RARE DISEASE
Sepsis in premature infants
Sepsis in premature infants
Sepsis in premature infants
Drug discovery
5
drugs
With orphan designations
Overview
Sepsis in premature infants is a life-threatening systemic infection characterized by dysregulated host response and organ dysfunction, occurring as early-onset (≤72 hours) or late-onset (>72 hours to 3 months). Common pathogens include Escherichia coli, Group B Streptococcus, and coagulase-negative staphylococci [1][3][12]. Preterm infants face elevated risks due to immature immunity, with mortality rates exceeding 20% in very low birth weight infants and significant long-term morbidities [4][9][14].
Burden
Global case fatality rate: 18%, rising to 24% in very low birth weight infants [4][9]
Survivors face increased risks of chronic lung disease, neurodevelopmental impairment, and technology-dependent care (e.g., tracheostomy) [9][14]
Disproportionately impacts low-resource settings, with sub-Saharan Africa reporting 28% of neonatal sepsis-related deaths [2][4]
Therapies
Immediate empiric therapy with ampicillin + gentamicin/aminoglycoside [3][13], adjusted post-culture
Intrapartum antibiotic prophylaxis for GBS-positive mothers reduces early-onset cases [3][12]
Antibiotic stewardship to minimize prolonged broad-spectrum use, linked to NEC and late-onset sepsis [3][8]
Categories: rare systemic and rheumatological diseases
Research Papers
1,479 drug discovery papers about Sepsis in premature infants, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,479 drug discovery papers about Sepsis in premature infants, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-25 | Early versus Late Initiation of Enteral Feeding in Premature Infants (28-34 Weeks GA) with Growth Restriction and Absent or Reversed End-Diastolic Flow on Umbilical Artery Doppler: A Randomised Controlled Trial.
The authors conducted an open-label RCT in growth-restricted preterm infants (28-34 wk) with Absent or Reversed end-diastolic flow on Antenatal Umbilical-Artery Doppler (AREDF) to compare early enteral feeding at 6 h (EIEF) with initiation at 48 h (LIEF). Eighty-seven infants were randomised (EIEF 44, LIEF 43). Feeds were advanced daily at 20, 40, 60, 90, 120, and 150 mL/kg/d, respectively, from the day of commencement of feeds. The primary outcome was time to full feeds; secondary outcomes included feed-intolerance (FI), NEC ≥ stage 2b, late-onset sepsis, mortality, and hospital stay. EIEF achieved full feeds earlier than LIEF (median 6 vs. 8 d). Rates of FI (20.9% vs. 25.6%), NEC (0 vs. 4.6%), mortality (6.8% vs. 16.3%), and hospital stay were not statistically different. Late-onset sepsis was lower with EIEF (6.8% vs. 27.9%). Early feeds from 6 h, with careful monitoring, enabled full feeds by day 6 without increasing adverse outcomes. The trial was registered prospectively at CTRI.org on 01/03/2019 (CTRI No. CTRI/2019/03/017899).
2026-09-23 | Probiotics and Risk of Death, Necrotizing Enterocolitis, and Sepsis in Very Preterm Infants.
Probiotics are reported to benefit preterm infants, but population-based clinical evidence is limited. In 2020, the Swedish Neonatal Society issued a national recommendation to supplement very preterm infants (28 weeks 0 days' to 31 weeks 6 days' gestation) with probiotics. To investigate whether probiotic supplementation was associated with risk of death, necrotizing enterocolitis (NEC), and/or culture-proven sepsis in infants born very preterm. This population-based cohort study examined data from the Swedish Neonatal Quality Register from January 1, 2017, through December 31, 2024. Live-born, very preterm infants, excluding those who died within the first 3 days of life or due to congenital or chromosomal abnormalities, were included. Daily probiotic supplementation of 1 billion colony-forming units of freeze-dried Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus initiated following birth and discontinued at postmenstrual week 34. Composites of death and/or NEC (Bell stage 2-3), death and/or surgical NEC (Bell stage 3), and death and/or culture-proven sepsis were assessed. Modified Poisson regression, propensity score-matched, and inverse probability of treatment weighting analyses were used for replication analyses. A multivariate bayesian modeling analysis accounting for the association between NEC and mortality was performed to estimate the association between probiotic exposure and mortality. Among 4695 infants (mean [SD] gestational age, 30.2 [1.1] weeks; 2550 male [54.3%]), probiotic exposure increased from 0% before the national recommendation in 2020 to 16.9% in 2020 and a mean (SD) of 64.8% (4.7%) in 2021 to 2024. Probiotic supplementation vs no supplementation was associated with lower risk of death and/or NEC (rate, 0.8% vs 3.4%; adjusted relative risk [ARR], 0.28 [95% CI, 0.14-0.56]). When assessed separately, risks of death (rate, 0.3% vs 1.4%; ARR, 0.16 [95% CI, 0.06-0.45]) and NEC (rate, 0.6% vs 2.5%; ARR, 0.25 [95% CI, 0.10-0.61]) were both lower in the probiotic group. Multivariate bayesian modeling suggested that a substantial proportion of the observed mortality reduction was mediated via reduced NEC incidence (42.3% [credible interval, 16.1%-100%]). Probiotic supplementation was not associated with death and/or culture-proven sepsis (rate, 3.4% vs 4.4%; ARR, 0.86 [95% CI, 0.58-1.26]). This cohort study of very preterm infants found that implementation of a multistrain probiotic was associated with a significant reduction in death and/or NEC, which may help inform shared decision-making between clinicians and families. These results should not be generalized to extremely preterm infants (<28 weeks' gestation).
2026-08-31 | Probiotic Implementation and Necrotizing Enterocolitis Risk in Preterm Infants.
Despite their widespread use, uncertainty remains about the effectiveness and safety of probiotics for preventing necrotizing enterocolitis (NEC) in preterm infants. Recent regulatory warnings, including from the US Food and Drug Administration, have further emphasized the need for robust clinical data on both the benefits and risks of probiotics for this population. To evaluate the association between implementation of a multistrain probiotic formulation and NEC incidence in preterm infants in a high-risk neonatal intensive care unit (NICU) setting. This multicenter retrospective cohort study was conducted at 2 NICUs in the Netherlands. Preterm infants (<30 weeks of gestational age [GA], birth weight [BW] <1000 g, or both) born between January 1, 2018, and July 1, 2024, were compared before and after the implementation of routine probiotic supplementation. The probiotic protocol was introduced in October 2020 or March 2021, depending on the center. Routine implementation of a multistrain probiotic formulation (Bifidobacterium infantis Bb-02, Bifidobacterium lactis BB-12, and Streptococcus thermophilus TH-4) as part of enteral feeding. The primary outcome was NEC incidence, classified as medical, surgical, or fatal. Secondary outcomes included all-cause mortality and mortality not associated with NEC. Primary and secondary outcomes were analyzed using generalized linear regression models, comparing preimplementation and postimplementation periods and adjusting for GA, sex, BW z score, 5-minute Apgar score, prenatal steroid use, and preterm premature rupture of membranes. Interrupted time-series analysis was performed as a sensitivity analysis to assess robustness against underlying temporal trends. Probiotic-related sepsis was monitored to assess safety. This study included 1413 infants (742 males [52.5%]), stratified into a preimplementation group (n = 598) and a postimplementation group (n = 815). Baseline characteristics were comparable between groups (median GA, 27.7 weeks [IQR, 26.0-29.0 weeks] and 27.9 weeks [IQR, 26.4-29.0 weeks]; median BW, 950 g [IQR, 770-1170 g] and 975 g [IQR, 790-1190 g]). Following probiotic implementation, NEC incidence decreased from 11.9% (n = 71) to 5.3% (n = 43) (adjusted risk ratio [ARR], 0.49 [95% CI, 0.34-0.70]; P < .001). No statistically significant evidence of underlying time trends was detected. All-cause mortality remained stable for the preimplementation and postimplementation groups (70 [11.7%] vs 94 [11.5%]; ARR, 1.06 [95% CI, 0.82-1.39]; P = .64); non-NEC-associated mortality increased from 7.2% (n = 43) to 9.6% (n = 78) (ARR, 1.42 [95% CI, 1.01-1.98]; P = .04). One case of probiotic-associated sepsis was identified. In this cohort study of preterm infants, implementation of a well-characterized multistrain probiotic was associated with a reduction in NEC incidence. This finding supports the use of the studied probiotic as an effective preventive strategy for NEC, although its effects on broader mortality outcomes remain uncertain.
2026-08-14 | Discordance between in vitro susceptibility and clinical response in early-onset neonatal sepsis caused by Morganella morganii: a case report in an extremely preterm infant.
Early-onset neonatal sepsis (EONS) caused by Morganella morganii is rare, particularly in extremely preterm infants, and poses diagnostic and therapeutic challenges. We report a case of EONS in an extremely preterm neonate in whom blood cultures identified Morganella morganii with in vitro susceptibility to gentamicin, which was initiated as part of the empirical treatment. Despite documented antimicrobial sensitivity, the infant showed no significant clinical improvement. Consequently, antibiotic therapy was modified based on both susceptibility testing and the evolving clinical picture, resulting in marked clinical recovery. This case highlights that antimicrobial susceptibility results should be interpreted in conjunction with the patient's clinical response and that treatment decisions in neonatal sepsis should not rely solely on in vitro sensitivity patterns, particularly when dealing with uncommon pathogens.
2026-08-14 | Routine probiotics and outcomes in infants < 29 weeks: a 13-year single-centre cohort with propensity-weighted sensitivity analyses.
Probiotic supplementation in preterm infants has been associated with reduced necrotising enterocolitis (NEC) and mortality, but reported effects vary across studies due to heterogeneity in populations, probiotic products, and co-interventions, with limited representation of extremely preterm infants. We performed a single-centre retrospective cohort study of infants born at < 29 weeks' gestation admitted for intensive care between 2012 and 2024 using electronic patient records. After excluding infants who died within the first 7 days and other predefined exclusions, 581 infants were analysed: 79 (13.6%) received no probiotics and 502 (86.4%) received probiotics (two products used sequentially during the study period). Baseline characteristics (gestational age, birthweight, sex, and antenatal steroid exposure) were similar between groups. Primary outcomes were in-hospital mortality and severe NEC, defined pragmatically as NEC requiring transfer for surgical management and/or surgery. Secondary outcomes included culture-positive late-onset sepsis (LOS) and time to full enteral feeds. Associations were examined using multivariable logistic regression adjusting for gestational age, birthweight, sex, antenatal steroid exposure, and calendar year, supported by propensity-score overlap-weighted sensitivity analysis. In-hospital mortality was 4.8% in probiotic-exposed infants versus 13.9% in unexposed infants. Probiotic exposure was associated with lower adjusted odds of in-hospital mortality (aOR 0.31; 95% CI 0.10-0.93; p = 0.036). No clear association was observed with severe NEC or culture-positive LOS. In this 13-year single-centre cohort of infants < 29 weeks' gestation, routine probiotic use was associated with lower in-hospital mortality, while effects on severe NEC and LOS were not clearly demonstrated. • Probiotic supplementation in preterm infants has been associated with reduced NEC and mortality, but results vary across studies. • Prior evidence is heterogeneous, with limited representation of extremely preterm infants and variability in probiotic strains, dosing, and co-interventions. • In a 13-year single-centre cohort of infants < 29 weeks' gestation, probiotic use was associated with lower in-hospital mortality after adjustment. • No clear difference in severe NEC (surgery/transfer) was observed between probiotic-exposed and unexposed infants.
cell therapies
2026-03-01 | Gut microbiota immaturity with DL-endopeptidase deficiency links antibiotic use to preterm late-onset sepsis.
