Open access Protocol Dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatment: protocol for a systematic review and individual participant data meta-­analysis Emily Evans-­Hoeker,1,2 Zheng Wang ‍ ‍,3 Henk Groen ‍ ‍,4 Astrid E P Cantineau,3 Ann Thurin‐Kjellberg,5,6 Christina Bergh,5,6 Joop S E Laven,7 Alexandra Dietz de Loos,7 Geranne Jiskoot,7 Jean-­Patrice Baillargeon ‍ ‍,8 Stefano Palomba ‍ ‍,9 Kyra Sim,10 Lisa J Moran,11 Juan J Espinós,12 Trine Moholdt ‍ ‍,13,14 Amy E Rothberg ‍ ‍,15,16 Donna Shoupe,17 Annemieke Hoek ‍ ‍,3 Richard S Legro,18 Ben W Mol ‍ ‍,19,20 Rui Wang ‍ ‍,19 On behalf of the Venus-­IPD Collaboration To cite: Evans-­Hoeker E, ABSTRACT Wang Z, Groen H, et al. Dietary Introduction Dietary and/or physical activity STRENGTHS AND LIMITATIONS OF THIS STUDY and/or physical activity interventions are often recommended for women ⇒ This, to our knowledge, is the first individual partic- interventions in women with ipant data meta-­analysis (IPDMA), which evaluates with overweight or obesity as the first step prior to overweight or obesity prior the effectiveness and safety of dietary and/or phys- to fertility treatment: protocol fertility treatment. However, randomised controlled trials (RCTs) so far have shown inconsistent results. ical activity interventions in women with infertility for a systematic review and individual participant data Therefore, we propose this individual participant and overweight or obesity on reproductive, maternal meta-­analysis. BMJ Open data meta-­a nalysis (IPDMA) to evaluate the and perinatal outcomes. 2022;12:e065206. doi:10.1136/ effectiveness and safety of dietary and/or physical ⇒ An IPDMA allows us to explore treatment–covariate bmjopen-2022-065206 activity interventions in women with infertility and interactions for important participant-­ level char- overweight or obesity on reproductive, maternal acteristics, which are usually impossible in meta-­ ► Prepublication history and and perinatal outcomes and to explore if there analyses based on study-­level data due to various additional supplemental material for this paper are available are subgroup(s) of women who benefit from each reporting and analysis strategies. online. To view these files, specific intervention or their combination (treatment– ⇒ Venus-­IPD collaboration provides a unique opportu- please visit the journal online covariate interactions). nity to harmonise outcome reporting in this IPDMA (http://dx.doi.org/10.1136/​ Methods and analysis We will include RCTs with dietary by collaborating with trial investigators. bmjopen-2022-065206). and/or physical activity interventions as core interventions ⇒ The various intervention strategy and follow-­up pe- prior to fertility treatment in women with infertility and riods may limit the available subgroup analyses. Received 27 May 2022 Accepted 10 October 2022 overweight or obesity. The primary outcome will be live birth. We will search MEDLINE, Embase, Cochrane Central Register of Controlled Trials and trial registries to identify INTRODUCTION eligible studies. We will approach authors of eligible trials The prevalence of obesity continues to to contribute individual participant data (IPD). We will rise worldwide, with around half of women perform risk of bias assessments according to the Risk of Bias 2 tool and a random-­effects IPDMA. We will then of reproductive age having overweight or explore treatment–covariate interactions for important obesity.1 Obesity is negatively associated with participant-­level characteristics. reproductive outcomes, including increased © Author(s) (or their Ethics and dissemination Formal ethical approval for risks of miscarriage and obstetric complica- employer(s)) 2022. Re-­use the project (Venus-­IPD) was exempted by the medical tions and decreased spontaneous pregnancy permitted under CC BY-­NC. No commercial re-­use. See rights ethics committee of the University Medical Center rate.2–4 In addition, risks of congenital anom- and permissions. Published by Groningen (METc code: 2021/563, date: 17 November alies and perinatal and neonatal death are BMJ. 2021). Data transfer agreement will be obtained from also increased.5 6 The mechanism behind the For numbered affiliations see each participating institute/hospital. Outcomes will be adverse effect of obesity on inferior reproduc- end of article. disseminated internationally through the collaborative tive performances in women remains unclear, group, conference presentations and peer-­reviewed Correspondence to although impaired ovarian folliculogenesis, publication. Dr Rui Wang; oocyte quality, embryo quality and uterine PROSPERO registration number CRD42021266201. ​r.​wang@​monash.