DOI: 10.6084/m9.figshare.28873748.v1
title: Supplementary Material for: Dietary Supplements for Endometriosis-Associated Pain: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

description: Introduction: In recent years, dietary supplements have emerged as popular "natural" alternatives to conventional pharmacological treatments for various conditions, including endometriosis. The growing popularity of supplements for endometriosis-associated pain, fueled by an expanding and minimally regulated market, underscores the need for robust evidence of efficacy, as a prerequisite for any consideration on effectiveness. This meta-analysis synthesizes evidence from randomized, placebo-controlled trials (RCTs), the gold standard in evidence-based medicine, to assess the efficacy of dietary supplements in endometriosis-associated pain. 
Methods: A systematic search of PubMed, Embase, Scopus, and the Cochrane Library was conducted up to November 5th, 2024, in adherence to PRISMA 2020 guidelines. Two independent reviewers screened studies using PICOS criteria: reproductive-age women with endometriosis (Population), dietary supplements (Intervention), placebo (Comparator), and pain-related outcomes (Outcomes), assessed in placebo-controlled RCTs adhering to CONSORT standards (Study type). Three pain domains were evaluated: i) symptom severity (visual analogue scale (VAS) for pelvic pain, dysmenorrhea, dyspareunia), ii) pain catastrophizing, and iii) quality of life (QoL), as measured by the Short Form-12 Health Survey (SF-12) and the Endometriosis Health Profile-30 (EHP-30). Risk of bias was assessed using the Cochrane RoB2 tool. Random-effects models were used to calculate pooled mean differences (MD) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed with the I² statistic, and subgroup analyses explored clinically relevant confounders. Sensitivity analyses excluded studies with conflicts of interest or trustworthiness issues, as defined by the Obstetrics and Gynecology Editors' Integrity Group (OGEIG). Publication bias was evaluated using Egger’s test, Begg’s test, and the trim-and-fill method. All analyses were conducted using STATA version 18.
Results: Nine RCTs (n=545 subjects; 274 in the treatment group and 271 in the placebo group) were included. Only three met the ‘absolute’ OGEIG trustworthiness criteria. No significant differences were observed between supplements and placebo for pelvic pain (pooled MD: -1.1; 95% CI, -3.0 to 0.8; I²=96.1%), dysmenorrhea (pooled MD: -2.0; 95% CI, -4.4 to 0.5; I²=93.8%), or dyspareunia (pooled MD: -2.0; 95% CI, -4.9 to 0.9; I²=96.5%). These findings remained consistent when the analysis was restricted to studies without conflicts of interest, those authored by researchers with no retractions, and those meeting OGEIG trustworthiness criteria. Subgroup analyses reduced heterogeneity and confirmed no significant benefits. Pain catastrophizing and quality-of-life measures showed little to no improvement.
Conclusion: While limited evidence precludes definitive conclusions about specific dietary supplements, available data suggests they lack efficacy for managing endometriosis-associated pain. Given the absence of demonstrated benefits, along with potential harms and costs, dietary supplements should not be recommended at this time for managing endometriosis-related pain. 
Study registration: PROSPERO ID CRD42024607058.