Early antibiotic exposure increases late-onset sepsis (LOS) risk in preterm infants, potentially via gut dysbiosis. Analyzing 4,938 longitudinal fecal samples from preterm infants in China, the US, and the UK, we identified a differential pace of gut microbiota development among preterm infants. Delayed maturation correlated with over one-third of LOS risk associated with early antibiotic exposure. Deficiency of a bacterial DL-endopeptidase represented a hallmark of delayed microbiota development and correlated with elevated LOS risk. Supplementation with DL-endopeptidase-producing Enterococcus faecium or Limosilactobacillus reuteri activated the NOD2 receptor via muramyl dipeptide (MDP), regulated macrophage differentiation and polarization, restrained hyperinflammation via cylindromatosis (CYLD) induction, and protected neonatal mice from LOS. A pilot randomized controlled trial showed that L. reuteri supplementation enhanced fecal NOD2 activation in preterm infants. These findings link microbiota immaturity and reduced DL-endopeptidase activity to antibiotic exposure and LOS risk and highlight a candidate biomarker that warrants further validation for clinical translation.
2025-11-25 | Therapeutic potential and translational challenges of extracellular vesicles in neonatal medicine
Extracellular vesicles (EVs) have emerged as promising therapeutic candidates for a range of neonatal diseases, including sepsis, necrotizing enterocolitis, hypoxic-ischemic encephalopathy (HIE), and bronchopulmonary dysplasia (BPD). Derived from diverse sources such as mesenchymal stem cells, breast milk, and even non-animal systems, EVs exhibit potent anti-inflammatory, immunomodulatory, and tissue-regenerative properties. Preclinical studies in neonatal models demonstrate their ability to reduce inflammation, preserve epithelial and endothelial barrier integrity, modulate immune cell phenotypes, and mitigate organ damage. Despite these encouraging findings, several critical barriers hinder their clinical translation. Challenges include incomplete characterization of EV molecular cargo, variability in isolation and quantification methods, lack of standardized dosing protocols, and limited safety data, particularly regarding procoagulant activity and thrombotic risk. The development of standardized, reproducible isolation techniques, rigorous molecular profiling, and GLP-compliant safety assessments is essential to establish clinical readiness. Current early-phase clinical trials targeting neonatal BPD, prevention of prematurity-related brain injury, and HIE indicate growing translational momentum. If these challenges are addressed, EV-based therapeutics could transform neonatal care, reducing mortality and long-term disability in vulnerable preterm and term infants.
2025-09-29 | Application of Umbilical Cord Blood for the Clinical Prevention and Treatment of Complications in Preterm Infants(Review).
Preterm infants face a heightened risk of various complications due to the immaturity of their physiological systems, with global rates of preterm birth increasing. These complications represent the leading causes of mortality in children. This review examines current research on the use of umbilical cord blood(UCB) for managing preterm complications, including bronchopulmonary dysplasia(BPD), hypoxic ischemic encephalopathy(HIE), necrotizing enterocolitis(NEC), sepsis and retinopathy of prematurity(ROP). UCB is rich in bioactive components, including hematopoietic stem cells(HSCs), mesenchymal stem cells(MSCs), and exosomes, which are crucial for neurological and vascular repair, anti-apoptosis, anti-inflammation, and immunomodulation. Both preclinical investigations and clinical trials have highlighted the potential of UCB therapy in mitigating the severity of preterm complications, enhancing clinical outcomes, and fostering long-term neural development. Current clinical studies aim to further confirm the safety and efficacy of UCB therapy, with future research concentrating on refining treatment protocols and tailoring personalized medical approaches to enhance the long-term well-being of preterm infants.
2025-06-19 | Safety and feasibility of allogeneic cord blood-derived cell therapy in preterm infants with severe brain injury (ALLO trial): a phase-1 trial protocol.
Severe intraventricular haemorrhage (IVH) and white matter injury (WMI) are major neurological complications in preterm infants, leading to long-term neurodevelopmental impairments. Despite advances in neonatal care, effective treatments are lacking. Umbilical cord blood cell (UCBC) therapy shows neuroprotective potential, with autologous sources ideal but often not feasible due to the unpredictability of preterm births. Allogeneic UCBCs offer an alternative, although immunogenicity and human leucocyte antigen (HLA) compatibility present challenges with knowledge gaps in their relevance in neonatal populations. This study aims to assess the feasibility and safety of partially HLA-matched allogeneic UCBC therapy in preterm infants with severe brain injury. The ALLO trial is an open-label, phase I, single-arm feasibility and safety study conducted at Monash Children's Hospital, Victoria, Australia. Preterm infants born before 28 weeks (ALLO-1) or between 28 weeks and 36+6 weeks (ALLO-2) gestational age with severe brain injury identified on neuroimaging will be enrolled. Severe brain injury is defined as grade 3 or 4 IVH or significant WMI. Exclusion criteria include major congenital anomalies or redirection to comfort care. Eligible infants will receive a single intravenous infusion of unrelated, allogeneic, partially HLA-matched (4/6 or 5/6 HLA match) UCBCs sourced from a public cord blood bank. The target dose is 50 million total nucleated cells per kilogram body weight. Infusion will occur within 2-3 weeks of confirmation of eligibility, contingent on clinical stability and absence of active sepsis. Primary outcome includes: (1) feasibility, defined as having more than 60% of enrolled infants with an eligible allogeneic partially matched cord blood unit available and (2) safety, defined as absence of severe adverse events within 48 hours of infusion or graft-versus-host disease within 3 months of infusion. Secondary outcomes include survival, neonatal morbidities, neurodevelopmental assessments and serum cytokine analysis. Monash HREC has granted full ethics approval (RES-23-0000-297A) for the study, including the research use of allogeneic cord blood from compassionate donations by healthy donors, facilitated through the Bone Marrow Donor Institute Cord Blood Bank within the AusCord network. Findings will be disseminated through peer-reviewed publications and conference presentations, contributing to the development of novel neuroreparative therapies for preterm brain injury. ACTRN12623001352695 (The Australian New Zealand Clinical Trials Registry).
2024-05-14 | Trends and risk factors analysis of NEC in preterm infants over 9 years
Abstract Background Investigating the trend of changes in the occurrence of necrotizing enterocolitis (NEC) in preterm infants during 9 years and analyzing the risk factors of NEC with the purpose of providing reference for clinical diagnosis and treatment of NEC. Methods Clinical data of NEC in preterm infants with Bell’s stage ≥ II from January 2013 to December 2021 in the Neonatology Department of the Third Affiliated Hospital of Zunyi Medical University was retrospectively analyzed. Trends in the occurrence of NEC in preterm infants were analyzed by the trend chi-square test. Subsequently, the general data (sex, gestational age, singleton or multiple births, birth weight, serum albumin, alkaline phosphatase, sepsis, blood transfusion, mechanical ventilation, RDS, arterial catheterization) and perinatal data (intrauterine distress, turbid amniotic fluid, premature rupture of membranes, mode of delivery, fetal heart abnormalities, diabetes mellitus) were collected; then, the risk factors for NEC were analyzed by univariate and multivariate logistic-regression analysis. Results In the past 9 years, 77 cases of NEC occurred, with the incidence rate of 1.95%, and the incidence of NEC in preterm infants has been increasing year by year ( P < 0.05). The results of univariate analysis showed that the morbidity of NEC in preterm infants was associated with premature rupture of membranes, blood transfusion, sepsis, and the of serum albumin ( P < 0.05). Multivariate logistic regression analysis revealed that blood transfusion (OR = 2.232, 95% CI: 1.012–4.923) and sepsis (OR = 0.899, 95% CI: 0.809–3.915) were independent risk factors of NEC in preterm infants, while high serum albumin (OR = 0.899, 95% CI: 0.809–3.915) was an independent protective factor of NEC in preterm infants. Conclusion The morbidity of NEC is gradually increasing. Inhibition of infection and limitation of blood transfusion are effective measures to reduce the occurrence of NEC. Meanwhile, high serum albumin is a protective factor for NEC.
proteins
2026-07-15 | Fortified Human Milk Compared with Unfortified Human Milk in Preterm Low Birth Weight Neonates: A Systematic Review and Meta-Analysis.
Background/Objectives: Our aim was to assess the benefits and risks of fortified vs. unfortified human milk in preterm/low birth weight neonates and to incorporate the INSPECT-SR tool to enhance evidence appraisal. Methods: PubMed and Scopus were searched from inception to 30 November 2025, limited to human studies published in English. Randomized controlled trials in neonates ≤ 34 weeks' gestation or ≤2500 g birth weight were included. Data extraction followed PRISMA guidelines. Risk of bias was assessed using Cochrane RoB 2, and trustworthiness using the INSPECT-SR tool. Random-effects models were used to pool mean differences (MDs) and odds ratios (ORs); heterogeneity was assessed with I2. Outcomes included weight, length, and head circumference gain velocities, feeding intolerance, necrotizing enterocolitis, late-onset sepsis, chronic lung disease, time to full enteral feeding, length of stay, and mortality. Results: Fifteen randomized controlled trials involving 1079 neonates (546 receiving fortified human milk and 533 receiving unfortified human milk) were included in the analysis. Fortified human milk was associated with significantly greater weight gain (MD 2.74 [1.27-4.22] g/kg/d; I2 = 95%), length gain (MD 0.08 [0.02-0.14] cm/week; I2 = 90%), and head circumference gain (MD 0.06 [0.03-0.10] cm/week; I2 = 87%). No significant differences were observed in feeding intolerance, necrotizing enterocolitis, late-onset sepsis, chronic lung disease, time to full enteral feeding, length of stay, or mortality. Subgroup analyses suggested that the publication era partially contributed to heterogeneity, although substantial residual heterogeneity remained. According to INSPECT-SR, two trials were judged as having no concerns, twelve as having some concerns, and one as having serious concerns regarding trustworthiness. Conclusions: Low-certainty evidence suggests that human milk fortification improves short-term anthropometric growth parameters in preterm and low birth weight infants without increasing major neonatal morbidities. However, the certainty of these findings is limited by substantial heterogeneity and concerns regarding study trustworthiness. Future adequately powered trials using contemporary fortification strategies and long-term follow-up are required to establish the clinical significance of these growth benefits.