​edu receptivity have been implicated.7–11 Evans-­Hoeker E, et al. BMJ Open 2022;12:e065206. doi:10.1136/bmjopen-2022-065206 1 Open access Various guidelines recommend lifestyle interventions Box 1 Outcome measures based on dietary and/or physical activity targeting at Primary outcome: a 5%–10% reduction in body weight as an initial step Live birth* prior to fertility treatment for women with infertility and overweight or obesity.12 13 However, evidence supporting Secondary outcomes: such a treatment strategy is limited, and randomised Body mass index: amount of weight loss in kg. controlled trials (RCTs) assessing the effect of lifestyle Dropout. interventions prior to fertility treatments have not Fertility outcomes consistently demonstrated an improvement in live birth Spontaneous resumption of ovulation. rate.14–16 Existing systemic reviews and/or meta-­analyses Spontaneous pregnancy. of study level data have demonstrated inconsistent results Ongoing pregnancy (>12 weeks). on live birth rate and miscarriage, partly due to varying Biochemical pregnancy. inclusion criteria.17–20 Additionally, these systemic review Clinical pregnancy (viable intrauterine pregnancy confirmed by ultra- sound)*, accounting for singleton pregnancy, twin pregnancy and higher and meta-­analyses are limited in the analysis of subgroup multiple pregnancy. effects and time-­to-­event outcomes due to inadequate Pregnancy loss* accounting for ectopic pregnancy, miscarriage, still- reporting or different reporting and analytical strate- birth and termination of pregnancy. gies in the primary trials. These issues can potentially be Gestational age at delivery* addressed through evidence synthesis using individual Time to pregnancy leading to live birth*. participant data (IPD) from relevant studies.21 22 The Preterm birth (<37 weeks). overall objective of this individual participant data meta-­ Obstetric outcomes† analysis (IPDMA) (Venus-­IPD project) is to better inform Hypertensive disorders of pregnancy. current practice regarding the effectiveness and safety of Gestational diabetes. dietary and/or physical activity interventions in women Antepartum haemorrhage. with overweight or obesity prior to initiating fertility Postpartum haemorrhage. treatments. Other maternal safety outcomes† The specific objectives of the Venus-­IPD project are: Ovarian hyperstimulation syndrome (mild; moderate; severe). 1. To identify whether dietary and/or physical activity in- Pulmonary embolism. terventions in women with infertility and overweight Endometritis. or obesity seeking fertility treatment improves live birth and/or other reproductive, maternal and peri- Neonatal outcomes natal outcomes. Birth weight* Large for gestational age; small for gestational age. 2. To explore if there are subgroup(s) of women who Neonatal mortality*. benefit from dietary and/or physical activity interven- Major congenital anomaly*. tions (treatment–covariate interactions). Admission to neonatal intensive care unit. 3. To evaluate attrition with dietary and/or physical activ- ity interventions. Cardiometabolic outcomes after the intervention (if 4. To explore the association between the magnitude of available) Waist circumference; hip circumference (cm). preconception weight change and reproductive and Waist-­hip ratio. perinatal outcomes. Blood pressure (mm Hg). 5. To explore the effect of dietary and/or physical activity Serum testosterone (ng/dL). interventions on cardiometabolic outcomes. Triglycerides (mmol/L). Total cholesterol (mmol/L). Low-­density lipoprotein cholesterol (mmol/L). METHODS High-­density lipoprotein cholesterol (mmol/L). This systematic review and IPDMA is registered on PROS- Glucose (mmol/L). PERO (CRD42021266201). The protocol is reported in Insulin (mmol/L). accordance with the Preferred Reporting Items for Systematic Insulin sensitivity index. Review and Meta-­Analysis of IPD and Preferred Reporting Haemoglobin A1c (mmol/mol). Items for Systematic Review and Meta-­Analysis Protocols.23 24 C reactive protein (mg/L). Metabolic syndrome. Eligibility criteria Note: Definitions not specifically stated will take into account the various Study type definition criteria between countries and regions. Only RCTs are considered eligible. Quasi-­RCTs will be †Definitions are based on International Statistical Classification of Diseases and Related Health Problems (ICD-­10). excluded. *The core outcome set for infertility.25 26 Study populations Women with infertility and overweight or obesity, who are eligible for fertility treatments. 