Bethou Adhisivam

Neonatology has undergone a remarkable transformation over the past six decades, evolving from a discipline focused predominantly on preventing neonatal death to one increasingly concerned with quality of survival, neurodevelopment, family-integrated care and long-term health. Despite substantial progress, neonatal mortality remains a major global health challenge. In 2024, approximately 2.3 million newborns died globally, with the highest mortality rates in sub-Saharan Africa and South Asia. India has achieved a substantial decline in neonatal mortality, from 28 to 17 per 1000 live births between 2015 and 2023, accompanied by rapid expansion of facility-based newborn care. However, prematurity, low birth weight, intrapartum complications, infection, antimicrobial resistance, inequitable access, workforce constraints and inadequate long-term follow-up remain major challenges. The epidemiology of neonatal disease is also changing, with increasing survival of extremely premature infants and greater recognition of bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, brain injury and developmental impairment. Neonatal research is similarly moving from descriptive epidemiology and rescue therapy towards prediction, prevention, precision medicine and implementation science. The next decade should prioritize prevention of prematurity, precision sepsis management, respiratory and brain protection, nutrition and gut health, Kangaroo Mother Care, zero separation, artificial intelligence and predictive analytics, long-term outcomes and affordable innovations. The ultimate measure of neonatal care should move beyond survival to enabling every newborn to develop and reach their full potential.

Background: Neonatal sepsis is a major health issue, particularly in resource-poor areas. This study aimed to assess the role of DNA methylation in regulating the inflammatory cytokine expression in late-onset neonatal sepsis (LOS). Methodology: We conducted a cross-sectional study comparing neonates with LOS (n=42) before and after 72 hours of antibiotic treatment (n=25) to healthy controls (HC) (n=42). We analysed DNA methylation patterns and inflammatory cytokine expression levels in both groups. Results: DNA methylation analysis revealed hypomethylation in pro-inflammatory genes and hypermethylation in anti-inflammatory genes in LOS neonates. These patterns were shifted in follow-up group, with significant changes in inflammatory marker levels, including TNF-α, IFN-γ, IL-10, and TGF-β. The gene expression results aligned with the DNA methylation findings, indicating that changes in the expression of inflammatory genes in late-onset neonatal sepsis (LONS) are influenced by DNA methylation. The results were further validated through an analysis of plasma cytokine levels. LOS cases showed elevated pro-inflammatory cytokines and reduced anti-inflammatory cytokines, except IL-10. In the follow-up group, pro-inflammatory cytokine levels decreased, while anti-inflammatory cytokines increased. Conclusion: DNA methylation regulates the expression of inflammatory cytokine genes in late-onset neonatal sepsis. Understanding these molecular changes could lead to better diagnostic and therapeutic approaches for managing neonatal sepsis.

Background: Klebsiella pneumoniae causes ~20% of sepsis in neonates, with ~40% crude mortality. A vaccine administered to pregnant women, protecting against ≥70% of K. pneumoniae infections, could avert ~400,000 cases and ~80,000 deaths annually, mostly in Africa and South Asia. Vaccine formulations targeting the capsular polysaccharide (K) or lipopolysaccharide (O) antigens are in development. Global K. pneumoniae populations display extensive K and O diversity, necessitating a polyvalent vaccine targeted to the serotypes associated with neonatal disease in relevant geographical regions. We investigated the prevalence of K and O types associated with neonatal sepsis in Africa and South Asia to inform maternal vaccine design. Methods and findings: We analysed 1,930 K. pneumoniae neonate blood isolates from 13 surveillance studies across 35 sites in 13 countries. We used pathogen whole-genome sequencing to predict K and O serotypes and adjust for local transmission clusters, and Bayesian hierarchical meta-analysis to estimate K and O prevalence overall and per region, treating site as a random effect. Eighty-seven K loci were identified. KL2, KL102, KL25, KL15, and KL62 accounted for 49% of isolates. We estimate that 20 K loci, combining the eight most prevalent per region, could cover 72.9% of all infections (95% credible interval: [69.4%, 76.5%]) and ≥70% in each of Eastern, Western, and Southern Africa and South Asia. Preliminary findings from three sites suggested sufficient temporal stability of K loci to maintain 20-valent K vaccine coverage over 5–10 years, but more longitudinal data are needed to support this prediction. O types were far less diverse ( n = 14 types). We estimate the top-5 (O1⍺β,2⍺, O1⍺β,2β, O2⍺, O2β, and O4) would cover 86.2% [82.6, 89.9%] of total infections (76%–92% per region), while the top-10 would cover ~99% of infections in all four regions. The main limitations of our study are the reliance on genome sequences to predict K and O serotypes (as serological typing is not available) and a lack of longitudinal data to explore stability of antigen prevalence over time. Conclusions: Neonatal sepsis is associated with diverse K and O types, with substantial geographic and temporal variation even after adjusting for localised transmission clusters. Despite this, a single 20-valent K vaccine could theoretically cover ≥70% of infections in all target regions. Locally-targeted vaccines could achieve higher coverage with lower valency, but are less feasible. In principle, very high coverage could be achieved with lower valency O-based vaccines, however, the protective efficacy against disease of antibodies targeting the O antigen remains uncertain. Further research is needed on cross-reactivity, antigen exposure, and stability of antigens over time, to better inform vaccine development.