2026-04-10 | Don't keep this endopeptidase on the DL.
Gut-derived bacterial DL-endopeptidase may confer protection from late onset sepsis (LOS) in preterm infants. In this issue of Cell Host & Microbe, Shen et al. identified delayed gut microbiome development in preterm infants as a risk factor for LOS and proposed a protective regulatory response by NOD2.
2026-03-01 | The role of breastfeeding in preventing neonatal infections in premature infants
Here is the paradox that neonatal intensive care units face daily: the most fragile infants, those born prematurely with the weakest immune defenses and most immature organ systems, are the ones most dependent on invasive interventions that simultaneously increase their infection risk while keeping them alive. Breastfeeding has long been proposed as a countermeasure to this immunological vulnerability, yet its specific protective effects among premature neonates remain incompletely quantified in Nordic populations where breastfeeding rates are already among the world’s highest. This research critically examined the association between breastfeeding patterns and neonatal infection incidence among 176 premature infants admitted to two Finnish university hospital neonatal units between May 2021 and February 2022. Participants were categorized into exclusive breastfeeding, partial breastfeeding, and formula-only feeding groups based on detailed feeding records maintained throughout their hospitalization at the University of Helsinki and University of Turku. Late-onset sepsis constituted the most frequent infection type at 34.7% of all documented infection episodes, followed by necrotizing enterocolitis at 18.9% and pneumonia at 16.3%. Infection rates differed dramatically across feeding categories: exclusively breastfed infants experienced an overall infection rate of 26.4% compared to 50.0% in partially breastfed and 88.5% in formula-only fed neonates. A dose-response relationship emerged between breastfeeding duration and clinical outcomes, with infant’s breastfed beyond eight weeks demonstrating 38.6 mean infection-free days versus 14.3 days among those breastfed for fewer than two weeks. Hospital length of stay declined proportionally with increasing breastfeeding duration from a mean of 48.2 days in the shortest breastfeeding group to 30.1 days in the longest. The breastfeeding support pathway flowchart developed from these clinical observations maps a structured approach from initial colostrum expression through progressive feeding establishment to measurable infection prevention outcomes. While these associations are striking in both magnitude and consistency, this research critically acknowledges that confounding by indication likely inflates effect estimates, as sicker infants are inherently less able to breastfeed successfully, creating a correlation that may partly reflect underlying health status rather than pure feeding effects.
2026-01-31 | Human Milk–Derived Peptide MAMP‐1 Ameliorates Sepsis‐Associated Acute Lung Injury in Mice Through APOA4 and the TLR4/NF‐κB Signaling Pathway
ABSTRACT Sepsis‐associated acute lung injury (SALI) significantly jeopardizes the health and survival prospects of neonates. Although breast milk has been identified to decrease the incidence and mortality rates associated with sepsis, the specific protective components remain unclear. In our research, milk‐derived antimicrobial peptide‐1 (MAMP‐1) is found to be significantly expressed and possessing favorable physicochemical properties within the breast milk for premature infants. In the experiment of MAMP‐1 acting on lipopolysaccharide (LPS)‐induced SALI in neonatal mice, MAMP‐1 pretreatment significantly increased survival rates, attenuated lung tissue damage, and reduced pro‐inflammatory cytokine levels in serum and lung tissue in LPS‐challenged mice. Transcriptome analysis further revealed that MAMP‐1 pretreatment inhibits the regulation of toll‐like receptor 4 (TLR4) signaling pathway, upregulates lipid metabolism related genes, especially apolipoprotein A‐IV (APOA4). This results in a reduced expression of key pro‐inflammatory factors and cholesterol levels, while simultaneously increasing high‐density lipoprotein cholesterol levels, thereby suppressing the dysregulated inflammatory response. These findings identify MAMP‐1 as a promising breast milk‐derived peptide for the prevention of neonatal SALI.
2025-12-30 | Effect of Oral Colostrum Administration Duration on Clinical Outcomes in Preterm Infants: A Randomized Controlled Trial.
Oral colostrum administration (OCA) for neonates is easy, simple, and safe. Previous studies have reported that OCA decreases the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) in preterm infants. However, the optimal duration of OCA has not been established. This study aimed to investigate the effect of OCA for different durations on the incidence of NEC (stage ≥2) and other morbidities. This randomized controlled study recruited premature infants born before 32 weeks of gestation. The infants were categorized into the following three groups: noncolostrum group, did not receive OCA; short-term colostrum group, received oral colostrum for 3 days; and extended colostrum group, received oral colostrum for 10 days. For additional analyses, the infants were also classified into two broader categories: colostrum (combining short-term and extended groups) and noncolostrum groups. In this study, 138 infants (46 in each group) were recruited. The incidence rates of NEC in the noncolostrum, short-term colostrum, and extended colostrum groups were 10.9% (n = 5), 4.3% (n = 2), and 0% (n = 0), respectively. Infants in the groups receiving colostrum exhibited a decreased incidence of NEC, although the difference was not significant when analyzed according to duration (OR: 0.19; 95% CI: 0.11-0.0.32, p = 0.057). Compared with the noncolostrum group, infants in the colostrum group achieved full enteral feeding earlier, had a shorter antibiotic duration, and exhibited lower rates of LOS (p = 0.004, p < 0.001, p = 0.004, respectively). The extended colostrum group exhibited the highest exclusive breastfeeding rate at discharge (p = 0.003). OCA improved feeding tolerance and reduced LOS in preterm infants. Although the effect on NEC was not significant, extended administration enhanced exclusive breastfeeding rates at discharge.
antibodies
2026-09-02 | TRANSFORMING NEONATAL SEPSIS CARE: CD23-TARGETED IGE-ANTIGEN COMPLEXES AS PRECISION IMMUNOTHERAPY FOR PRETERM INFANTS
Neonatal sepsis remains a major global cause of infant mortality, with preterm neonates facing the greatest risk of rapid deterioration, septic shock, and poor outcomes. Current standard care, which relies mostly on broad-spectrum antibiotics and supportive interventions, does not target the core immunological dysfunctions of the preterm infant. While past immunomodulatory approaches, such as intravenous immunoglobulin, have shown little benefit, advances in immunology now highlight the promise of targeted therapies. This review summarizes the complex, multifactorial immune deficits seen in premature neonates, including profound hypogammaglobulinemia, compromised physical barriers, and adaptive T-cell immaturity. Furthermore, it discusses the innovative therapeutic potential of IgE-antigen complexes (IgE-ACs) targeting the CD23 (FcεRII) receptor. By engaging this pathway, IgE-ACs can modulate immune signaling to dampen hyper-inflammatory responses, enhance pathogen clearance without excessive inflammation, accelerate adaptive T-cell priming, and reduce the risk of post-infectious immune paralysis. These mechanisms point to IgE-AC/CD23 modulation as a novel and potentially transformative strategy to improve outcomes in neonatal intensive care.
2026-05-30 | Assessment of survival and neonatal morbidity rates of very low birth weight infants in Türkiye: Turkish Neonatal Society SECRETS (TNS-SECRETS) study.
This prospective multicenter study of the Turkish Neonatal Society includes data from a large cohort of very low birth weight (VLBW) infants from 78 referral centers in Türkiye. The objective was to evaluate survival and neonatal morbidity rates among VLBW infants. All preterm infants with a birth weight (BW) ≤ 1500 g and a gestational age (GA) between 230/7 and 316/7 weeks were included. Respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL) hemodynamically significant patent ductus arteriosus (hsPDA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), sepsis and retinopathy of prematurity (ROP) were defined as neonatal morbidities. A total of 3042 VLBW infants were enrolled. The mean GA and median BW were 27 ± 2.2 weeks and 1080 g (ranges, 320 and 1500 g), respectively. The incidences of neonatal morbidities were as follows: RDS 76.3%, IVH 28%, PVL 0.9%, hsPDA 31.5%, BPD 39.5%, NEC 14%, and ROP 25%. Early and late sepsis were diagnosed in 19.3% and 44.6% of the study group. The overall mortality rate was 21.7%, and survival without major morbidity was 42.8%. Mortality among infants ≤ 28 weeks of gestation was 34.8%, whereas it was 5.5% for infants > 28 weeks of GA. This study provides a comprehensive overview of outcomes among VLBW infants in Türkiye and offers valuable insights for other developing countries. As neonatal morbidity and mortality rates remain higher than those reported in developed countries, targeted strategies to improve neonatal care practices for extremely preterm infants should be prioritized.Trial registration Clinical trials gov, Survival and Neonatal Outcomes of Very Low Birth Weight Infants in Türkiye: Turkish Neonatal Society SECRETS-TR Study (TNS-SECRETS), NCT 06,543,524, 2024-08-07.
2026-05-19 | Autophagy markers in umbilical cord blood-derived PBMCs and their association with preterm morbidities: a prospective multicenter cohort study.
Autophagy is a crucial cellular degradation pathway that maintains homeostasis during stress. Preterm infants are exposed to significant oxidative and metabolic stress during the perinatal transition. This study aimed to evaluate the levels of autophagy markers (Beclin-1, LC3B-I and LC3B-II) in the umbilical cord blood of preterm infants and investigate their association with neonatal morbidities and mortality. This prospective multicentre cohort study included 60 preterm infants. Umbilical cord blood samples were analysed for Beclin-1, LC3B-I and LC3B-II levels using Western blot. The LC3B-I/LC3B-II ratio was calculated as an indicator of autophagic flux. The relationship between these markers and major neonatal outcomes (respiratory distress syndrome (RDS), intraventricular haemorrhage (IVH), haemodynamically significant patent ductus arteriosus (hsPDA), early neonatal sepsis (ENS) and mortality) was evaluated using Mann-Whitney U tests and multivariable logistic regression adjusted for gestational age. A significant positive correlation was observed between gestational age and Beclin-1 levels (r=0.406, p=0.005). In subgroup analyses, non-survivors exhibited significantly lower median Beclin-1 levels (0.45 vs 0.92, p=0.047) and a depressed LC3B-I/LC3B-II ratio (0.48 vs 1.90, p=0.018) compared with survivors. Similarly, infants with IVH had significantly lower LC3B-I levels (0.07 vs 0.65, p=0.011). However, in multivariable logistic regression analyses adjusted for gestational age, the independent statistical significance of these markers was attenuated, suggesting that the observed autophagic impairment is closely linked to gestational immaturity. No significant associations were found for RDS, hsPDA or ENS. This study identifies lower cord blood Beclin-1 levels and an altered LC3B ratio as potential markers of vulnerability in preterm infants, particularly for mortality and IVH. The findings suggest that autophagic capacity at birth is developmentally regulated, with more immature infants displaying compromised autophagy initiation.
