Neonatal hyperbilirubinemia is common, but bilirubin-induced neurologic dysfunction (BIND) remains an important cause of preventable morbidity, particularly in preterm infants. Japan has developed a distinctive approach centered on unbound bilirubin (UB), the biologically active fraction. Nakamura and colleagues pioneered neonatal UB measurement in the 1970s and incorporated UB measurements into the Kobe University (Nakamura) criteria in 1991. With improved survival of extremely preterm infants, bilirubin encephalopathy was still observed despite modest total serum bilirubin (TSB) levels that persisted beyond the first postnatal week. These observations led Morioka to revise the criteria in 2017, incorporating gestational age (GA), corrected GA, UB levels, and staged treatment throughout the prolonged neonatal course. Clinical experience suggests that this approach may reduce phototherapy exposure without increasing UB levels or exchange transfusion, although multicenter evidence with long-term neurodevelopmental outcomes remains limited. The Japanese experience emphasizes longitudinal monitoring and bilirubin-albumin binding characteristics beyond TSB levels alone. Transcutaneous bilirubin, albumin, and bilirubin-albumin molar ratio may facilitate screening, while emerging fluorescence-based methods may improve UB accessibility. UB measurement should be viewed as a framework for individualized risk assessment, with principles adaptable to diverse populations and clinical settings.
Every clinical decision to start or discontinue phototherapy ultimately depends on a single laboratory value of a total serum bilirubin (TSB) level. Yet that value is neither the biologically most relevant marker of bilirubin neurotoxicity nor necessarily measured with sufficient analytical accuracy. Although TSB remains the most widely used clinically available marker to guide phototherapy, it is an indirect measure of bilirubin neurotoxicity. Unbound bilirubin (UB) levels are considered biologically more relevant, representing the fraction of bilirubin that can cross the blood-brain barrier and potentially cause neurotoxicity. However, UB measurements are not routinely available, technically demanding, and lacks broad standardization for clinical use. The bilirubin-to-albumin (B/A) ratio may provide a pragmatic intermediate marker, as it partly reflects bilirubin-binding capacity, but its clinical value is limited by variability in albumin binding and the influence of illness severity, acidosis, and competing substances. Therefore, despite its limitations, TSB levels remain the practical standard for treatment decisions. But clinically relevant analytical bias remains an important limitation of TSB measurements, emphasizing that the reliability of the assay is as important as the choice of biomarker.
BACKGROUND:Hyperbilirubinemia is a leading cause of sensorineural hearing loss (SNHL) and auditory neuropathy spectrum disorder (ANSD) in neonates. This review synthesizes current evidence to describe key aspects of cochlear implantation (CI) in neonates with hyperbilirubinemia. OBJECTIVE:To educate a wide audience on the pathophysiology, audiometric challenges, hearing aid trial considerations, optimal timing, and expected outcomes of CI in neonates with bilirubin-induced hearing loss. METHODS:A comprehensive review was conducted on PubMed and Cochrane databases to explore current clinical practice guidance for evaluating neonates with hyperbilirubinemia for CI. RESULTS:Bilirubin has neurotoxic effects on the auditory pathway in neonates, making it challenging to have strict audiometric criteria for CI. Hearing trials serve the dual purpose of diagnosis and therapy for infants with hearing loss and can identify strong candidates for CI or, conversely, exclude children who may not benefit from CI. Optimal timing of CI balances diagnostic certainty with earlier intervention. Provider counseling is crucial in preparing families for expected outcomes after CI, which are generally favorable, but can vary among infants depending on factors such as interdisciplinary care coordination. CONCLUSION:Audiologic monitoring, careful CI decision-making, and realistic outcome counseling optimize candidate selection and care for neonates with bilirubin-induced hearing loss.
Albumin is the crux of the exchangeable (i.e., miscible) bilirubin pool, controlling via its high affinity binding the distribution of bilirubin within and across the intravascular and extravascular spaces. It follows that clinicians should leverage the administration of bilirubin free albumin in the management of hazardous hyperbilirubinemia to avoid or reverse bilirubin neurotoxicity. A standard double volume exchange transfusion does exactly that via the albumin laden fresh frozen plasma used to reconstitute the blood infused during the procedure. Albumin priming - the infusion of bilirubin-free albumin prior to a double volume exchange transfusion - augments the infant's pre-exchange albumin mass and albumin bilirubin binding capacity. As such, albumin priming can enhance bilirubin clearance over the course of the subsequent exchange transfusion and provide an immediate stepwise gain in neuroprotection during the pre-exchange period. The potential for neuroprotection against worsening bilirubin-induced neurological dysfunction is the principal reason to albumin prime and prime early when caring for a neonate with signs of intermediate to advanced stage acute bilirubin encephalopathy. Albumin priming should also be considered in asymptomatic infants whose bilirubin - albumin molar ratios approach or exceed albumin's saturable binding limits, as a preventive measure to attenuate bilirubin neurotoxicity risk.
