Plasma Transfusion in Neonatal Sepsis: Promising Theory, Conflicting Evidence

Neonatal sepsis remains one of the most formidable challenges in modern medicine, standing among the leading causes of death for newborns worldwide. According to recent population meta-analyses and Global Burden of Disease data, the worldwide incidence of neonatal sepsis reaches approximately 2,824 cases per 100,000 live births, with an overall mortality of 17.6 percent. In 2021 alone, 206,451 neonatal sepsis-related deaths were recorded globally. The burden is strikingly uneven: in high-income nations such as Switzerland, neonatal intensive care unit sepsis incidence is around 1.3 percent with mortality near 10 percent, while in low-resource settings such as Uganda, hospitalization sepsis rates climb as high as 35.5 percent. This stark regional disparity reflects differences in socioeconomic conditions, healthcare infrastructure, and access to effective interventions, underscoring an urgent need for therapies that can be applied across diverse clinical environments.

The biological characteristics of newborns further complicate management. The neonatal immune system is not yet fully developed, so once sepsis occurs, infants are prone to rapid progression toward septic shock and multiple organ dysfunction syndrome. At the same time, the metabolic and enzyme systems of the liver and kidneys remain immature, limiting the ability to clear drugs. Antibiotics routinely used in adults, such as fluoroquinolones and sulfonamides, cannot be directly administered to neonates. Against this backdrop, researchers have increasingly focused on adjunctive therapies built upon standard antibiotic treatment, and plasma transfusion has emerged as one of the most debated candidates. Yet the timing and precise indications for plasma transfusion in neonates remain deeply controversial, prompting a new editorial in the World Journal of Pediatrics by Fang-Rui Ding and Xiao-Yan Li that systematically examines the theoretical foundation, risks, and current clinical application of this approach.

The rationale for using plasma transfusion in sepsis originated in trauma care. Trauma and sepsis share a striking degree of pathophysiological similarity. Both conditions trigger acute intravascular volume depletion and tissue hypoperfusion, as systemic vasodilation and elevated vascular permeability drive massive fluid extravasation, destabilizing the circulation and rapidly progressing to shock. Both disorders also induce severe coagulopathy, marked by excessive consumption of coagulation factors, disrupted anticoagulant pathways, and dysregulated fibrinolysis. Given these overlapping mechanisms, and given that multiple studies have demonstrated that early and active plasma transfusion in trauma patients significantly improves survival and clinical outcomes, it is biologically plausible to infer that plasma might confer comparable benefits in sepsis. This reasoning has shaped clinical intuition for decades, even in the absence of direct evidence in septic patients.

Neonates, especially preterm infants, have inherently low levels of coagulation factors, insufficient immunoglobulins and complement, and a fragile vascular endothelial barrier. When sepsis strikes, the systemic inflammatory response further consumes immune and coagulation-related mediators, worsening disease progression. In theory, plasma transfusion could rapidly replenish these deficient bioactive substances. Immunoglobulin supplementation could strengthen specific immune defenses against pathogens, neutralize toxins, and facilitate infection control. Coagulation factors and fibronectin could optimize hemostasis, preventing and treating sepsis-associated coagulopathy. Complement components could boost bacteriolytic and opsonizing capacity, promoting pathogen clearance. Colloid supplementation might also help maintain blood volume and plasma osmotic pressure, improving tissue perfusion and correcting septic shock. These mechanisms form a coherent and appealing therapeutic hypothesis.

Animal studies have lent support to these theoretical inferences. In a septic rat model, Chang and colleagues found that plasma transfusion raised the 48-hour survival rate from 14 percent to 57 percent compared with normal saline resuscitation. In foals, McTaggart and colleagues demonstrated that plasma transfusion elevated serum immunoglobulin G levels in both healthy and septic animals, and although it exerted no benefit on neutrophil function in healthy foals, it significantly improved neutrophil activity in septic ones. More strikingly, Pereira and colleagues studied neonatal puppies with sepsis and found that combined treatment with plasma and antibiotics improved immune and metabolic parameters, including blood glucose, white blood cell counts, and IgM levels, within 24 hours, shortened recovery of leukocyte indices, reduced lactate levels, and resulted in zero mortality, compared with a 22 percent mortality rate in the antibiotic-only group. Despite these encouraging results, the editorial’s authors caution that no high-grade human evidence has confirmed clinical efficacy, and findings from animal models may not be directly applicable to human neonates because of inherent species and environmental differences.

In humans, the picture grows considerably murkier. Clinical studies of plasma transfusion in sepsis have produced conflicting results, and some have associated transfusion with increased incidence of complications and poorer prognosis. Qin and colleagues, analyzing data from the Medical Information Mart for Intensive Care III database, found that both 28-day and 90-day mortality were significantly higher in the plasma transfusion group than in the non-transfusion group, and plasma transfusion did not improve prognosis even among sepsis patients with coagulopathy, regardless of coagulation state. In a pediatric study by Duan and colleagues involving 262 children with sepsis, 28-day mortality, in-hospital mortality, and multiple organ dysfunction syndrome morbidity were all significantly higher in the plasma transfusion group. Plasma transfusion demonstrated no benefit and was instead significantly associated with an increased risk of adverse outcomes, findings that directly challenge the intuitive appeal of the therapy.