2026-05-14 | Neonatal early-onset sepsis: A changing paradigm of pathogens and high-risk cohorts.
The causative pathogens of neonatal early-onset sepsis (EOS) have changed over time with a shift towards gram-negative organisms. This change is likely multifactorial and due in part to a high prevalence of maternal intrapartum antibiotic exposure leading to alterations in rectovaginal colonization with antibiotic-resistant organisms and subsequent neonatal colonization and infection. As a result, neonatal EOS secondary to gram-negative pathogens, particularly Escherichia coli (E. coli), is becoming more aggressive, resistant and difficult to treat, and not exclusive to very low birth weight infants with more EOS emerging in late preterm and term infants. Therefore, a heightened awareness regarding the dangers of resistant bacterial infections in neonates is critical, as well as a reevaluation of current maternal and neonatal surveillance and prevention efforts.
2026-03-31 | Understanding Neonatal Sepsis: Infection Foci and Risk Profiles in Preterm and Term Infants
Background/Objectives: Neonatal sepsis remains a major contributor to neonatal morbidity and mortality worldwide, yet diagnostic uncertainty and heterogeneous clinical presentation continue to challenge early recognition and management. Early onset sepsis (EOS), typically arising within the first 72 hours of life, is strongly influenced by maternal and perinatal factors. Limited data exist on the temporal evolution of infec-tion foci during the first week of life. Methods: To identify the predominant infection localization sites in preterm and term neonates with suspected or confirmed sepsis and to determine maternal and neonatal risk factors associated with early disease severity, persistent sepsis, and adverse outcomes .Results: A total of 297 neonates met inclusion criteria. Most infants (99.3%) were admitted before 72 hours of life. Respiratory involvement was the predominant infection focus on Day 1 (57.2%) and remained common through Day 3. CNS, gastrointestinal, and skin involvement were infrequent. Lower gestational age (p=0.035) and pro-longed rupture of membranes >18 hours (p=0.043) independently predicted sepsis at Day 1. Advanced sep-sis at admission was associated with lower birth weight, lower gestational age, older maternal age, and ab-sence of intrapartum antibiotics (all p≤0.001). Persistent sepsis at Day 7 was linked to prematurity (p=0.008), higher mortality (p< 0.001), and prolonged hospitalization (p=0.001). Conclusions: Respiratory involvement is the most common early infection focus in neonates with EOS. Prematurity, low birth weight, prolonged rupture of membranes, and maternal intrapartum infection significantly increase the risk of severe disease.
other
2025-10-10 | The Gut as a Source of Infection for Fungal Pathogens: Increased Fecal Candida albicans Precedes Onset of Candida Late-Onset Sepsis in Very Preterm Infants.
The skin-to-blood route is traditionally considered the main pathway in Candida late-onset sepsis (LOS) development in preterm infants. However, emerging evidence suggests that the gut also serves as a source of infection. We aimed to characterize fecal mycobiota and microbiota profiles preceding onset of Candida LOS to assess the role of the preterm gut microbiome in disease development. This multicenter case-control study included very preterm infants (<30 weeks of gestation) with Candida LOS. Each case was matched to nonaffected controls by gestational and postnatal age, hospital site, and/or cumulative antibiotic exposure prior to day of LOS onset (t = 0). Fecal samples collected at t = 0 and the 5 preceding days were analyzed by ITS1 and 16S RNA sequencing. Microbial amplicon yields, composition, and interkingdom correlations were assessed. Of 2397 screened infants, fecal samples were available for 8 of 19 infants with Candida LOS. In these 8 cases, the ITS/16S amplicon yield ratio was increased (P < .001), and the relative abundance of fecal Candida albicans correlated positively with fungal amplicon yield (ρ = 0.71, adjusted P = .005), suggesting increased absolute abundance up to 5 days before onset. Additionally, bacterial yields were significantly lower (P = .02) and α-diversity significantly decreased (P = .012) when compared to the controls. Increased fecal C albicans preceded Candida LOS onset, implicating the preterm gut as a potential source of infection. Reduced bacterial yields and diversity suggest ecological alterations that may facilitate Candida pathogenicity in the preterm gut. These findings support further research into gut-derived Candida LOS and the potential for microbiota-targeted prevention strategies.
2025-05-23 | Group B Streptococcus maternal colonization and neonatal sepsis in Belgium between 2012 and 2021: a description of the epidemiological situation and identification of risk factors.
Group B Streptococcus (GBS) infection is a leading cause of neonatal morbidity. Maternal rectovaginal GBS colonization is a primary risk factor for early onset neonatal GBS infection. In Belgium, pregnant women are screened and, if positive or at risk of transmission, offered intrapartum antibiotic prophylaxis (IAP). We aimed to provide the first comprehensive overview of Belgian data and identify possible risk factors of maternal GBS colonization and neonatal infection. We calculated proportions of maternal screening, colonization and incidence of all neonatal GBS infections and identified their risk factors using log binomial regression from national registries' data between 2012-2021. Of all women, 90.2% were screened and of them, 18.5% were GBS colonized. These proportions were stable over time. Risk factors for maternal GBS colonization included Sub-Saharan (aRR = 1.45, [1.41-1.48]) and North-African origin (aRR = 1.31, [1.28-1.34]) and 5 + parity (aRR = 1.21, [1.18-1.25]). Neonatal GBS sepsis incidence showed a gradually decreasing trend in two individual data sources. Flanders' overall neonatal GBS sepsis estimates were around 0.49 cases per 1000 livebirths. Risk factors for neonatal GBS infection included preterm birth (aRR = 7-41, depending on level of prematurity) and very low birthweight (aRR = 14.83, [6.48-33.94]). Babies of colonized women were at higher risk without (aRR = 7.05, [5.05-9.85]) than with IAP (aRR = 4.34, [3.28-5.74]) compared to non-colonized women. The maternal colonization rate and the neonatal GBS sepsis incidence in Belgium is comparable to European data. We identified already known risk factors and effectiveness of IAP. Mothers at risk for GBS colonization and premature/low birth weight deliveries could benefit most from additional maternal vaccination strategy.
2024-07-23 | Neonatal intestinal colonization of Streptococcus agalactiae and the multiple modes of protection limiting translocation.
Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is a predominant pathogen of neonatal sepsis, commonly associated with early-onset neonatal sepsis. GBS has also been associated with cases of late-onset sepsis potentially originating from the intestine. Previous findings have shown GBS can colonize the infant intestinal tract as part of the neonatal microbiota. To better understand GBS colonization dynamics in the neonatal intestine, we collected stool and milk samples from prematurely born neonates for identification of potential pathogens in the neonatal intestinal microbiota. GBS was present in approximately 10% of the cohort, and this colonization was not associated with maternal GBS status, delivery route, or gestational weight. Interestingly, we observed the relative abundance of GBS in the infant stool negatively correlated with maternal IgA concentration in matched maternal milk samples. Using a preclinical murine model of GBS infection, we report that both vertical transmission and direct oral introduction resulted in intestinal colonization of GBS; however, translocation beyond the intestine was limited. Finally, vaccination of dams prior to breeding induced strong immunoglobulin responses, including IgA responses, which were associated with reduced mortality and GBS intestinal colonization. Taken together, we show that maternal IgA may contribute to infant immunity by limiting the colonization of GBS in the intestine.
2023-04-11 | Gene filtering strategies for machine learning guided biomarker discovery using neonatal sepsis RNA-seq data
Machine learning (ML) algorithms are powerful tools that are increasingly being used for sepsis biomarker discovery in RNA-Seq data. RNA-Seq datasets contain multiple sources and types of noise (operator, technical and non-systematic) that may bias ML classification. Normalisation and independent gene filtering approaches described in RNA-Seq workflows account for some of this variability and are typically only targeted at differential expression analysis rather than ML applications. Pre-processing normalisation steps significantly reduce the number of variables in the data and thereby increase the power of statistical testing, but can potentially discard valuable and insightful classification features. A systematic assessment of applying transcript level filtering on the robustness and stability of ML based RNA-seq classification remains to be fully explored. In this report we examine the impact of filtering out low count transcripts and those with influential outliers read counts on downstream ML analysis for sepsis biomarker discovery using elastic net regularised logistic regression, L1-reguarlised support vector machines and random forests. We demonstrate that applying a systematic objective strategy for removal of uninformative and potentially biasing biomarkers representing up to 60% of transcripts in different sample size datasets, including two illustrative neonatal sepsis cohorts, leads to substantial improvements in classification performance, higher stability of the resulting gene signatures, and better agreement with previously reported sepsis biomarkers. We also demonstrate that the performance uplift from gene filtering depends on the ML classifier chosen, with L1-regularlised support vector machines showing the greatest performance improvements with our experimental data.
2023-03-16 | Maternal immunisation against Group B Streptococcus: A global analysis of health impact and cost-effectiveness.
Group B Streptococcus (GBS) can cause invasive disease (iGBS) in young infants, typically presenting as sepsis or meningitis, and is also associated with stillbirth and preterm birth. GBS vaccines are under development, but their potential health impact and cost-effectiveness have not been assessed globally. We assessed the health impact and value (using net monetary benefit (NMB), which measures both health and economic effects of vaccination into monetary units) of GBS maternal vaccination in an annual cohort of 140 million pregnant women across 183 countries in 2020. Our analysis uses a decision tree model, incorporating risks of GBS-related health outcomes from an existing Bayesian disease burden model. We extrapolated country-specific GBS-related healthcare costs using data from a previous systematic review and calculated quality-adjusted life years (QALYs) lost due to infant mortality and long-term disability. We assumed 80% vaccine efficacy against iGBS and stillbirth, following the WHO Preferred Product Characteristics, and coverage based on the proportion of pregnant women receiving at least 4 antenatal visits. One dose was assumed to cost $50 in high-income countries, $15 in upper-middle income countries, and $3.50 in low-/lower-middle-income countries. We estimated NMB using alternative normative assumptions that may be adopted by policymakers. Vaccinating pregnant women could avert 127,000 (95% uncertainty range 63,300 to 248,000) early-onset and 87,300 (38,100 to 209,000) late-onset infant iGBS cases, 31,100 deaths (14,400 to 66,400), 17,900 (6,380 to 49,900) cases of moderate and severe neurodevelopmental impairment, and 23,000 (10,000 to 56,400) stillbirths. A vaccine effective against GBS-associated prematurity might also avert 185,000 (13,500 to 407,000) preterm births. Globally, a 1-dose vaccine programme could cost $1.7 billion but save $385 million in healthcare costs. Estimated global NMB ranged from $1.1 billion ($-0.2 to 3.8 billion) under the least favourable normative assumptions to $17 billion ($9.1 to 31 billion) under the most favourable normative assumptions. The main limitation of our analysis was the scarcity of data to inform some of the model parameters such as those governing health-related quality of life and long-term costs from disability, and how these parameters may vary across country contexts. In this study, we found that maternal GBS vaccination could have a large impact on infant morbidity and mortality. Globally, a GBS maternal vaccine at reasonable prices is likely to be a cost-effective intervention.
small molecules
2026-09-25 | Early versus Late Initiation of Enteral Feeding in Premature Infants (28-34 Weeks GA) with Growth Restriction and Absent or Reversed End-Diastolic Flow on Umbilical Artery Doppler: A Randomised Controlled Trial.
