Comparative efficacy and safety of oral iron polymaltose complex vs. ferrous sulphate in the treatment of pediatric iron deficiency anemia: a systematic review, meta-analysis and trial sequential analysis

Oral iron supplementation is the first-line therapy for pediatric iron deficiency anemia (IDA). Ferrous sulphate (FS) remains the conventional standard of care but frequently induces gastrointestinal (GI) adverse effects. Iron polymaltose complex (IPC) has emerged as an alternative with improved tolerability, though its comparative efficacy remains debated. This systematic review and meta-analysis compared the efficacy and safety of oral IPC versus FS in the pediatric population. Electronic databases (PubMed, Embase, and Scopus) were systematically searched from inception to March 2026 for randomized controlled trials (RCTs) comparing oral IPC and FS in pediatric patients. The primary outcomes assessed were mean change from baseline in hemoglobin and serum ferritin levels, while secondary outcomes analyzed included mean change from baseline in serum iron and the incidence of gastrointestinal adverse effects. Pooled estimates were calculated using random-effects models. Certainty of evidence was graded via the GRADE framework, and Trial Sequential Analysis (TSA) evaluated the conclusiveness of primary outcomes. Eight RCTs involving 643 participants met the inclusion criteria. Meta-analysis demonstrated that FS achieved a significantly greater mean increase from baseline in hemoglobin (MD: -0.87 g/dL, 95% CI: -1.15 to -0.59, P < 0.00001) and serum ferritin levels (MD: -12.82 µg/L, 95% CI: -24.71 to -0.93, P = 0.03) compared to IPC. TSA confirmed that cumulative data for mean change in hemoglobin recovery reached sufficient statistical power, whereas ferritin data remained underpowered, highly heterogeneous ( \({{I}}²=80%\) ), and inconclusive. Primary pooled safety analyses revealed no statistically significant differences between IPC and FS in the risk of total adverse events (RR: 0.54, 95% CI: 0.10–2.97, P = 0.48) or diarrhea (RR: 0.51, 95% CI: 0.23–1.11, P = 0.09; \({{I}}²=0%\) ). Secondary sensitivity modeling excluding active symptom solicitation suggested a lower overall burden of total adverse events for IPC. FS yields a greater mean increase in hemoglobin levels and iron store replenishment in pediatric IDA. Primary safety analyses demonstrate no clear evidence of a difference between IPC and FS regarding diarrhea risk or baseline overall adverse events. However, when accounting for methodological reporting variations across trials, sensitivity analysis suggests IPC may lower total adverse event rates in specific pediatric contexts.