Complement deficiency and neonatal immunity: a serum-limited, context-dependent framework

Neonatal infection remains a major cause of morbidity and mortality worldwide, particularly among preterm infants, who are at high risk of severe bacterial sepsis. Although this vulnerability has traditionally been attributed to global immune immaturity, emerging evidence supports the possibility that complement deficiency may represent an important contributor to impaired neonatal immune function. Complement activity and component levels are consistently reduced in newborns and correlate with gestational age. Functional studies show that neonatal neutrophils regain bactericidal capacity in adult serum, whereas neonatal serum suppresses adult neutrophil function, indicating that humoral factors play a major, though not exclusive, role in immune performance. We propose a hypothesis-generating framework in which neonatal immunity is influenced by complement availability within a broader network of humoral and cellular interactions. However, this model is challenged by the observation that fresh frozen plasma, despite increasing complement levels, does not improve clinical outcomes in neonatal sepsis. This discrepancy suggests that complement insufficiency may contribute predominantly to baseline susceptibility rather than to established sepsis physiology, where broader inflammatory mechanisms predominate. These observations support a context-dependent, hypothesis-generating model of neonatal immunity and highlight the need for prospective mechanistic and clinical studies evaluating functionally limiting complement pathways and targeted therapeutic strategies. IMPACT: Proposes a serum-limited framework linking complement immaturity to neonatal immune vulnerability. Integrates complement availability with developmental and microenvironmental context to explain variability. Provides a testable model with implications for risk stratification and targeted immunomodulation.