2 Evans-­Hoeker E, et al. BMJ Open 2022;12:e065206. doi:10.1136/bmjopen-2022-065206 Open access Study intervention inclusion using COVIDENCE. Additional reviewer(s) will Any intervention consisting of dietary, physical activity solve conflicts or disagreements. The screening process interventions or a combination of both. Optional will begin with title/abstract review and will be followed elements are medication, psychological counselling and by full text review. supportive non-­ surgical weight management interven- tions. Bariatric surgery will be excluded. Risk of bias assessment Study risk of bias will be assessed by two reviewers (EE-­H and Study comparator ZW) independently based on the Risk of Bias 2 tool.27 The Regular or standard advice with respect to healthy diet following five domains will be assessed: (1) risk of bias arising and physical activity, routine care or no intervention. from the randomisation process; (2) risk of bias due to devi- ations from the intended interventions effect of adhering to Outcomes intervention); (3) missing outcome data; (4) risk of bias in All outcomes in the core outcomes set for infertility measurement of the outcome; and (5) risk of bias in selection research will be included and the definition of these of the reported result. Studies will be rated on each criterion outcomes will be used.25 26 with either ‘low risk of bias’, ‘some concerns’ or ‘high risk of bias’. Trial authors will be contacted when further informa- Primary outcome tion is needed for the assessments. The primary outcome will be live birth (counted as birth events, eg, twin live birth is counted as one live birth event).25 26 Development of the database Establishing the Venus-IPD collaboration Secondary outcomes We have established the Venus-­ IPD collaboration by Secondary outcomes will include viable intrauterine preg- inviting leading authors of eligible trials identified in nancy confirmed by ultrasound (accounting for singleton, our search in 2021. Leading authors of new trials iden- twin and higher order multiple pregnancies); pregnancy tified in future search before project completion will be loss (accounting for ectopic pregnancy, miscarriage, still- invited via email to join the collaboration. The protocol birth and termination of pregnancy); gestational age at for the IPDMA will be shared with new authors who wish delivery; birth weight; neonatal mortality; major congen- to participate in the project. ital anomaly; and time to pregnancy leading to live birth. In addition to the core outcome set, we will assess live Data management birth resulting from spontaneous pregnancies, resump- In accordance with the study objectives, IPD will be tion of ovulation, maternal and perinatal complications, requested. Leading authors of included RCTs will be dropout, amount of weight loss and cardiometabolic provided with a list of data items requested. Deiden- outcomes. Detailed outcome measures are presented in tified raw data can be transferred by a variety of secure box 1. The final outcomes reported will be determined methods (courier, secure email or secure electronic by the availability of data on these outcomes and some transfer) depending on the authors’ institutional regu- parameters may be used for future analysis. lations and preference. All authors will be asked to sign a Data Sharing Agreements detailing the conditions for Setting data release. IPD will be stored on a secure server at the There will be no restriction on setting. University Medical Center Groningen. Identification of studies Data checking and cleaning The following electronic databases will be used to iden- Data consistency between the IPD and the trial publica- tify potentially eligible studies: MEDLINE, Embase and tions will be verified, and possible data errors, duplications Cochrane Central Register of Controlled Trials (CENTRAL). and missing values will be identified and investigated. Key authors in the area of fertility treatment will be consulted The trial investigators will be asked to solve discrepancies for additional literature and unpublished manuscripts. Cita- or concerns about the dataset. Data will be harmonised tions in identified studies and previously published meta-­ across studies, for example, in terms of uniform cut-­offs analyses will be reviewed. In addition, clinical trial registries and units where applicable. Cleaned IPD will be collated including International Clinical Trials Registry Platform into a single database. and ​ClinicalTrials.