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

A comprehensive recent study published in JAMA Pediatrics has illuminated this paradox, presenting data that delineate a nearly 2% annual increase in neonatal deaths associated specifically with impaired fetal growth and deficient prenatal nutrition. This upward trajectory runs counter to the general decline in neonatal fatalities, spotlighting an insidious and less overt public health challenge. The findings compel the medical community and public health officials to scrutinize the complex and multifactorial origins of fetal malnutrition and growth retardation amid a backdrop of otherwise advancing perinatal care.

From a physiological perspective, fetal growth restriction (FGR) and malnutrition represent conditions where the fetus fails to achieve its genetically predetermined growth potential due to suboptimal intrauterine environments. The etiologies rarely reside in isolated causes; rather, they encompass a spectrum of maternal, placental, and environmental factors. Deficits in placental nutrient transfer, maternal malabsorption, micronutrient deficiencies, chronic illness, and socio-economic stressors are recurring contributors. This compromised prenatal state alters cellular growth factors, disrupts metabolic programming, and impairs organogenesis, all of which culminate in increased vulnerability to neonatal mortality.

Crucially, while neonatal intensive care has improved survival among neonates suffering from prematurity and other acute conditions, these technological gains confer limited protective effect against deaths stemming from chronic intrauterine malnutrition. The biological underpinnings of slow fetal growth involve diminished nutritive support and oxygenation that predispose infants to complications including hypoglycemia, thermoregulation failure, and impaired immune function after birth. Such physiological fragility often overwhelms neonatal adaptive mechanisms, particularly in resource-limited settings or where prenatal nutrition is inadequately addressed.

The upward trend in mortality from impaired fetal nutrition accentuates existing disparities in maternal health, which are compounded by socio-economic determinants. Populations facing food insecurity, limited access to quality prenatal care, and higher prevalence of comorbidities such as hypertension and diabetes present a vulnerable nexus for fetal growth compromise. Moreover, lifestyle factors including substance abuse, stress, and environmental exposures exacerbate the risk profile for fetal undernutrition. This highlights an urgent need to recalibrate public health strategies beyond neonatal care towards upstream prevention focused on maternal well-being.

Emerging research has suggested that nutritional physiology and the roles of specific growth factors during pregnancy have profound implications on fetal development. Growth factors such as insulin-like growth factor (IGF), placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) govern cellular proliferation and angiogenesis pivotal for optimal placental function and nutrient transfer. Dysregulation of these molecules in malnourished pregnancies disrupts fetal growth patterns and has been correlated with adverse perinatal outcomes. Therapeutic targeting of these pathways remains an investigational frontier with promising potential.

Prenatal care paradigms, while broadly improved, often fall short in effectively identifying and managing nutritional deficits underlying fetal growth failure. Current surveillance methods, including ultrasonographic biometric measurements and Doppler assessment of placental blood flow, provide snapshots of fetal well-being but may not capture subtle yet critical nutrient deficiencies. Developing more sensitive biomarkers and integrating nutritional assessments into routine obstetrical practice could enable earlier interventions and better outcomes.

An additional dimension worth considering is the intergenerational impact of poor prenatal nutrition and slow fetal growth. Epigenetic modifications induced by nutrient deprivation during critical developmental windows may predispose offspring to chronic diseases in adulthood, including cardiovascular disease, diabetes, and metabolic syndrome. This fetal programming phenomenon underscores the long-term societal and economic costs tied to unresolved issues of prenatal malnutrition and neonatal mortality.

International comparisons reveal that while many countries have successfully reduced neonatal mortality through multifactorial interventions, disparities persist in the prevalence of fetal growth restrictive conditions. The United States, despite its medical infrastructure, appears to be grappling with complex demographic and socioeconomic challenges that impede uniform improvements in prenatal nutrition. These findings warrant a concerted effort to integrate nutritional policy, public health, and maternal-fetal medicine in comprehensive frameworks.

In sum, this recent analysis sheds critical light on a growing and somewhat paradoxical public health issue: despite advancements in neonatal intensive care saving countless lives, the silent epidemic of fetal growth impairment and nutrition-related neonatal deaths continues unabated. Addressing this challenge necessitates a multidisciplinary approach encompassing enhanced prenatal nutrition programs, refined diagnostic tools, targeted research into molecular growth pathways, and socioecological interventions aimed at mitigating risk factors before birth.

The study’s corresponding author, Dr. Muzamil Khan, emphasizes that improvements in neonatal survival will require holistic strategies that extend well beyond hospital walls. Elevating maternal nutrition, improving access to prenatal care, and addressing social determinants of health collectively form the cornerstone of future efforts to reverse the concerning rise in mortality from slow fetal growth and malnutrition in U.S. newborns. Ultimately, bridging the gap between medical innovation and equitable prenatal health remains vital to ensuring a healthier start for the nation’s most vulnerable lives.

Subject of Research: Neonatal mortality linked to slow fetal growth and prenatal malnutrition in the United States

Article Title: [Not specified in the provided content]

News Publication Date: [Not specified in the provided content]

Web References: doi:10.1001/jamapediatrics.2025.1710

References: [Not specified in the provided content]

Image Credits: [Not specified in the provided content]

Keywords: Neonatology, Mortality rates, United States population, Nutrition, Growth factors, Prenatal care, Pregnancy