Beyond questions of efficacy, plasma transfusion carries substantial safety risks. Allergic reactions occur at an approximate incidence of 1 to 3 percent. Transfusion-related acute lung injury, or TRALI, has an estimated incidence of 0.08 to 15.1 percent in critically ill patients and accounts for 34 percent of transfusion-related fatalities, although improved mechanistic understanding and donor selection have reduced risks in recent years. Transfusion-associated circulatory overload, or TACO, occurs in roughly 1 percent of transfusions overall but reaches 3.6 to 5.8 percent in critically ill patients, with widespread underdiagnosis and underreporting. While donor screening and pathogen inactivation have substantially reduced infection transmission, residual risks persist, with HIV and hepatitis C transmission rates of approximately 0.02 per 10,000 transfusions, and newly emerging pathogens remain a potential threat. Plasma transfusion may also increase nosocomial infection risk through transfusion-related immunomodulation, a phenomenon linked to postoperative infection in critically ill patients.

Current practice reveals a striking gap between guidelines and reality. Plasma transfusion is relatively common in neonatal intensive care units, with use varying dramatically across centers from 0.17 percent to 8.2 percent, and rates are generally higher for surgical cases and extremely preterm neonates. International guidelines are consistent in their core recommendation: plasma should be given only for active bleeding accompanied by coagulation disorders, and prophylactic transfusion is not recommended. No current sepsis guideline recommends plasma for sepsis itself. Yet observational surveys consistently reveal widespread non-adherence. In European countries, only 29.4 percent of plasma transfusions were given for bleeding, while in South Africa 75 percent of transfusions complied with national guidelines. The authors attribute this deviation to two interrelated factors: the lack of effective targeted interventions for neonatal septic shock, which drives clinicians to adopt plasma as a salvage therapy out of clinical urgency, and the extrapolation of trauma resuscitation experience combined with assumptions about neonatal immune and coagulation immaturity.

The limited human studies specific to neonatal sepsis offer mixed signals. A 1994 study by Acunas and colleagues involving 67 infected neonates found that while intravenous immunoglobulin exerted prominent immune-enhancing effects, plasma transfusion failed to elevate key anti-infective IgG or alter inflammatory markers such as C-reactive protein and fibronectin, indicating no clinical benefit. Conversely, a Nigerian retrospective study by Ogunlesi and colleagues in neonatal tetanus with suspected sepsis observed lower mortality in plasma-transfused neonates, though the difference was statistically insignificant due to small sample size, and all blood culture-positive patients in the transfusion group survived. Eisenfeld and colleagues further demonstrated that plasma transfusion significantly improved neutrophil chemotactic function in critically ill neonates with suspected severe sepsis. Data from other neonatal contexts add further complexity, with studies linking plasma transfusion to retinopathy of prematurity, bronchopulmonary dysplasia, hemodynamically significant patent ductus arteriosus, and necrotizing enterocolitis, though results remain contradictory and appear to depend heavily on transfusion timing, indication, and patient characteristics.

The editorial concludes that there are no definitive evidence-based data confirming that plasma transfusion benefits neonatal sepsis, but this does not mean benefits are absent. The authors call for large-sample, multicenter retrospective and prospective randomized controlled trials with carefully defined inclusion criteria, appropriate coagulation and infection outcomes, and stratified analysis by gestational age and weight to enable individualized treatment. They also urge deeper mechanistic research into the roles of immunoglobulins, coagulation factors, complements, and fibronectin in plasma, alongside safety studies addressing both short-term risks such as TACO, viral transmission, and allergic reactions, and long-term neonatal complications. Until such evidence arrives, plasma transfusion in neonatal sepsis remains a therapy caught between biological plausibility and clinical uncertainty, a gap that only rigorous research can close.

Subject of Research: The use of plasma transfusion as an adjunctive therapy for neonatal sepsis, including its theoretical benefits, clinical evidence, safety risks, and guideline recommendations.

Article Title: Plasma transfusion in neonatal sepsis

Article References: Ding, F.-R., & Li, X.-Y. (2026). Plasma transfusion in neonatal sepsis. World Journal of Pediatrics. https://doi.org/10.1007/s12519-026-01095-6

Image Credits: AI Generated

DOI: 10.1007/s12519-026-01095-6

Keywords: neonatal sepsis, plasma transfusion, fresh frozen plasma, neonatal intensive care, coagulopathy, septic shock, transfusion-related acute lung injury, immunoglobulins, randomized controlled trials, preterm infants, transfusion safety, clinical guidelines