Inflammatory Mediators in the Pathway from Breastfeeding Difficulty to Postpartum Depression: A Systematic Review Following Moose Guidelines.

Background: Breastfeeding difficulty, particularly pain and mastitis, has been consistently associated with an increased risk of postpartum depression (PPD). Emerging evidence suggests that systemic inflammation may mediate this relationship, but the extent and consistency of this pathway remain unclear. The study objective is to systematically review observational studies examining the role of inflammatory biomarkers (IL-6, CRP, TNF-α, and IL-1β) in the association between breastfeeding difficulty (pain, mastitis, or cessation) and postpartum depressive symptoms. Methodology: Following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines, we searched PubMed, Web of Science, PsycInfo, CINAHL, and Scopus from inception to July 2026. Observational studies assessing breastfeeding-related factors, inflammatory markers measured in biological fluids during the postpartum period (≤ 6 months), and standardized depression measures were included. Quality was assessed using the Newcastle-Ottawa Scale. Due to high heterogeneity, a narrative synthesis was performed. Results: Twelve studies met inclusion criteria (N=2,847 postpartum women). IL-6 was the most consistently elevated biomarker among women with breastfeeding difficulty and concurrent depressive symptoms, with 7 of 9 studies reporting significant positive associations. CRP showed mixed findings (4 of 8 studies significant). TNF-α and IL-1β demonstrated weaker or inconsistent associations. Mastitis was associated with the most pronounced inflammatory responses and the strongest depression correlations. Breastfeeding cessation due to pain was consistently linked to elevated IL-6 and higher EPDS scores across 5 longitudinal studies. Conclusions: Evidence supports IL-6 as a potential mediator between breastfeeding difficulty and PPD, though substantial heterogeneity in study design, biomarker timing, and depression assessment limits pooled analysis. Standardized methodologies and prospective studies with repeated biomarker measures are urgently needed to establish causal pathways and inform prevention strategies.