​gov will be searched. The grey literature including Google Scholar and any other relevant sources will Data analysis be reviewed. No language, time period or publication status Individual participant data meta-analysis restrictions will be applied. The search strategy is presented After data checking and harmonisation, the analyt- in a online supplemental file. ical approach for the IPDMA will be determined. For outcomes where multiple included studies are small or Inclusion of studies have rare events (including zero event), we will perform a Study selection process one-­stage IPDMA. Otherwise, a two-­stage random effects Two reviewers (EE-­ H and ZW) will perform indepen- IPDMA will be preferable.28 The first stage will involve dent screening and determination of the eligibility and analysing the IPD in each study separately, to account for Evans-­Hoeker E, et al. BMJ Open 2022;12:e065206. doi:10.1136/bmjopen-2022-065206 3 Open access the clustering of participants within trials and to obtain ► Women with obesity (BMI ≥30). the estimates of interest and their variances. The primary ► Women adherent to the intervention (as per-­protocol outcome will be analysed by logistic regression models. analysis). OR with 95% CIs will be calculated with adjustment for ► Using a one-­stage IPDMA (if two stage is used in the baseline covariates (age and baseline body mass index main analysis). (BMI)). Secondary outcome measures will be estimated using ORs for binary outcomes, mean difference for Publication bias continuous outcomes and HR for time-­to-­event outcomes. A contour enhanced funnel plot will be used to investi- To assess potential effect modifiers, treatment–covariate gate potential publication bias (small study effects) when interaction terms between participant level covariates and more than 10 studies are included. Data availability bias the intervention will be added to the analyses. will be evaluated by incorporating evidence from studies In the second stage, the derived effect estimates, that is, without IPD. treatment effects or treatment–covariate interactions, will be pooled across studies using a random effects model Overall certainty of evidence based on the assumed differences in treatment effect due We will evaluate the overall certainty of the body of to between-­ study heterogeneity. Restricted maximum evidence by considering risk of bias, inconsistency, indi- likelihood will be used for these models. Heterogeneity rectness, imprecision and publication bias using the will be summarised using τ2 and I2.29 The results will be GRADE framework.34 presented in forest plots. Only within-­study interaction Ethics and dissemination will be considered as recommended by current guidance Formal ethical approval for the Venus-­IPD project was on IPDMA.30 exempted by the medical ethics committee of the Univer- The main analysis will be based on the intention-­ sity Medical Center Groningen (METc code: 2021/563, to-­treat principle. We will conduct this IPDMA using date: 17 November 2021). Contributors will be asked to Stata V.17 (StataCorp, College Station, Texas, USA). A submit only de-­identified datasets (ie, specific identifiable detailed statistical analysis plan will be developed before information will be erased before sharing). Additional commencing the analysis. restrictions on data use or storage may apply to some IPD Unavailable IPD data when applicable. Findings will be disseminated interna- Studies without IPD will not be pooled with studies with tionally through the collaborative group, conference IPD in this IPDMA. The aggregate data of RCTs without presentations and peer-­reviewed publication. IPD will be synthesised separately, and the results will be compared with the those based on IPDMA. Patient and public involvement Patient and public representatives have acknowledged the Missing data importance of the Venus-­IPD project and will be involved The percentage of individual participant missing data in the interpretation and reporting of the findings as well will be recorded. Missing data in each study will be dealt as wider disseminations. with separately using multiple imputation when missing at random assumption is not violated.31–33 DISCUSSION Treatment–covariate interaction analysis The Venus-­IPD project has the potential to inform clini- Treatment–covariate interaction analysis will be cians, healthcare providers and women with overweight performed for the primary outcome by exploring the or obesity seeking fertility treatment regarding whether following treatment–covariate interactions. postponing fertility treatment to receive dietary and/or ► Baseline BMI. physical activity interventions would be helpful to improve ► Intervention type (dietary, physical activity, their reproductive, maternal and perinatal outcomes. In addi- combination). tion, by collecting the IPD, specific subsets of women for ► Magnitude of weight loss (or BMI points change). whom these interventions provide the greatest benefit ► Polycystic ovary syndrome (PCOS) versus non-­PCOS. may be identified. Meanwhile, we acknowledge that the ► Age. classification of