Lina F. Chalak

Neonatal health in the United States is influenced by a combination of biological, social, environmental, nutritional, and healthcare factors, with structural exposures—such as historical redlining, air pollution, and neighborhood disadvantages—associated with differences in perinatal outcomes. This review synthesizes nearly a century of multidisciplinary evidence linking adverse exposures in utero to persistent disparities in neonatal survival and neurodevelopment. We outline biological mechanisms, notably stress-mediated alterations of the fetal HPA axis and epigenetic changes, that may mediate the effects of social and environmental adversity before birth. Historical and contemporary data highlight the enduring impact of discriminatory policies on neonatal outcomes, emphasizing how structural racism and environmental injustice have been linked to higher rates of preterm birth and low birth weight. In addition, disparities in prenatal care access, food insecurity, infection, and inflammatory conditions represent important pathways through which social conditions may affect fetal growth and neonatal outcomes. Advances in exposomics and biomarker science now allow more precise measurement of early-life exposures, while place-based policy interventions, including urban greening and zoning reform, show promise in mitigating harm. Integrating these scientific and policy approaches is essential to disrupt intergenerational cycles of risk and advance perinatal equity. Bridging socioeconomics, environmental, and biological research offers a path forward to ensuring that all infants- regardless of background- have the opportunity for a healthy start. Impact Review linking social and structural exposures, especially in redlining, air pollution, and environmental injustice disparities in neonatal survival and neurodevelopment. Highlights novel advances in exposomics and place-based policy interventions that target root causes and offer promising strategies to improve perinatal equity. Provides an integrated biological, clinical, and policy framework for disrupting intergenerational cycles of risk and advancing neonatal health equity.

Fetal inflammatory response (FIR), a histological indicator of intrauterine inflammation, is associated with adverse outcomes in extremely preterm infants. While FIR has been linked to early brain injury, its long-term impact on neurodevelopment remains underexplored. To assess the relationship between FIR severity and neurodevelopmental outcomes at two years in infants born <29 weeks' gestation and to examine whether term-equivalent MRI brain abnormalities are associated with these outcomes. In this prospective cohort study, 93 preterm infants underwent standardized placental histopathologic assessment for FIR, term-equivalent brain MRI scored using the Kidokoro system, and Bayley-III assessments at two years. Primary analyses compared infants with no FIR versus any FIR. Stratified analyses by FIR severity (Stage 1 vs ≥Stage 2) were conducted as secondary, exploratory analyses. Multivariable linear regression models adjusted for gestational age were used to assess associations among FIR, MRI findings, and neurodevelopmental scores. Exploratory attenuation analyses were performed to assess whether MRI abnormalities influenced observed associations. Among 93 infants included in the analysis, FIR was present in 52%. Compared with infants without FIR, those with FIR had higher global brain abnormality scores on term-equivalent MRI, driven primarily by white matter injury. In adjusted models, FIR was associated with differences in cognitive and language outcomes at two years. Exploratory stratified analyses suggested heterogeneity by FIR severity; MRI abnormalities attenuated associations between FIR and neurodevelopmental outcomes, suggesting that early brain injury may represent an important correlate along the pathway linking inflammation and later development. In extremely preterm infants, placental FIR is associated with early brain MRI abnormalities and neurodevelopmental outcomes at two years. These findings highlight the importance of intrauterine inflammation as an early biologic exposure while underscoring the contribution of cumulative prenatal and postnatal factors to brain injury and long-term development. Larger studies incorporating detailed postnatal inflammatory trajectories are needed to confirm these associations and clarify underlying mechanisms. Demonstrates that severity of placental fetal inflammatory response is associated with neurodevelopmental outcomes at two years of age in extremely preterm infants Identifies a biphasic relationship between FIR severity and neurodevelopment, underscoring that severe intrauterine inflammation may confer disproportionate risk compared with milder inflammatory exposure Provides evidence that term-equivalent brain MRI abnormalities, particularly white matter injury, partially mediate the association between intrauterine inflammation and later cognitive and language development.