Despite advances in infection prevention, infections due to Staphylococcus aureus continue to be an important cause of morbidity and mortality in NICUs. Whole genome sequencing (WGS) using advanced analytic approaches for defining transmission have shed new insights into transmission and persistence patterns in the NICU. WGS has also helped uncover important associations between transmission, persistence, and the risk of invasive infections. Current infection prevention strategies rely on hand hygiene compliance and surveillance and decolonization of patients positive for S. aureus. Parent decolonization may also play a role in decreasing parent-child transmission. In the future, precision surveillance of high-risk strains and targeted infection prevention efforts to decrease bacterial burden of those specific strains may provide a more effective and efficient approach to decreasing risk of invasive infections.
Congenital syphilis is a preventable infection caused by vertical transmission of Treponema pallidum during pregnancy. Despite effective screening and curative treatment, rates in the United States have risen sharply over the past decade, paralleling increasing syphilis rates among reproductive-aged adults. This resurgence reflects systemic gaps in healthcare access, public health infrastructure, and social support systems. Adverse outcomes include stillbirth, neonatal death, prematurity, and long-term neurologic, skeletal, and auditory complications.This review summarizes current U.S. epidemiologic trends and examines multifactorial drivers of rising congenital syphilis, including inadequate or absent prenatal care, missed or delayed screening, reinfection during pregnancy, and social determinants such as poverty, substance use, and healthcare inequities. System-level challenges such as inconsistent screening practices, treatment delays, and under-resourced public health programs-further sustain transmission.Evidence-based prevention strategies include universal early pregnancy screening, repeat testing for high-risk patients, prompt penicillin treatment, strengthened partner services, and expanded prenatal care access. Policy initiatives and community-based outreach are essential to address structural disparities and improve care engagement.Congenital syphilis is a sentinel marker of healthcare system performance. Coordinated clinical, public health, and policy efforts are urgently needed to reverse current trends and achieve elimination in the United States.
Congenital cytomegalovirus (cCMV) infection is the most common congenital infection worldwide and a leading cause of sensorineural hearing loss (SNHL). Most newborns with cCMV will be asymptomatic at birth; however, a subset will go on to develop disease, including SNHL and neurodevelopmental problems, later in life. Given this, advocacy for newborn cCMV screening is growing. Targeted versus universal screening remains a hotly debated topic. This review will assess current diagnostic and screening modalities and explore unanswered questions.
BACKGROUND:Very preterm infants are born before a critical window of nutrient accrual that occurs during the third trimester, resulting in a nutritional deficit that is vital to restore to support further growth and development. Although the gut is underdeveloped, optimizing administration of nutrition via the enteral route has been linked to improved long term outcomes, particularly when mother's own milk is prioritized as the initial source of nutrition. OBJECTIVE:The goal of this review was to synthesize current evidence on best enteral nutrition practices for very preterm infants focusing on strategies that optimize long term neurodevelopment and infant health outcomes. CONTENT:This review examines the physiological importance of early enteral nutrition to support growth and neurodevelopment of very preterm infants. Clinical outcomes data related to different types of enteral nutrition sources are reviewed, as well as evidence-based practices regarding initiation of enteral nutrition, advancement, supplementation and fortification. Additionally, limitations in the existing literature are identified to inform future research directions. CONCLUSIONS:The collective evidence reviewed in this manuscript supports early, consistent, and human milk-based enteral nutrition as a central modifiable factor to improve growth, brain development, and long-term neurodevelopmental outcomes. While there are remaining uncertainties regarding the ideal timing for initiation, specific advancement strategies, and fortification methods, the available data supports the following: minimizing enteral fasting, prioritizing mother's own milk, and using protocolized feeding guidelines.
Feeding premature infants in the NICU is a ubiquitous need, one where mother's own milk (MOM) has been shown to have nutritional and therapeutic benefits lasting well into childhood. Beyond the need for and importance of enteral MOM feeding, there is a paucity of high-level evidence to inform what, when and how to feed premature infants. Thus, variation in nutritional practices is common within and between NICUs, and parents of premature infants commonly experience distress with the removal of typically parent-led feeding decisions. Furthermore, NICU parent voices remain poorly represented in the literature and feeding outcomes measured are often limited to growth metrics, which fail to capture parent priorities and meaningful outcomes the life course of the parent and child. In this review, we discuss the parent perspectives of NICU nutritional feeding practices, highlighting the gaps in the literature and opportunities to improve the long-term wellness of the dyad when feeding guidelines consider parents' perspectives.
