From Harmless to Harmful: Meta-Analysis and Systematic Review of Adverse Clinical Outcomes in Sickle Cell Trait

Background: Sickle cell trait (SCT) has traditionally been considered a benign condition; however, emerging evidence suggests it may have serious clinical consequences. This systematic review and meta-analysis aim to synthesize current research on the adverse clinical outcomes associated with SCT. Methods: A systematic review search was conducted on PubMed, Embase, and Central Cochrane Registry to identify studies reporting on the clinical outcomes of SCT. Studies were included if they evaluated conditions such as diabetes, end-stage renal disease (ESRD), pulmonary embolism (PE), deep vein thrombosis (DVT), and chronic kidney disease (CKD)(EGFR <60) in individuals with SCT against a matched sample of controls without a history of SCT (matched on age, race, sex). Cross-sectional studies were included. Data extraction and quality assessment were performed independently by two reviewers. From 88 records initially identified from bibliographic databases, 12 studies were eligible and therefore included the meta-analysis. For measuring association between SCT and DVT, PE, CKD, ESRD and diabetes a meta-analysis using the random-effects method was performed to pool weighted odds ratios (OR) of risk estimates, and heterogeneity was assessed using the I² statistic. For effect sizes, a confidence interval of 95% was used, and a p-value of less than 0.05 was used for statistical significance Results: The meta-analysis included 12 studies, including a total of 1128624 individuals with either SCT or no SCT/SCD. The pooled analysis revealed significant associations between SCT and CKD, ESRD, DVT and PE. Individuals with SCT had an increased risk of ESRD (pooled OR = 2.21, 95% CI: 1.87-2.85, p<0.01), PE (pooled OR = 1.75, 95% CI: 1.53-2.01, p<0.01), DVT (pooled OR = 1.54, 95% CI: 0.99-2.30, p=0.05), and CKD (pooled OR = 1.79, 95% CI: 1.54-2.08). There was no significant association seen with SCT and diabetes. Low heterogeneity was observed in the outcomes of ESRD and CKD (I² = 0% and 43%, respectively), warranting further investigation into underlying factors. Conclusions: This systematic review and meta-analysis demonstrate that SCT is associated with an increased risk of several serious clinical conditions, challenging the traditional view of SCT as a benign trait. These results may have important public policy implications for risk stratification and genetic counseling of SCT carriers as well as the need for heightened clinical awareness and monitoring of individuals with SCT to prevent and manage potential complications Keywords: Sickle Cell Trait, Diabetes, End-Stage Renal Disease, Pulmonary Embolism, Deep Vein Thrombosis, Chronic Kidney Disease, Meta-Analysis, Systematic Review