The Effect of Combined Oral Contraceptive Pills on the Cardiovascular Risk in Pre-menopausal Women with Endometriosis-systematic Review and Meta-analysis

Abstract

Background: Endometriosis is associated with increased cardiovascular (CV) risk. While Combined Oral Contraceptive Pills (COCPs) are a mainstay treatment, they may independently affect CV health. It remains unclear whether COCPs exacerbate risk in these patients or mitigate it by reducing chronic disease-related inflammation. Objectives: To compare the effects of COCPs versus no treatment/placebo, and Progestin-Only Pills (POPs) versus COCPs, on cardiovascular events and biomarkers in pre-menopausal women with endometriosis. Methods: We searched electronic databases (Medline, Popline, Cochrane, and Embase) and grey literature up to March 2023. Eligible participants were pre-menopausal women with radiologically or surgically diagnosed endometriosis. Outcomes included hard CV events (e.g., MI, stroke, CV mortality) and CV profiles (lipids, inflammatory, and coagulation markers). Eligible study designs included randomized clinical trials (RCTs) and non-randomized studies of interventions (NRSIs). We excluded non-comparative studies and studies where COCPs were not the sole hormonal treatment. Two reviewers independently performed screening, data extraction, risk of bias assessment (RoB 2.0), and GRADE certainty assessment. Effect estimates were calculated as post-intervention mean differences or change-from-baseline values (for outcomes with baseline imbalances) with 95% confidence intervals (CI). Meta-analysis utilized random-effects models (fixed-effects were used if studies < 3). For missing data, we employed imputation methods using a correlation coefficient of 0.5 for change-from-baseline SDs and stringent imputation strategies for missing outcome data. Clinical significance was assessed using clinically anchored Minimal Important Differences (MIDs). Results: No studies reported on hard cardiovascular events. Four RCTs met inclusion criteria (one COCP vs. placebo; three POP vs. COCP). Of these, two open-label, single-center RCTs, conducted in Italy provided numerical data for meta-analysis of POP vs COCP, involving a total of 153 participants (age range 18–40 years). Meta-analysis of POP vs. COCP showed a statistically significant reduction in Total Cholesterol (TC) favoring POPs (MD: -12.86 mg/dl; 95% CI: -21.91, -3.82; p=0.005). While the effect estimate exceeded the clinical threshold (MID: -10 mg/dl), the 95% CI crossed the MID, indicating imprecision. Differences for LDL (MD: 3.2 mg/dl; 95% CI: -6.91, 13.3; p=0.54) and HDL (MD: -0.38 mg/dl; 95% CI: -4.21, 3.46; p=0.85) were not statistically significant and were limited by imprecision (according to the C.I criterion for LDL, and Optimal Information Size (OIS) for HDL). For Triglycerides (TG), a single RCT showed a statistically and clinically significant benefit for POPs (MD: -40.83mg/dl; 95% CI: -58.99, -22.61; p<0.0001), though limited by the OIS criterion. Sensitivity analyses for missing outcome data confirmed robust results for TC, HDL, and LDL, but results for TG were non-robust. Discussion: This systematic review and meta-analysis is constrained by the limited number of included studies. The certainty of evidence (GRADE) was downgraded due to imprecision for all outcomes, resulting in moderate certainty for TC, HDL, and LDL, and low certainty for TG due to additional high risk of bias from missing outcome data. Conclusion: While POPs may offer a more favorable lipid profile than COCPs in women with endometriosis, evidence remains limited. Future high-quality research with extended follow-up is required to evaluate hard cardiovascular outcomes and a broader range of biomarkers, including inflammatory, coagulative, and endothelial dysfunction markers.