Nutritional care and growth patterns in the neonatal intensive care unit (NICU) can impact lifelong health. Standardized measurement and reporting of growth outcomes are critical to improve the quality of information generated in research and population surveillance, facilitate comparisons and meta-analyses across individual studies, and strengthen the evidence used to generate clinical practice recommendations. Anthropometrics, specifically weight, length, and head circumference, are feasible and practical methods to monitor nutritional status. For research purposes, we recommend these anthropometrics be measured at birth (as a measure of fetal growth), 28 days old (to assess short-term growth), and 36 weeks postmenstrual age (PMA) (to determine the postnatal growth pattern in the NICU). We also encourage recording number of days to regain birthweight as a measure of short-term growth. Research publications should describe clearly the methods used to measure anthropometrics and reference curves used to calculate z-scores. Body composition is a complementary marker of nutritional status, but currently validated techniques have practical limitations in the NICU. When body composition tools are available, fat-free mass and fat mass should be measured at ∼36 weeks PMA. We also describe key knowledge gaps and research priorities regarding growth patterns of preterm infants in the NICU.
Maternal diet and nutritional status during lactation have important implications for human milk composition and lactation outcomes, yet the strength and consistency of these associations remain incompletely understood. This narrative review synthesizes current evidence on (1) the role of maternal dietary intake on human milk macronutrients, fatty acids, human milk oligosaccharides (HMOs), and other bioactive compounds; (2) the influence of maternal nutritional status, including body mass index (BMI), gestational weight gain, gestational diabetes, food insecurity, and biochemical nutrient markers, on milk composition; and (3) the relationship between maternal diet and nutritional status and lactation outcomes, including initiation, duration, and milk production. Methodological heterogeneity in dietary assessment, milk sampling protocols, and definitions of nutritional status limits comparability across studies. Standardized approaches and mechanistic research are needed to clarify causal pathways and identify modifiable targets to optimize milk composition and support successful lactation.
Initial nutrition during the fetal-to-neonatal transition is critical for preterm infants and requires balancing physiologic adaptation, metabolic tolerance, and risk of morbidity. Although traditional approaches favored delayed enteral feeding with prolonged parenteral nutrition to protect the immature gastrointestinal tract, accumulating evidence supports earlier initiation of enteral nutrition and more selective use of parenteral nutrition based on gestational age, illness severity, and antenatal factors.This review synthesizes evidence guiding initial nutrition-defined as the period from birth to sustained full enteral feeding-with a focus on clinical application. We review enteral strategies including oropharyngeal colostrum administration, timing and volume of early feeds, duration of trophic feeding, early total enteral feeding, and feeding advancement rates, highlighting populations with robust evidence and those underrepresented in trials. Parenteral fluid practices are discussed in relation to physiologic postnatal weight loss, fetal growth restriction, and risks of both fluid overload and nutrient under delivery.We further address parenteral macronutrient and micronutrient provision, transition from parenteral to enteral nutrition, and limitations of peripheral parenteral nutrition delivery, noting areas reliant on expert consensus. We identify key evidence gaps and research priorities. Optimizing individualized initial nutrition strategies remains essential to improve growth, reduce morbidity, and support neurodevelopmental outcomes in preterm infants.
Neonatal nutrition research is pivotal for optimizing long-term health outcomes in high-risk infants, particularly preterm and critically ill neonates, where the foundational "first 1000 days" concept increasingly links early nutritional interventions to lifelong neurodevelopmental, metabolic, and socio-economic trajectories. Despite substantial advances, translating this evolving pre-clinical knowledge base into consistent clinical improvements remains slow. This review synthesizes persistent barriers hindering progress in the field, including inconsistent definitions and reporting standards for nutritional intake and growth metrics, inadequate electronic health record infrastructure for automated nutrient calculations across parenteral and enteral sources, restrictive regulatory and consent frameworks that limit equitable enrollment in high-risk populations, and mounting institutional pressures that erode the physician-scientist pipeline. Natural variability in human milk further complicates precise nutritional delivery, where nutrient delivery scales predictably with caloric density, yet routine direct measurement remains underutilized. To accelerate meaningful advancements, the field requires standardized reporting guidelines, enhanced decision-support tools, innovative trial designs, and strengthened career support for physician-scientists. Addressing these interconnected barriers through collaboration, technological integration, and multi-level policy reform holds the potential to shift neonatal nutrition science from incremental gains to rapid improvements in infant survival, growth, and lifelong health.
