This study protocol was developed and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Guidelines [21], and was submitted for registration with the International Prospective Register of Systematic Reviews (PROSPERO), an open access online database of systematic review protocols, in May of 2021.

Eligibility criteria

Any observational study—prospective and retrospective comparative cohort studies, case control studies, case series, and case reports—that examine the influence of bariatric surgery on ART outcomes will be eligible for inclusion. Cross sectional studies will be excluded. Studies will be required to have taken place in a developed country. Participants will be required to have used ART following their bariatric surgery. We will include human studies written in English from 1978, the year the first IVF baby was born [22], to present day. We will exclude animal studies; studies with pediatric populations (participants < 18 years old); and studies with populations restricted to specific diseases, conditions, or metabolic disorders. Dissertations, conference proceedings, and abstracts will also be excluded.

Eligibility criteria will follow the Population, Intervention, Comparison, Outcomes, Timeframe, Study framework [23, 24].

Population

Studies with women and men participants of reproductive age (≥ 18 years old), who have a prior history of bariatric surgery, and are undergoing ART will be included. Studies which exclusively investigated selected populations with specific disease conditions (e.g., individuals with polycystic ovary syndrome or testicular cancer) or metabolic disorders (e.g., diabetes or Gaucher disease) will be excluded, as well as studies that do not use body mass index (BMI) as a parameter for obesity (e.g., waist to hip ratio and body weight). According to WHO, obesity is defined as abnormal or excessive fat accumulation that presents a risk to health [25]. Obesity will be defined based on the participant’s BMI prior to their bariatric surgery (BMI is over 40, or if BMI exceeds 35 with severe comorbidities) [26, 27]. Participant’s BMI should have been measured following their bariatric surgery and/or prior to starting fertility treatment; however, this data may not be recorded in all included studies.

Interventions

Studies examining ART interventions, specifically IVF, ICSI, and fertility preservation, will be deemed eligible for inclusion.

Comparator

No comparator group will be used.

Outcomes

Studies examining intrauterine, intracervical, or artificial insemination will be excluded as these procedures only handle sperm and are not considered types of ART for the purposes of this study [28]. Studies investigating the effect of bariatric surgery on natural cycle conceptions will also be excluded. Studies with available data on live birth rate will be eligible for inclusion.

Information sources

Our search strategy will employ medical subject headings (MeSH) terms as well as keywords related to fertility and bariatric surgery. We will search MEDLINE, EMBASE, SCOPUS, and the Cochrane Central Register of Controlled Trials (CENTRAL). PROSPERO, OSF Pre-print, and SCOPUS will be searched to identify any ongoing or recently completed systematic reviews. For completeness, we will search the gray literature (e.g., clinicaltrial.gov, the International Clinical Trials Registry Platform (ICTRP), and OpenGrey) as well as the reference lists of included studies and of relevant reviews identified through the search. A preliminary search was carried out on May 28, 2021.

Search strategy

The specific search strategy employed has been developed in consultation with a medical librarian with expertise in systematic review searching. Our search will include the terms “bariatric surgery,” “assisted reproductive techniques,” “in vitro fertilization,” and “obesity.” A draft of the MEDLINE search strategy is included (Table 1 in Appendix). After the MEDLINE search strategy has been finalized, it will be formatted for other databases of interest and will employ database-specific vocabulary when applicable. The search will be performed by the first reviewer (KA).

Selection process

The results from this systematic literature search will be complied into EndNote, a reference manager software. Duplicates will be removed. The articles will then be uploaded to the Covidence platform, a web-based review software, which identifies and removes any further duplicates, streamlines screening of citations, and facilitates the resolution of conflicts between reviewers. Keywords and MeSH terms will be highlighted on the platform to facilitate screening. Citation abstracts and full-text articles will be uploaded to Covidence. Prior to the formal screening process, team members will be provided with training on how to use Covidence and receive background information on this research topic. A pilot of the screening will be conducted to ensure a high agreement among raters.

Two reviewers (KA and IC) will first independently screen title and abstracts in duplicate according to defined eligibility criteria. Potentially relevant articles will then be advanced to full-text review, which will be completed by two reviewers (KA and IC). The reasons for exclusion of studies will be recorded in Covidence. Differences will be resolved through discussion between the two reviewers. When reviewers disagree, the article will be referred to the senior author (HL).