The authors conducted an open-label RCT in growth-restricted preterm infants (28-34 wk) with Absent or Reversed end-diastolic flow on Antenatal Umbilical-Artery Doppler (AREDF) to compare early enteral feeding at 6 h (EIEF) with initiation at 48 h (LIEF). Eighty-seven infants were randomised (EIEF 44, LIEF 43). Feeds were advanced daily at 20, 40, 60, 90, 120, and 150 mL/kg/d, respectively, from the day of commencement of feeds. The primary outcome was time to full feeds; secondary outcomes included feed-intolerance (FI), NEC ≥ stage 2b, late-onset sepsis, mortality, and hospital stay. EIEF achieved full feeds earlier than LIEF (median 6 vs. 8 d). Rates of FI (20.9% vs. 25.6%), NEC (0 vs. 4.6%), mortality (6.8% vs. 16.3%), and hospital stay were not statistically different. Late-onset sepsis was lower with EIEF (6.8% vs. 27.9%). Early feeds from 6 h, with careful monitoring, enabled full feeds by day 6 without increasing adverse outcomes. The trial was registered prospectively at CTRI.org on 01/03/2019 (CTRI No. CTRI/2019/03/017899).
2026-09-23 | Probiotics and Risk of Death, Necrotizing Enterocolitis, and Sepsis in Very Preterm Infants.
Probiotics are reported to benefit preterm infants, but population-based clinical evidence is limited. In 2020, the Swedish Neonatal Society issued a national recommendation to supplement very preterm infants (28 weeks 0 days' to 31 weeks 6 days' gestation) with probiotics. To investigate whether probiotic supplementation was associated with risk of death, necrotizing enterocolitis (NEC), and/or culture-proven sepsis in infants born very preterm. This population-based cohort study examined data from the Swedish Neonatal Quality Register from January 1, 2017, through December 31, 2024. Live-born, very preterm infants, excluding those who died within the first 3 days of life or due to congenital or chromosomal abnormalities, were included. Daily probiotic supplementation of 1 billion colony-forming units of freeze-dried Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus initiated following birth and discontinued at postmenstrual week 34. Composites of death and/or NEC (Bell stage 2-3), death and/or surgical NEC (Bell stage 3), and death and/or culture-proven sepsis were assessed. Modified Poisson regression, propensity score-matched, and inverse probability of treatment weighting analyses were used for replication analyses. A multivariate bayesian modeling analysis accounting for the association between NEC and mortality was performed to estimate the association between probiotic exposure and mortality. Among 4695 infants (mean [SD] gestational age, 30.2 [1.1] weeks; 2550 male [54.3%]), probiotic exposure increased from 0% before the national recommendation in 2020 to 16.9% in 2020 and a mean (SD) of 64.8% (4.7%) in 2021 to 2024. Probiotic supplementation vs no supplementation was associated with lower risk of death and/or NEC (rate, 0.8% vs 3.4%; adjusted relative risk [ARR], 0.28 [95% CI, 0.14-0.56]). When assessed separately, risks of death (rate, 0.3% vs 1.4%; ARR, 0.16 [95% CI, 0.06-0.45]) and NEC (rate, 0.6% vs 2.5%; ARR, 0.25 [95% CI, 0.10-0.61]) were both lower in the probiotic group. Multivariate bayesian modeling suggested that a substantial proportion of the observed mortality reduction was mediated via reduced NEC incidence (42.3% [credible interval, 16.1%-100%]). Probiotic supplementation was not associated with death and/or culture-proven sepsis (rate, 3.4% vs 4.4%; ARR, 0.86 [95% CI, 0.58-1.26]). This cohort study of very preterm infants found that implementation of a multistrain probiotic was associated with a significant reduction in death and/or NEC, which may help inform shared decision-making between clinicians and families. These results should not be generalized to extremely preterm infants (<28 weeks' gestation).
2026-08-31 | Probiotic Implementation and Necrotizing Enterocolitis Risk in Preterm Infants.
Despite their widespread use, uncertainty remains about the effectiveness and safety of probiotics for preventing necrotizing enterocolitis (NEC) in preterm infants. Recent regulatory warnings, including from the US Food and Drug Administration, have further emphasized the need for robust clinical data on both the benefits and risks of probiotics for this population. To evaluate the association between implementation of a multistrain probiotic formulation and NEC incidence in preterm infants in a high-risk neonatal intensive care unit (NICU) setting. This multicenter retrospective cohort study was conducted at 2 NICUs in the Netherlands. Preterm infants (<30 weeks of gestational age [GA], birth weight [BW] <1000 g, or both) born between January 1, 2018, and July 1, 2024, were compared before and after the implementation of routine probiotic supplementation. The probiotic protocol was introduced in October 2020 or March 2021, depending on the center. Routine implementation of a multistrain probiotic formulation (Bifidobacterium infantis Bb-02, Bifidobacterium lactis BB-12, and Streptococcus thermophilus TH-4) as part of enteral feeding. The primary outcome was NEC incidence, classified as medical, surgical, or fatal. Secondary outcomes included all-cause mortality and mortality not associated with NEC. Primary and secondary outcomes were analyzed using generalized linear regression models, comparing preimplementation and postimplementation periods and adjusting for GA, sex, BW z score, 5-minute Apgar score, prenatal steroid use, and preterm premature rupture of membranes. Interrupted time-series analysis was performed as a sensitivity analysis to assess robustness against underlying temporal trends. Probiotic-related sepsis was monitored to assess safety. This study included 1413 infants (742 males [52.5%]), stratified into a preimplementation group (n = 598) and a postimplementation group (n = 815). Baseline characteristics were comparable between groups (median GA, 27.7 weeks [IQR, 26.0-29.0 weeks] and 27.9 weeks [IQR, 26.4-29.0 weeks]; median BW, 950 g [IQR, 770-1170 g] and 975 g [IQR, 790-1190 g]). Following probiotic implementation, NEC incidence decreased from 11.9% (n = 71) to 5.3% (n = 43) (adjusted risk ratio [ARR], 0.49 [95% CI, 0.34-0.70]; P < .001). No statistically significant evidence of underlying time trends was detected. All-cause mortality remained stable for the preimplementation and postimplementation groups (70 [11.7%] vs 94 [11.5%]; ARR, 1.06 [95% CI, 0.82-1.39]; P = .64); non-NEC-associated mortality increased from 7.2% (n = 43) to 9.6% (n = 78) (ARR, 1.42 [95% CI, 1.01-1.98]; P = .04). One case of probiotic-associated sepsis was identified. In this cohort study of preterm infants, implementation of a well-characterized multistrain probiotic was associated with a reduction in NEC incidence. This finding supports the use of the studied probiotic as an effective preventive strategy for NEC, although its effects on broader mortality outcomes remain uncertain.
2026-08-14 | Discordance between in vitro susceptibility and clinical response in early-onset neonatal sepsis caused by Morganella morganii: a case report in an extremely preterm infant.
Early-onset neonatal sepsis (EONS) caused by Morganella morganii is rare, particularly in extremely preterm infants, and poses diagnostic and therapeutic challenges. We report a case of EONS in an extremely preterm neonate in whom blood cultures identified Morganella morganii with in vitro susceptibility to gentamicin, which was initiated as part of the empirical treatment. Despite documented antimicrobial sensitivity, the infant showed no significant clinical improvement. Consequently, antibiotic therapy was modified based on both susceptibility testing and the evolving clinical picture, resulting in marked clinical recovery. This case highlights that antimicrobial susceptibility results should be interpreted in conjunction with the patient's clinical response and that treatment decisions in neonatal sepsis should not rely solely on in vitro sensitivity patterns, particularly when dealing with uncommon pathogens.
2026-08-14 | Routine probiotics and outcomes in infants < 29 weeks: a 13-year single-centre cohort with propensity-weighted sensitivity analyses.
Probiotic supplementation in preterm infants has been associated with reduced necrotising enterocolitis (NEC) and mortality, but reported effects vary across studies due to heterogeneity in populations, probiotic products, and co-interventions, with limited representation of extremely preterm infants. We performed a single-centre retrospective cohort study of infants born at < 29 weeks' gestation admitted for intensive care between 2012 and 2024 using electronic patient records. After excluding infants who died within the first 7 days and other predefined exclusions, 581 infants were analysed: 79 (13.6%) received no probiotics and 502 (86.4%) received probiotics (two products used sequentially during the study period). Baseline characteristics (gestational age, birthweight, sex, and antenatal steroid exposure) were similar between groups. Primary outcomes were in-hospital mortality and severe NEC, defined pragmatically as NEC requiring transfer for surgical management and/or surgery. Secondary outcomes included culture-positive late-onset sepsis (LOS) and time to full enteral feeds. Associations were examined using multivariable logistic regression adjusting for gestational age, birthweight, sex, antenatal steroid exposure, and calendar year, supported by propensity-score overlap-weighted sensitivity analysis. In-hospital mortality was 4.8% in probiotic-exposed infants versus 13.9% in unexposed infants. Probiotic exposure was associated with lower adjusted odds of in-hospital mortality (aOR 0.31; 95% CI 0.10-0.93; p = 0.036). No clear association was observed with severe NEC or culture-positive LOS. In this 13-year single-centre cohort of infants < 29 weeks' gestation, routine probiotic use was associated with lower in-hospital mortality, while effects on severe NEC and LOS were not clearly demonstrated. • Probiotic supplementation in preterm infants has been associated with reduced NEC and mortality, but results vary across studies. • Prior evidence is heterogeneous, with limited representation of extremely preterm infants and variability in probiotic strains, dosing, and co-interventions. • In a 13-year single-centre cohort of infants < 29 weeks' gestation, probiotic use was associated with lower in-hospital mortality after adjustment. • No clear difference in severe NEC (surgery/transfer) was observed between probiotic-exposed and unexposed infants.
cell therapies
2026-03-01 | Gut microbiota immaturity with DL-endopeptidase deficiency links antibiotic use to preterm late-onset sepsis.