Despite advancements in nutritional management during the neonatal intensive care unit hospitalization, preterm infants remain smaller than term-born counterparts at the time of hospital discharge. The goal for nutritional management after discharge from the neonatal intensive care unit is to address ongoing nutrient and growth catch-up requirements and support growth and neurodevelopment while balancing the potential risks of too much growth. The current standard of care approach to post-hospitalization nutrition includes an individualized approach to nutritional supplementation with human milk fortification and/or nutrient enriched formulas, and incorporation of parental feeding choice and support of breastfeeding if desired into clinical decisions. Key gaps in the current literature include a need for evidence-based lactation and feeding support methods, and studies on a broad range of neonatal intensive care unit graduates, including those across the spectrum of prematurity and infants with other complex medical needs. Future research should aim for consistency in definitions of nutritional exposures and growth and developmental outcomes, involve parents in study design and choice of outcomes, and consider study design strategies which optimize longitudinal attrition rates. Addressing these gaps will provide clearer insights into the optimal nutritional strategy to improve long-term health outcomes for infants at the highest risk.
Low-dose aspirin is recommended by nearly every major obstetric society for women at high risk of preeclampsia. There is consistent and robust data surrounding preeclampsia prevention, particularly severe early-onset disease; however, there are signals in the data that question the safety of continuation until delivery due to potential increased risk of bleeding. There is robust data from the non-pregnant population that demonstrates concern with long-term aspirin use and bleeding risk. The obstetric literature lacks such robust studies around bleeding concerns, particularly around the time of delivery in individuals using aspirin in pregnancy. This review provides a comprehensive, review of bleeding and hemorrhage risk associated with aspirin use in pregnancy and highlights the consideration for aspirin discontinuation prior to delivery.
Neonatal sepsis due to Multidrug resistant organisms (MDRO) is a huge burden in resource limited settings of South Asia and Africa. The epidemiology, risk factors, diagnostic and management challenges differ significantly in the resource limited settings as compared to the resource rich settings, particularly for Gram-negative MDROs. Lack of diagnostic facilities, limited access to therapeutic options, inability to effectively control horizontal transmission in the neonatal care units due to limited resources are major hurdles in combating MDRO infections in neonates. The low sensitivity of gold standard blood cultures and paucity of pharmacokinetic data in neonates make the overall picture grim.Research studies over the past decade have identified high resistance to the first line and second line treatment regimens recommended by the World Health Organisation (WHO). The progress towards finding customised solutions has been slow. Novel betalactam-betalactamase antibiotics are effective against several MDROs but are expensive. Repurposed antibiotics like fosfomycin and flomoxef hold promise as therapeutic options.The continued critical gaps need to be urgently addressed as national priorities and through international support and cooperation.
Low-dose aspirin (LDA) is a safe, inexpensive, and evidence-based intervention that reduces the risk of preeclampsia among pregnant individuals at elevated risk. Despite strong evidence and national guideline recommendations, implementation of LDA prophylaxis remains inconsistent, and emerging evidence suggests that disparities in LDA use may contribute to inequities in maternal health outcomes. This review summarizes the current literature on disparities in LDA use for preeclampsia prevention and explores opportunities for equitable implementation. Existing studies demonstrate disparities across multiple stages of the LDA prevention pathway, including preeclampsia risk identification, clinician counseling and prescribing, patient uptake, and adherence. National data suggest that Black and Hispanic patients, publicly insured patients, non-English-speaking patients, and individuals receiving care in resource-constrained settings may be less likely to receive or use LDA prophylaxis. Patients eligible based on multiple moderate-risk factors appear particularly vulnerable to missed prescribing opportunities. Importantly, disparities persist even after LDA recommendation, highlighting the role of barriers related to trust, communication, health literacy, and structural determinants of health. Conceptualizing LDA delivery as a multistep implementation process provides a framework for understanding how inequities emerge and propagate throughout the care continuum. Emerging quality improvement and implementation initiatives suggest that standardized risk screening, electronic health record tools, clinician education, multilingual patient resources, workflow redesign, and team-based care approaches may improve equitable delivery of LDA prophylaxis. However, long-term outcome data remain limited. Addressing disparities in preeclampsia prevention will require equity-centered implementation strategies that move beyond guideline dissemination alone and focus on ensuring consistent delivery of evidence-based care across diverse patient populations.