Background: Preterm birth is increasingly recognized as a determinant of health across the lifespan, influencing neurodevelopment, psychiatric risk, cardiovascular function, and mortality. This review synthesizes current evidence linking early life adversity, including that associated with prematurity, to the brain-heart axis. We further describe the “fetus to fifty” model, highlighting how the early life experiences of preterm-born infants impact adult trajectories across the lifespan. Summary: Cardiovascular and neurodevelopmental vulnerabilities in preterm-born infants are closely linked. Emerging evidence suggests that suboptimal perinatal hemodynamics and inflammation contribute to a shared cardio-cerebral phenotype, in which premature cardiovascular aging may impair cerebrovascular reserve and increase the risk of cognitive decline. Key Messages: We review the fundamental physiology underlying the early origins of diseases relating to mental health, personality, psychiatric diagnosis, neuroanatomical changes, and cardiopulmonary outcomes, emphasizing the interplay between biological vulnerability and social determinants. Lastly, we identify gaps in knowledge and future research directions to better understand preterm-born adults.

{4–5}: Background: The use of invasive mechanical ventilation in newborns has several risks, including ventilator-induced lung injury, ventilation-associated pneumonia, and hyperventilation leading to potential brain injury, prolonged hospitalisations, and increased mortality. The SafeBoosC-IIIv trial aims to assess the benefits and harms of treatment guided by cerebral oximetry monitoring in newborns receiving invasive mechanical ventilation within the first 28 days from birth. The SafeBoosC consortium is a global network of neonatologists from multiple neonatal intensive care units worldwide. Methods: The SafeBoosC-IIIv trial is an investigator-initiated, multinational, randomised, pragmatic, superiority phase III clinical trial. The trial will be conducted in two steps. This is a protocol for step one. The objective of step one is to assess if treatment guided by cerebral oximetry monitoring according to the SafeBoosC treatment guideline compared with usual care in newborns receiving invasive mechanical ventilation increases the number of hospital-free days. The participants will be newborns with a gestational age more than or equal to 28 + 0 weeks, postnatal age less than 28 days, expected to receive invasive mechanical ventilation (intubation) for at least 24 h, and a cerebral oximeter available so monitoring can be started within 6 h after initiation of invasive mechanical ventilation. Exclusion criteria will be suspicion of or confirmed brain injury or congenital heart malformation likely to require surgery. A total of 1,610 participants will be randomised 1:1 to treatment guided by cerebral oximetry monitoring or usual care. The primary outcome will be hospital-free days, and the secondary outcomes will be serious adverse events and invasive mechanical ventilation-free days. All outcomes will be assessed at 90 days after randomisation. Discussion: The SafeBoosC-IIIv trial has several strengths, including detailed predefined methodology, a high degree of external validity due to centres in several countries, and the trial will be built upon the already established SafeBoosC consortium and the experience from the previous SafeBoosC-II and SafeBoosC-III trials. The SafeBoosC-IIIv trial has limitations, including current lack of funding for step two, lack of blinding of the clinical staff, and the clinicians may have limited experience in using the device. Trial registration: ClinicalTrials.gov: NCT05907317, registered 8 June 2023, https://clinicaltrials.gov/study/NCT05907317?cond=NCT05907317&rank=1

After Neonatal Intensive Care Unit (NICU) discharge, vulnerable babies at risk of neurodevelopmental impairment and other chronic problems often require specialized follow-up care to monitor their development and address any potential issues. Typically, this involves multiple follow-up visits usually focused on neurodevelopment and growth. With advances in obstetric care, high-risk fetuses are being identified earlier, marking another timepoint in which personalized medicine can be delivered from before birth to after discharge including neuronicu care. Our program embeds this focus into a comprehensive, multi-disciplinary primary care model, which offers significant benefits for at-risk infants, and provides an integrated approach to their care. We present the benefits of integrating this model of care with other specialty clinic services into a cohesive, multi-disciplinary follow-up system that maximizes the potential for optimal care and outcomes. Through close collaboration of our multiple specialists at each point of the medical journey of each infant from “Fetus to Five,” we describe our program where the priority is each child’s needs to be met efficiently and comprehensively, as a pathway to thriving developmental outcomes and overall family satisfaction. Impact The future of such comprehensive programs lies in expanding access to comprehensive, integrated care offering services that extend into adolescence and adulthood that supports NICU graduates throughout their lifespan, ensuring optimal health and developmental outcomes

Newborns requiring invasive mechanical ventilation are at high risk of neurodevelopmental impairment, prolonged hospitalisation, and increased mortality. T