Early antibiotic exposure increases late-onset sepsis (LOS) risk in preterm infants, potentially via gut dysbiosis. Analyzing 4,938 longitudinal fecal samples from preterm infants in China, the US, and the UK, we identified a differential pace of gut microbiota development among preterm infants. Delayed maturation correlated with over one-third of LOS risk associated with early antibiotic exposure. Deficiency of a bacterial DL-endopeptidase represented a hallmark of delayed microbiota development and correlated with elevated LOS risk. Supplementation with DL-endopeptidase-producing Enterococcus faecium or Limosilactobacillus reuteri activated the NOD2 receptor via muramyl dipeptide (MDP), regulated macrophage differentiation and polarization, restrained hyperinflammation via cylindromatosis (CYLD) induction, and protected neonatal mice from LOS. A pilot randomized controlled trial showed that L. reuteri supplementation enhanced fecal NOD2 activation in preterm infants. These findings link microbiota immaturity and reduced DL-endopeptidase activity to antibiotic exposure and LOS risk and highlight a candidate biomarker that warrants further validation for clinical translation.
2025-11-25 | Therapeutic potential and translational challenges of extracellular vesicles in neonatal medicine
Extracellular vesicles (EVs) have emerged as promising therapeutic candidates for a range of neonatal diseases, including sepsis, necrotizing enterocolitis, hypoxic-ischemic encephalopathy (HIE), and bronchopulmonary dysplasia (BPD). Derived from diverse sources such as mesenchymal stem cells, breast milk, and even non-animal systems, EVs exhibit potent anti-inflammatory, immunomodulatory, and tissue-regenerative properties. Preclinical studies in neonatal models demonstrate their ability to reduce inflammation, preserve epithelial and endothelial barrier integrity, modulate immune cell phenotypes, and mitigate organ damage. Despite these encouraging findings, several critical barriers hinder their clinical translation. Challenges include incomplete characterization of EV molecular cargo, variability in isolation and quantification methods, lack of standardized dosing protocols, and limited safety data, particularly regarding procoagulant activity and thrombotic risk. The development of standardized, reproducible isolation techniques, rigorous molecular profiling, and GLP-compliant safety assessments is essential to establish clinical readiness. Current early-phase clinical trials targeting neonatal BPD, prevention of prematurity-related brain injury, and HIE indicate growing translational momentum. If these challenges are addressed, EV-based therapeutics could transform neonatal care, reducing mortality and long-term disability in vulnerable preterm and term infants.
2025-09-29 | Application of Umbilical Cord Blood for the Clinical Prevention and Treatment of Complications in Preterm Infants(Review).
Preterm infants face a heightened risk of various complications due to the immaturity of their physiological systems, with global rates of preterm birth increasing. These complications represent the leading causes of mortality in children. This review examines current research on the use of umbilical cord blood(UCB) for managing preterm complications, including bronchopulmonary dysplasia(BPD), hypoxic ischemic encephalopathy(HIE), necrotizing enterocolitis(NEC), sepsis and retinopathy of prematurity(ROP). UCB is rich in bioactive components, including hematopoietic stem cells(HSCs), mesenchymal stem cells(MSCs), and exosomes, which are crucial for neurological and vascular repair, anti-apoptosis, anti-inflammation, and immunomodulation. Both preclinical investigations and clinical trials have highlighted the potential of UCB therapy in mitigating the severity of preterm complications, enhancing clinical outcomes, and fostering long-term neural development. Current clinical studies aim to further confirm the safety and efficacy of UCB therapy, with future research concentrating on refining treatment protocols and tailoring personalized medical approaches to enhance the long-term well-being of preterm infants.
2025-06-19 | Safety and feasibility of allogeneic cord blood-derived cell therapy in preterm infants with severe brain injury (ALLO trial): a phase-1 trial protocol.
Severe intraventricular haemorrhage (IVH) and white matter injury (WMI) are major neurological complications in preterm infants, leading to long-term neurodevelopmental impairments. Despite advances in neonatal care, effective treatments are lacking. Umbilical cord blood cell (UCBC) therapy shows neuroprotective potential, with autologous sources ideal but often not feasible due to the unpredictability of preterm births. Allogeneic UCBCs offer an alternative, although immunogenicity and human leucocyte antigen (HLA) compatibility present challenges with knowledge gaps in their relevance in neonatal populations. This study aims to assess the feasibility and safety of partially HLA-matched allogeneic UCBC therapy in preterm infants with severe brain injury. The ALLO trial is an open-label, phase I, single-arm feasibility and safety study conducted at Monash Children's Hospital, Victoria, Australia. Preterm infants born before 28 weeks (ALLO-1) or between 28 weeks and 36+6 weeks (ALLO-2) gestational age with severe brain injury identified on neuroimaging will be enrolled. Severe brain injury is defined as grade 3 or 4 IVH or significant WMI. Exclusion criteria include major congenital anomalies or redirection to comfort care. Eligible infants will receive a single intravenous infusion of unrelated, allogeneic, partially HLA-matched (4/6 or 5/6 HLA match) UCBCs sourced from a public cord blood bank. The target dose is 50 million total nucleated cells per kilogram body weight. Infusion will occur within 2-3 weeks of confirmation of eligibility, contingent on clinical stability and absence of active sepsis. Primary outcome includes: (1) feasibility, defined as having more than 60% of enrolled infants with an eligible allogeneic partially matched cord blood unit available and (2) safety, defined as absence of severe adverse events within 48 hours of infusion or graft-versus-host disease within 3 months of infusion. Secondary outcomes include survival, neonatal morbidities, neurodevelopmental assessments and serum cytokine analysis. Monash HREC has granted full ethics approval (RES-23-0000-297A) for the study, including the research use of allogeneic cord blood from compassionate donations by healthy donors, facilitated through the Bone Marrow Donor Institute Cord Blood Bank within the AusCord network. Findings will be disseminated through peer-reviewed publications and conference presentations, contributing to the development of novel neuroreparative therapies for preterm brain injury. ACTRN12623001352695 (The Australian New Zealand Clinical Trials Registry).
2024-05-14 | Trends and risk factors analysis of NEC in preterm infants over 9 years
Abstract Background Investigating the trend of changes in the occurrence of necrotizing enterocolitis (NEC) in preterm infants during 9 years and analyzing the risk factors of NEC with the purpose of providing reference for clinical diagnosis and treatment of NEC. Methods Clinical data of NEC in preterm infants with Bell’s stage ≥ II from January 2013 to December 2021 in the Neonatology Department of the Third Affiliated Hospital of Zunyi Medical University was retrospectively analyzed. Trends in the occurrence of NEC in preterm infants were analyzed by the trend chi-square test. Subsequently, the general data (sex, gestational age, singleton or multiple births, birth weight, serum albumin, alkaline phosphatase, sepsis, blood transfusion, mechanical ventilation, RDS, arterial catheterization) and perinatal data (intrauterine distress, turbid amniotic fluid, premature rupture of membranes, mode of delivery, fetal heart abnormalities, diabetes mellitus) were collected; then, the risk factors for NEC were analyzed by univariate and multivariate logistic-regression analysis. Results In the past 9 years, 77 cases of NEC occurred, with the incidence rate of 1.95%, and the incidence of NEC in preterm infants has been increasing year by year ( P < 0.05). The results of univariate analysis showed that the morbidity of NEC in preterm infants was associated with premature rupture of membranes, blood transfusion, sepsis, and the of serum albumin ( P < 0.05). Multivariate logistic regression analysis revealed that blood transfusion (OR = 2.232, 95% CI: 1.012–4.923) and sepsis (OR = 0.899, 95% CI: 0.809–3.915) were independent risk factors of NEC in preterm infants, while high serum albumin (OR = 0.899, 95% CI: 0.809–3.915) was an independent protective factor of NEC in preterm infants. Conclusion The morbidity of NEC is gradually increasing. Inhibition of infection and limitation of blood transfusion are effective measures to reduce the occurrence of NEC. Meanwhile, high serum albumin is a protective factor for NEC.
proteins
2026-07-15 | Fortified Human Milk Compared with Unfortified Human Milk in Preterm Low Birth Weight Neonates: A Systematic Review and Meta-Analysis.
Background/Objectives: Our aim was to assess the benefits and risks of fortified vs. unfortified human milk in preterm/low birth weight neonates and to incorporate the INSPECT-SR tool to enhance evidence appraisal. Methods: PubMed and Scopus were searched from inception to 30 November 2025, limited to human studies published in English. Randomized controlled trials in neonates ≤ 34 weeks' gestation or ≤2500 g birth weight were included. Data extraction followed PRISMA guidelines. Risk of bias was assessed using Cochrane RoB 2, and trustworthiness using the INSPECT-SR tool. Random-effects models were used to pool mean differences (MDs) and odds ratios (ORs); heterogeneity was assessed with I2. Outcomes included weight, length, and head circumference gain velocities, feeding intolerance, necrotizing enterocolitis, late-onset sepsis, chronic lung disease, time to full enteral feeding, length of stay, and mortality. Results: Fifteen randomized controlled trials involving 1079 neonates (546 receiving fortified human milk and 533 receiving unfortified human milk) were included in the analysis. Fortified human milk was associated with significantly greater weight gain (MD 2.74 [1.27-4.22] g/kg/d; I2 = 95%), length gain (MD 0.08 [0.02-0.14] cm/week; I2 = 90%), and head circumference gain (MD 0.06 [0.03-0.10] cm/week; I2 = 87%). No significant differences were observed in feeding intolerance, necrotizing enterocolitis, late-onset sepsis, chronic lung disease, time to full enteral feeding, length of stay, or mortality. Subgroup analyses suggested that the publication era partially contributed to heterogeneity, although substantial residual heterogeneity remained. According to INSPECT-SR, two trials were judged as having no concerns, twelve as having some concerns, and one as having serious concerns regarding trustworthiness. Conclusions: Low-certainty evidence suggests that human milk fortification improves short-term anthropometric growth parameters in preterm and low birth weight infants without increasing major neonatal morbidities. However, the certainty of these findings is limited by substantial heterogeneity and concerns regarding study trustworthiness. Future adequately powered trials using contemporary fortification strategies and long-term follow-up are required to establish the clinical significance of these growth benefits.
2026-04-10 | Don't keep this endopeptidase on the DL.
Gut-derived bacterial DL-endopeptidase may confer protection from late onset sepsis (LOS) in preterm infants. In this issue of Cell Host & Microbe, Shen et al. identified delayed gut microbiome development in preterm infants as a risk factor for LOS and proposed a protective regulatory response by NOD2.