intervention type can only be limited to Continuous variables will be treated as continuous broad categories in this IPDMA. Lastly, the findings of without categorisation. Non-­ linear association will be this study may identify the minimum amount of weight explored using restricted cubic spline according to loss required to observe a benefit. The findings can then current practice.30 be used to inform fertility treatment strategies and deci- Sensitivity analysis sions regarding the design of future studies. Sensitivity analysis will test the robustness of our conclu- Author affiliations sions for the analysis of the primary outcome. This will be 1 Department of Obstetrics and Gynaecology, Virginia Tech Carilion School of explored by limiting the analysis to: Medicine, Roanoke, Virginia, USA ► Studies with overall low risk of bias. 2 Shady Grove Fertility, Roanoke, Virginia, USA 4 Evans-­Hoeker E, et al. BMJ Open 2022;12:e065206. doi:10.1136/bmjopen-2022-065206 Open access 3 Department of Obstetrics and Gynaecology, University Medical Centre Groningen, Provenance and peer review Not commissioned; externally peer reviewed. Groningen, The Netherlands Data availability statement No datasets were generated for this publication as 4 Department of Epidemiology, University Medical Centre Groningen, Groningen, The this is a protocol. Netherlands 5 Department of Obstetrics and Gynaecology, University of Gothenburg Sahlgrenska Supplemental material This content has been supplied by the author(s). It has Academy, Gothenburg, Sweden not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been 6 peer-­reviewed. Any opinions or recommendations discussed are solely those Department of Reproductive Medicine, Sahlgrenska University Hospital, of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and Gothenburg, Sweden 7 responsibility arising from any reliance placed on the content. Where the content Department of Obstetrics and Gynaecology, Erasmus University Medical Center, includes any translated material, BMJ does not warrant the accuracy and reliability Rotterdam, Zuid-­Holland, Netherlands of the translations (including but not limited to local regulations, clinical guidelines, 8 Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada terminology, drug names and drug dosages), and is not responsible for any error 9 Department of Obstetrics and Gynaecology, University "Magna Graecia" of and/or omissions arising from translation and adaptation or otherwise. Catanzaro, Catanzaro, Italy 10 Metabolism & Obesity Service, Royal Prince Alfred Hospital, Sydney, New South Open access This is an open access article distributed in accordance with the Wales, Australia Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which 11 permits others to distribute, remix, adapt, build upon this work non-­commercially, Monash Centre for Health Research and Implementation, School of Public Health and license their derivative works on different terms, provided the original work is and Preventive Medicine, Monash University, Clayton, Victoria, Australia 12 properly cited, appropriate credit is given, any changes made indicated, and the use Clínica Fertty, Universidad Autónoma de Barcelona, Universidad Autónoma de is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. Barcelona, Barcelona, Spain 13 Department of Circulation and Medical Imaging, Norwegian University of Science ORCID iDs and Technology, Trondheim, Trøndelag, Norway Zheng Wang http://orcid.org/0000-0003-1592-6765 14 Department of Obstetrics and Gynaecology, St Olavs Hospital Trondheim University Henk Groen http://orcid.org/0000-0002-6629-318X Hospital, Trondheim, Trøndelag, Norway Jean-­Patrice Baillargeon http://orcid.org/0000-0002-1336-081X 15 Department of Internal Medicine, Division of Metabolism, Endocrinology & Stefano Palomba http://orcid.org/0000-0003-2767-8295 Diabetes, University of Michigan, Ann Arbor, Michigan, USA Trine Moholdt http://orcid.org/0000-0003-1024-8088 16 Department of Nutritional Sciences, School of Public Health, University of Amy E Rothberg http://orcid.org/0000-0002-0243-9135 Michigan, Ann Arbor, Michigan, USA Annemieke Hoek http://orcid.org/0000-0003-4441-7142 17 Department of Obstetrics and Gynaecology, University of Southern California Keck Ben W Mol http://orcid.org/0000-0001-8337-550X School of Medicine, Los Angeles, California, USA Rui Wang http://orcid.org/0000-0002-6622-8134 18 Department of Obstetrics and Gynaecology, Penn State College of Medicine, Hershey, Pennsylvania, USA 19 Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia 20 Aberdeen Centre for Women's Health Research, Institute of Applied Health REFERENCES 1 Vahratian A. 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