ (1052281)\n34 or/28-33 (1452988)\n35 27 and 34 (225)\nAppendix 6. AMED search strategy\nOvid platform\nSearched from 1985 to 18 August 2020\n1 exp Obesity/ (2115)\n2 (obesity or obese or overweight).tw. (3015)\n3 exp Body weight/ (848)\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n68\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n4 BMI.tw. (1134)\n5 body mass index.tw. (2127)\n6 weight.tw. (9971)\n7 or/1-6 (13101)\n8 exp Fertility/ (68)\n9 exp Infertility female/ (215)\n10 exp Ovarian disease/ (275)\n11 (infertil$ adj5 female$).tw. (227)\n12 (infertil$ adj5 wom?n).tw. (57)\n13 (subfertil$ adj5 wom?n).tw. (2)\n14 (subfertil$ adj5 female$).tw. (0)\n15 Polycystic Ovar$.tw. (98)\n16 PCOS.tw. (54)\n17 exp Amenorrhea/ (39)\n18 amenorrh?ea.tw. (95)\n19 oligomenorrh$.tw. (11)\n20 exp Menstruation disorders/ (589)\n21 hyperandrogenism.tw. (6)\n22 (ivf or icsi).tw. (52)\n23 intrauterine insemination$.tw. (8)\n24 iui.tw. (6)\n25 ovar$ hyperstimulation.tw. (5)\n26 or/8-25 (1202)\n27 7 and 26 (64)\nAppendix 7. CINAHL search strategy\nEbsco platform\nSearched from 1961 to 26 September 2019. The CENTRAL search on 18 August 2020 includes CINAHL references.\n/uni00A0\n# Query Results\nS35 S20 AND S34 771\nS34 S21 OR S22 or S23 or S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31\nOR S32 OR S33\n1,352,629\nS33 TX allocat* random* 11,021\nS32 (MH \"Quantitative Studies\") 23,323\nS31 (MH \"Placebos\") 11,475\nS30 TX placebo* 59,197\nS29 TX random* allocat* 11,021\nS28 (MH \"Random Assignment\") 56,644\nS27 TX randomi* control* trial* 175,687\nS26 TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (dou-\nbl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1\nblind*) or (trebl* n1 mask*) )\n1,033,852\nS25 TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) 241\n/uni00A0\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n69\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nS24 TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) 241\nS23 TX clinic* n1 trial* 251,068\nS22 PT Clinical trial 86,871\nS21 (MH \"Clinical Trials+\") 267,348\nS20 S9 AND S19 3,829\nS19 S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 27,803\nS18 TX intrauterine insemination 462\nS17 (MH \"Fertilization in Vitro\") OR (MH \"Fertility\") 9,858\nS16 TX (ivf or icsi) 4,846\nS15 TX hyperandrogenism 697\nS14 TX subfertil* 885\nS13 TX infertil* 16,371\nS12 TX Polycystic Ovar* 4,117\nS11 (MM \"Polycystic Ovary Syndrome\") 2,587\nS10 (MM \"Infertility\") 7,396\nS9 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 343,194\nS8 TX weight 211,089\nS7 TX BMI 43,745\nS6 TX Body Mass Index 102,302\nS5 (MM \"Body Mass Index\") 11,041\nS4 TX overweight 27,892\nS3 TX obese 35,589\nS2 TX Obesity 119,085\nS1 (MH \"Obesity+\") 88,246\n/uni00A0/uni00A0(Continued)\n/uni00A0\nW H A T ' S /uni00A0 N E W\n/uni00A0\nDate Event Description\n1 April 2021 Amended Typo corrected in/uni00A0abstract and PLS\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n70\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nH I S T O R Y\nProtocol first published: Issue 4, 2017\nReview first published: Issue 3, 2021\n/uni00A0\nDate Event Description\n8 February 2020 Amended Correction to affiliation of 2 authors. Changes to the methods as\nnoted in the section Differences between protocol and review.\n/uni00A0\nC O N T R I B U T I O N S /uni00A0 O F /uni00A0 A U T H O R S\nFB and SAT were involved in the design and conduct of the review, data analysis, dra/f_ting of the manuscript, and critical discussion. SHJ\nand MvW were involved in the design and conduct of the review, supervised data analysis, checked data extraction, and were involved in\nmanuscript revision and critical discussion. All review authors read and approved the final manuscript.\nD E C L A R A T I O N S /uni00A0 O F /uni00A0 I N T E R E S T\nNone of the review authors have or have had affiliations or involvement in organisations with an interest in the review findings. MvW is a\nCochrane Editor and Deputy Editor of Human Reproduction.\nS O U R C E S /uni00A0 O F /uni00A0 S U P P O R T\nInternal sources\n• None, Other\nExternal sources\n• None, Other\nD 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\nThe review objective was amended to improve clarity that the interventions are targeted to weight reduction in obese women with\nsubfertility. The inclusion of cluster-randomised trials was excluded from the review as they are not an appropriate study design. Lastly,\nthe measure of treatment effect for dichotomous data was calculated using odds ratios (OR) rather than risk ratios (RR). We chose the OR\nwhile this is considered a mathematically more stable effect measure .\nI N D E X /uni00A0 T E R M S\nMedical Subject Headings (MeSH)\nAbortion, Spontaneous /uni00A0[epidemiology];/uni00A0 Appetite Depressants /uni00A0[therapeutic use];/uni00A0 Bias;/uni00A0 Carnitine /uni00A0[therapeutic use];/uni00A0 Clomiphene\n/uni00A0[therapeutic use];/uni00A0 Dexfenfluramine /uni00A0[therapeutic use];/uni00A0 Drug Therapy, Combination /uni00A0[methods];/uni00A0 Hypoglycemic Agents /uni00A0[adverse effects]\n/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\n/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\nRandomized Controlled Trials as Topic;/uni00A0 *Weight Loss\nMeSH check words\nFemale; Humans; Pregnancy\nPharmacological and non-pharmacological strategies for obese women with subfertility (Review)\nCopyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n71","source_license":"CC-BY-4.0","license_restricted":false}