2026-03-01 | The role of breastfeeding in preventing neonatal infections in premature infants
Here is the paradox that neonatal intensive care units face daily: the most fragile infants, those born prematurely with the weakest immune defenses and most immature organ systems, are the ones most dependent on invasive interventions that simultaneously increase their infection risk while keeping them alive. Breastfeeding has long been proposed as a countermeasure to this immunological vulnerability, yet its specific protective effects among premature neonates remain incompletely quantified in Nordic populations where breastfeeding rates are already among the world’s highest. This research critically examined the association between breastfeeding patterns and neonatal infection incidence among 176 premature infants admitted to two Finnish university hospital neonatal units between May 2021 and February 2022. Participants were categorized into exclusive breastfeeding, partial breastfeeding, and formula-only feeding groups based on detailed feeding records maintained throughout their hospitalization at the University of Helsinki and University of Turku. Late-onset sepsis constituted the most frequent infection type at 34.7% of all documented infection episodes, followed by necrotizing enterocolitis at 18.9% and pneumonia at 16.3%. Infection rates differed dramatically across feeding categories: exclusively breastfed infants experienced an overall infection rate of 26.4% compared to 50.0% in partially breastfed and 88.5% in formula-only fed neonates. A dose-response relationship emerged between breastfeeding duration and clinical outcomes, with infant’s breastfed beyond eight weeks demonstrating 38.6 mean infection-free days versus 14.3 days among those breastfed for fewer than two weeks. Hospital length of stay declined proportionally with increasing breastfeeding duration from a mean of 48.2 days in the shortest breastfeeding group to 30.1 days in the longest. The breastfeeding support pathway flowchart developed from these clinical observations maps a structured approach from initial colostrum expression through progressive feeding establishment to measurable infection prevention outcomes. While these associations are striking in both magnitude and consistency, this research critically acknowledges that confounding by indication likely inflates effect estimates, as sicker infants are inherently less able to breastfeed successfully, creating a correlation that may partly reflect underlying health status rather than pure feeding effects.
2026-01-31 | Human Milk–Derived Peptide MAMP‐1 Ameliorates Sepsis‐Associated Acute Lung Injury in Mice Through APOA4 and the TLR4/NF‐κB Signaling Pathway
ABSTRACT Sepsis‐associated acute lung injury (SALI) significantly jeopardizes the health and survival prospects of neonates. Although breast milk has been identified to decrease the incidence and mortality rates associated with sepsis, the specific protective components remain unclear. In our research, milk‐derived antimicrobial peptide‐1 (MAMP‐1) is found to be significantly expressed and possessing favorable physicochemical properties within the breast milk for premature infants. In the experiment of MAMP‐1 acting on lipopolysaccharide (LPS)‐induced SALI in neonatal mice, MAMP‐1 pretreatment significantly increased survival rates, attenuated lung tissue damage, and reduced pro‐inflammatory cytokine levels in serum and lung tissue in LPS‐challenged mice. Transcriptome analysis further revealed that MAMP‐1 pretreatment inhibits the regulation of toll‐like receptor 4 (TLR4) signaling pathway, upregulates lipid metabolism related genes, especially apolipoprotein A‐IV (APOA4). This results in a reduced expression of key pro‐inflammatory factors and cholesterol levels, while simultaneously increasing high‐density lipoprotein cholesterol levels, thereby suppressing the dysregulated inflammatory response. These findings identify MAMP‐1 as a promising breast milk‐derived peptide for the prevention of neonatal SALI.
2025-12-30 | Effect of Oral Colostrum Administration Duration on Clinical Outcomes in Preterm Infants: A Randomized Controlled Trial.
Oral colostrum administration (OCA) for neonates is easy, simple, and safe. Previous studies have reported that OCA decreases the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) in preterm infants. However, the optimal duration of OCA has not been established. This study aimed to investigate the effect of OCA for different durations on the incidence of NEC (stage ≥2) and other morbidities. This randomized controlled study recruited premature infants born before 32 weeks of gestation. The infants were categorized into the following three groups: noncolostrum group, did not receive OCA; short-term colostrum group, received oral colostrum for 3 days; and extended colostrum group, received oral colostrum for 10 days. For additional analyses, the infants were also classified into two broader categories: colostrum (combining short-term and extended groups) and noncolostrum groups. In this study, 138 infants (46 in each group) were recruited. The incidence rates of NEC in the noncolostrum, short-term colostrum, and extended colostrum groups were 10.9% (n = 5), 4.3% (n = 2), and 0% (n = 0), respectively. Infants in the groups receiving colostrum exhibited a decreased incidence of NEC, although the difference was not significant when analyzed according to duration (OR: 0.19; 95% CI: 0.11-0.0.32, p = 0.057). Compared with the noncolostrum group, infants in the colostrum group achieved full enteral feeding earlier, had a shorter antibiotic duration, and exhibited lower rates of LOS (p = 0.004, p < 0.001, p = 0.004, respectively). The extended colostrum group exhibited the highest exclusive breastfeeding rate at discharge (p = 0.003). OCA improved feeding tolerance and reduced LOS in preterm infants. Although the effect on NEC was not significant, extended administration enhanced exclusive breastfeeding rates at discharge.
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2026-09-02 | TRANSFORMING NEONATAL SEPSIS CARE: CD23-TARGETED IGE-ANTIGEN COMPLEXES AS PRECISION IMMUNOTHERAPY FOR PRETERM INFANTS
Neonatal sepsis remains a major global cause of infant mortality, with preterm neonates facing the greatest risk of rapid deterioration, septic shock, and poor outcomes. Current standard care, which relies mostly on broad-spectrum antibiotics and supportive interventions, does not target the core immunological dysfunctions of the preterm infant. While past immunomodulatory approaches, such as intravenous immunoglobulin, have shown little benefit, advances in immunology now highlight the promise of targeted therapies. This review summarizes the complex, multifactorial immune deficits seen in premature neonates, including profound hypogammaglobulinemia, compromised physical barriers, and adaptive T-cell immaturity. Furthermore, it discusses the innovative therapeutic potential of IgE-antigen complexes (IgE-ACs) targeting the CD23 (FcεRII) receptor. By engaging this pathway, IgE-ACs can modulate immune signaling to dampen hyper-inflammatory responses, enhance pathogen clearance without excessive inflammation, accelerate adaptive T-cell priming, and reduce the risk of post-infectious immune paralysis. These mechanisms point to IgE-AC/CD23 modulation as a novel and potentially transformative strategy to improve outcomes in neonatal intensive care.
2026-05-30 | Assessment of survival and neonatal morbidity rates of very low birth weight infants in Türkiye: Turkish Neonatal Society SECRETS (TNS-SECRETS) study.
This prospective multicenter study of the Turkish Neonatal Society includes data from a large cohort of very low birth weight (VLBW) infants from 78 referral centers in Türkiye. The objective was to evaluate survival and neonatal morbidity rates among VLBW infants. All preterm infants with a birth weight (BW) ≤ 1500 g and a gestational age (GA) between 230/7 and 316/7 weeks were included. Respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL) hemodynamically significant patent ductus arteriosus (hsPDA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), sepsis and retinopathy of prematurity (ROP) were defined as neonatal morbidities. A total of 3042 VLBW infants were enrolled. The mean GA and median BW were 27 ± 2.2 weeks and 1080 g (ranges, 320 and 1500 g), respectively. The incidences of neonatal morbidities were as follows: RDS 76.3%, IVH 28%, PVL 0.9%, hsPDA 31.5%, BPD 39.5%, NEC 14%, and ROP 25%. Early and late sepsis were diagnosed in 19.3% and 44.6% of the study group. The overall mortality rate was 21.7%, and survival without major morbidity was 42.8%. Mortality among infants ≤ 28 weeks of gestation was 34.8%, whereas it was 5.5% for infants > 28 weeks of GA. This study provides a comprehensive overview of outcomes among VLBW infants in Türkiye and offers valuable insights for other developing countries. As neonatal morbidity and mortality rates remain higher than those reported in developed countries, targeted strategies to improve neonatal care practices for extremely preterm infants should be prioritized.Trial registration Clinical trials gov, Survival and Neonatal Outcomes of Very Low Birth Weight Infants in Türkiye: Turkish Neonatal Society SECRETS-TR Study (TNS-SECRETS), NCT 06,543,524, 2024-08-07.
2026-05-19 | Autophagy markers in umbilical cord blood-derived PBMCs and their association with preterm morbidities: a prospective multicenter cohort study.
Autophagy is a crucial cellular degradation pathway that maintains homeostasis during stress. Preterm infants are exposed to significant oxidative and metabolic stress during the perinatal transition. This study aimed to evaluate the levels of autophagy markers (Beclin-1, LC3B-I and LC3B-II) in the umbilical cord blood of preterm infants and investigate their association with neonatal morbidities and mortality. This prospective multicentre cohort study included 60 preterm infants. Umbilical cord blood samples were analysed for Beclin-1, LC3B-I and LC3B-II levels using Western blot. The LC3B-I/LC3B-II ratio was calculated as an indicator of autophagic flux. The relationship between these markers and major neonatal outcomes (respiratory distress syndrome (RDS), intraventricular haemorrhage (IVH), haemodynamically significant patent ductus arteriosus (hsPDA), early neonatal sepsis (ENS) and mortality) was evaluated using Mann-Whitney U tests and multivariable logistic regression adjusted for gestational age. A significant positive correlation was observed between gestational age and Beclin-1 levels (r=0.406, p=0.005). In subgroup analyses, non-survivors exhibited significantly lower median Beclin-1 levels (0.45 vs 0.92, p=0.047) and a depressed LC3B-I/LC3B-II ratio (0.48 vs 1.90, p=0.018) compared with survivors. Similarly, infants with IVH had significantly lower LC3B-I levels (0.07 vs 0.65, p=0.011). However, in multivariable logistic regression analyses adjusted for gestational age, the independent statistical significance of these markers was attenuated, suggesting that the observed autophagic impairment is closely linked to gestational immaturity. No significant associations were found for RDS, hsPDA or ENS. This study identifies lower cord blood Beclin-1 levels and an altered LC3B ratio as potential markers of vulnerability in preterm infants, particularly for mortality and IVH. The findings suggest that autophagic capacity at birth is developmentally regulated, with more immature infants displaying compromised autophagy initiation.
2026-05-14 | Neonatal early-onset sepsis: A changing paradigm of pathogens and high-risk cohorts.
The causative pathogens of neonatal early-onset sepsis (EOS) have changed over time with a shift towards gram-negative organisms. This change is likely multifactorial and due in part to a high prevalence of maternal intrapartum antibiotic exposure leading to alterations in rectovaginal colonization with antibiotic-resistant organisms and subsequent neonatal colonization and infection. As a result, neonatal EOS secondary to gram-negative pathogens, particularly Escherichia coli (E. coli), is becoming more aggressive, resistant and difficult to treat, and not exclusive to very low birth weight infants with more EOS emerging in late preterm and term infants. Therefore, a heightened awareness regarding the dangers of resistant bacterial infections in neonates is critical, as well as a reevaluation of current maternal and neonatal surveillance and prevention efforts.