Data extraction process

A standardized data extraction form will be created by one of the reviewers (IC). Two reviewers (KA and IC) will independently extract the data into a standardized Excel spread sheet. Reviewers will resolve disagreements through discussions, and any remaining disagreements will be resolved in consultation with the senior author (HL).

Data items prioritization

The following demographic and study data will be extracted from all included studies: study authors, year of study, study setting (e.g., country/city), study design, and study aim. Participant demographics including age; BMI and/or weight loss; diagnosis; antral follicle count (AFC) on ultrasound; anti-Mullerian hormone; and day 3 follicle stimulating hormone levels, supplements, and comorbidities will also be extracted.

Primary outcome

The primary outcome for this systematic review was chosen based on Reproductive Endocrinology and Infertility Committee’s guidelines [29]. The main outcome that will be analyzed is cumulative live birth rate defined as a pregnancy that results in a baby, irrespective of the duration of pregnancy, which, after such separation or extraction, shows evidence of life [30].

Secondary outcomes

Additional outcomes about the intervention will include time to conception, number of rounds of ART, type of bariatric surgery, and length of time between bariatric surgery and initiation of ART. The following sex-specific secondary outcomes will also be extracted:

Female outcomes Male outcomes
Fertilization rate
Implantation rate
Miscarriage rate
Total number of mature oocytes
Number of mature oocytes
Complications
Pre-term birth
Mode of delivery
Gestational weight gain
Intrauterine growth restrictions
Total gonadotropin dose
Sperm motility
Sperm morphology
Total sperm count
Sperm concentration
Mature spermatozoa

Risk of bias

The risk of bias for each of the included studies will be assessed by two reviewers independently (KA and IC). A quality assessment will be conducted on each of the included studies using the National Institutes of Health (NIH) Study Quality Assessment Tools [31]. Several NIH quality assessment tools exist to assess a wide variety of study designs. As such, the tool that will be utilized will be specific to the study design of the article being reviewed. We will summarize the risk of bias within studies using the tools appropriate to the study design. Differences will be resolved through discussion between the two reviewers or in consultation with a third reviewer (HL) when necessary.

Data analysis

We expect that there will be limited scope for meta-analysis due to the range of different types of bariatric surgeries, ART interventions, and fertility outcomes measured across studies. However, if the data will allow, we plan to pool outcomes in a meta-analysis. Dichotomous data will be recorded as a rate or count and continuous data will be recorded as the mean value or proportion. Statistical heterogeneity will be assessed using I2. Substantial heterogeneity will be defined as I2 > 75% [32]. The R Software (R Studio, 2013, Vienna, Austria) will be used to pool primary and secondary outcomes in meta-analyses using forest plots. The pooled data will be computed using the DerSimonian-Laird method, under a random-effect model, and the 95% confidence interval (CI) will be estimated for the dichotomous outcomes (live birth or no live birth) [32]. If possible, a meta-regression will be performed for secondary outcomes.

The following subgroup analyses plan to be investigated: (1) timeline between bariatric surgery and ART; (2) categories of BMI (obesity class 1, class 2, and class 3); (3) type of ART intervention (IVF vs ICSI); (4) age; and (5) sex. If appropriate, a sensitivity analysis will be conducted based on the quality of studies (“good” vs “fair” vs “poor”) to determine the robustness of the results.

Variable length of follow-up can lead to unit of analysis error. As such, separate analyses based on previously defined length of follow-up will be carried out. In the case of missingness of relevant data, authors will be contacted to request sufficient information. If this is not possible, missing data will be accounted for in the risk of bias assessment and explored in a sensitivity analysis.

In the likely circumstance that substantial heterogeneity prohibits the appropriate use of a meta-analysis, we will provide a qualitative synthesis of the findings from the included studies, structured around type of assisted reproductive technology involved, fertility outcomes, significant improvement in quantity and p value, and effect size. We will provide summaries of study characteristics, variable measures, data analysis models, significant study findings, and reported effect sizes.

Reporting bias and certainty assessment

If possible, publication bias will be assessed with a funnel plot and the quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for both primary and secondary outcomes. The four levels of quality (high, moderate, low, and very low) will be used to assess the evidence related to the primary outcome. GRADE profiler (GRADEPRO) [33] will be used to import data from Review Manager 5.2.4 to create a “summary of findings” table.

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