2026-03-31 | Understanding Neonatal Sepsis: Infection Foci and Risk Profiles in Preterm and Term Infants
Background/Objectives: Neonatal sepsis remains a major contributor to neonatal morbidity and mortality worldwide, yet diagnostic uncertainty and heterogeneous clinical presentation continue to challenge early recognition and management. Early onset sepsis (EOS), typically arising within the first 72 hours of life, is strongly influenced by maternal and perinatal factors. Limited data exist on the temporal evolution of infec-tion foci during the first week of life. Methods: To identify the predominant infection localization sites in preterm and term neonates with suspected or confirmed sepsis and to determine maternal and neonatal risk factors associated with early disease severity, persistent sepsis, and adverse outcomes .Results: A total of 297 neonates met inclusion criteria. Most infants (99.3%) were admitted before 72 hours of life. Respiratory involvement was the predominant infection focus on Day 1 (57.2%) and remained common through Day 3. CNS, gastrointestinal, and skin involvement were infrequent. Lower gestational age (p=0.035) and pro-longed rupture of membranes >18 hours (p=0.043) independently predicted sepsis at Day 1. Advanced sep-sis at admission was associated with lower birth weight, lower gestational age, older maternal age, and ab-sence of intrapartum antibiotics (all p≤0.001). Persistent sepsis at Day 7 was linked to prematurity (p=0.008), higher mortality (p< 0.001), and prolonged hospitalization (p=0.001). Conclusions: Respiratory involvement is the most common early infection focus in neonates with EOS. Prematurity, low birth weight, prolonged rupture of membranes, and maternal intrapartum infection significantly increase the risk of severe disease.
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2025-10-10 | The Gut as a Source of Infection for Fungal Pathogens: Increased Fecal Candida albicans Precedes Onset of Candida Late-Onset Sepsis in Very Preterm Infants.
The skin-to-blood route is traditionally considered the main pathway in Candida late-onset sepsis (LOS) development in preterm infants. However, emerging evidence suggests that the gut also serves as a source of infection. We aimed to characterize fecal mycobiota and microbiota profiles preceding onset of Candida LOS to assess the role of the preterm gut microbiome in disease development. This multicenter case-control study included very preterm infants (<30 weeks of gestation) with Candida LOS. Each case was matched to nonaffected controls by gestational and postnatal age, hospital site, and/or cumulative antibiotic exposure prior to day of LOS onset (t = 0). Fecal samples collected at t = 0 and the 5 preceding days were analyzed by ITS1 and 16S RNA sequencing. Microbial amplicon yields, composition, and interkingdom correlations were assessed. Of 2397 screened infants, fecal samples were available for 8 of 19 infants with Candida LOS. In these 8 cases, the ITS/16S amplicon yield ratio was increased (P < .001), and the relative abundance of fecal Candida albicans correlated positively with fungal amplicon yield (ρ = 0.71, adjusted P = .005), suggesting increased absolute abundance up to 5 days before onset. Additionally, bacterial yields were significantly lower (P = .02) and α-diversity significantly decreased (P = .012) when compared to the controls. Increased fecal C albicans preceded Candida LOS onset, implicating the preterm gut as a potential source of infection. Reduced bacterial yields and diversity suggest ecological alterations that may facilitate Candida pathogenicity in the preterm gut. These findings support further research into gut-derived Candida LOS and the potential for microbiota-targeted prevention strategies.
2025-05-23 | Group B Streptococcus maternal colonization and neonatal sepsis in Belgium between 2012 and 2021: a description of the epidemiological situation and identification of risk factors.
Group B Streptococcus (GBS) infection is a leading cause of neonatal morbidity. Maternal rectovaginal GBS colonization is a primary risk factor for early onset neonatal GBS infection. In Belgium, pregnant women are screened and, if positive or at risk of transmission, offered intrapartum antibiotic prophylaxis (IAP). We aimed to provide the first comprehensive overview of Belgian data and identify possible risk factors of maternal GBS colonization and neonatal infection. We calculated proportions of maternal screening, colonization and incidence of all neonatal GBS infections and identified their risk factors using log binomial regression from national registries' data between 2012-2021. Of all women, 90.2% were screened and of them, 18.5% were GBS colonized. These proportions were stable over time. Risk factors for maternal GBS colonization included Sub-Saharan (aRR = 1.45, [1.41-1.48]) and North-African origin (aRR = 1.31, [1.28-1.34]) and 5 + parity (aRR = 1.21, [1.18-1.25]). Neonatal GBS sepsis incidence showed a gradually decreasing trend in two individual data sources. Flanders' overall neonatal GBS sepsis estimates were around 0.49 cases per 1000 livebirths. Risk factors for neonatal GBS infection included preterm birth (aRR = 7-41, depending on level of prematurity) and very low birthweight (aRR = 14.83, [6.48-33.94]). Babies of colonized women were at higher risk without (aRR = 7.05, [5.05-9.85]) than with IAP (aRR = 4.34, [3.28-5.74]) compared to non-colonized women. The maternal colonization rate and the neonatal GBS sepsis incidence in Belgium is comparable to European data. We identified already known risk factors and effectiveness of IAP. Mothers at risk for GBS colonization and premature/low birth weight deliveries could benefit most from additional maternal vaccination strategy.
2024-07-23 | Neonatal intestinal colonization of Streptococcus agalactiae and the multiple modes of protection limiting translocation.
Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is a predominant pathogen of neonatal sepsis, commonly associated with early-onset neonatal sepsis. GBS has also been associated with cases of late-onset sepsis potentially originating from the intestine. Previous findings have shown GBS can colonize the infant intestinal tract as part of the neonatal microbiota. To better understand GBS colonization dynamics in the neonatal intestine, we collected stool and milk samples from prematurely born neonates for identification of potential pathogens in the neonatal intestinal microbiota. GBS was present in approximately 10% of the cohort, and this colonization was not associated with maternal GBS status, delivery route, or gestational weight. Interestingly, we observed the relative abundance of GBS in the infant stool negatively correlated with maternal IgA concentration in matched maternal milk samples. Using a preclinical murine model of GBS infection, we report that both vertical transmission and direct oral introduction resulted in intestinal colonization of GBS; however, translocation beyond the intestine was limited. Finally, vaccination of dams prior to breeding induced strong immunoglobulin responses, including IgA responses, which were associated with reduced mortality and GBS intestinal colonization. Taken together, we show that maternal IgA may contribute to infant immunity by limiting the colonization of GBS in the intestine.
2023-04-11 | Gene filtering strategies for machine learning guided biomarker discovery using neonatal sepsis RNA-seq data
Machine learning (ML) algorithms are powerful tools that are increasingly being used for sepsis biomarker discovery in RNA-Seq data. RNA-Seq datasets contain multiple sources and types of noise (operator, technical and non-systematic) that may bias ML classification. Normalisation and independent gene filtering approaches described in RNA-Seq workflows account for some of this variability and are typically only targeted at differential expression analysis rather than ML applications. Pre-processing normalisation steps significantly reduce the number of variables in the data and thereby increase the power of statistical testing, but can potentially discard valuable and insightful classification features. A systematic assessment of applying transcript level filtering on the robustness and stability of ML based RNA-seq classification remains to be fully explored. In this report we examine the impact of filtering out low count transcripts and those with influential outliers read counts on downstream ML analysis for sepsis biomarker discovery using elastic net regularised logistic regression, L1-reguarlised support vector machines and random forests. We demonstrate that applying a systematic objective strategy for removal of uninformative and potentially biasing biomarkers representing up to 60% of transcripts in different sample size datasets, including two illustrative neonatal sepsis cohorts, leads to substantial improvements in classification performance, higher stability of the resulting gene signatures, and better agreement with previously reported sepsis biomarkers. We also demonstrate that the performance uplift from gene filtering depends on the ML classifier chosen, with L1-regularlised support vector machines showing the greatest performance improvements with our experimental data.
2023-03-16 | Maternal immunisation against Group B Streptococcus: A global analysis of health impact and cost-effectiveness.
Group B Streptococcus (GBS) can cause invasive disease (iGBS) in young infants, typically presenting as sepsis or meningitis, and is also associated with stillbirth and preterm birth. GBS vaccines are under development, but their potential health impact and cost-effectiveness have not been assessed globally. We assessed the health impact and value (using net monetary benefit (NMB), which measures both health and economic effects of vaccination into monetary units) of GBS maternal vaccination in an annual cohort of 140 million pregnant women across 183 countries in 2020. Our analysis uses a decision tree model, incorporating risks of GBS-related health outcomes from an existing Bayesian disease burden model. We extrapolated country-specific GBS-related healthcare costs using data from a previous systematic review and calculated quality-adjusted life years (QALYs) lost due to infant mortality and long-term disability. We assumed 80% vaccine efficacy against iGBS and stillbirth, following the WHO Preferred Product Characteristics, and coverage based on the proportion of pregnant women receiving at least 4 antenatal visits. One dose was assumed to cost $50 in high-income countries, $15 in upper-middle income countries, and $3.50 in low-/lower-middle-income countries. We estimated NMB using alternative normative assumptions that may be adopted by policymakers. Vaccinating pregnant women could avert 127,000 (95% uncertainty range 63,300 to 248,000) early-onset and 87,300 (38,100 to 209,000) late-onset infant iGBS cases, 31,100 deaths (14,400 to 66,400), 17,900 (6,380 to 49,900) cases of moderate and severe neurodevelopmental impairment, and 23,000 (10,000 to 56,400) stillbirths. A vaccine effective against GBS-associated prematurity might also avert 185,000 (13,500 to 407,000) preterm births. Globally, a 1-dose vaccine programme could cost $1.7 billion but save $385 million in healthcare costs. Estimated global NMB ranged from $1.1 billion ($-0.2 to 3.8 billion) under the least favourable normative assumptions to $17 billion ($9.1 to 31 billion) under the most favourable normative assumptions. The main limitation of our analysis was the scarcity of data to inform some of the model parameters such as those governing health-related quality of life and long-term costs from disability, and how these parameters may vary across country contexts. In this study, we found that maternal GBS vaccination could have a large impact on infant morbidity and mortality. Globally, a GBS maternal vaccine at reasonable prices is likely to be a cost-effective intervention.
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Drug Discovery Landscape
5 orphan drug designations for Sepsis in premature infants.
5 orphan drug designations for Sepsis in premature infants.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Melatonin | small molecules | EMA | — | Worphmed Srl |
bovine lactoferrin | proteins | FDA | Metrodora Therapeutics, LLC | |
Lipopolysaccharide of Ochrobactrum intermedium | small molecules | EMA | — | Diomune S.L. |
Octenidine dihydrochloride | small molecules | EMA | — | Schülke & Mayr GmbH |
Pagibaximab | antibodies | EMA | Covance Clinical Development GmbH |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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