Furosemide is the most commonly used diuretic in preterm infants despite an incompletely understood relationship between dosing, exposure, and safety within this population. The goals of this study were to characterize furosemide population pharmacokinetics (popPK) in preterm infants and to evaluate safety by relating simulated furosemide exposure to events of ototoxicity, nephrocalcinosis, and nephrolithiasis. A total of 146 plasma furosemide concentrations from 51 preterm (23-28.9 weeks' gestational age) infants across two studies (one randomized, placebo-controlled, dose-escalating safety trial and one opportunistic, observational study) were included in the analysis. Standard nonlinear mixed effects popPK modeling techniques were applied. Exposure was simulated using the final popPK model (area under the curve) and Monte Carlo simulations (maximum concentration [Cmax]). Logistic regression was used to evaluate the relationship between exposure and safety events. The final popPK model was a one-compartment model with the covariates of weight on volume of distribution and both weight and post-natal age on clearance. The model showed accurate predictions, adequate precision, and good model fit. Simulations indicated that furosemide 2 mg/kg administered enterally every 6 h would result in few (approximately 4%) Cmax values exceeding a 50 µg/mL threshold reported to be associated with treatment-associated ototoxicity, and no more than 1% for all other dosing regimens. Events of hearing loss, nephrocalcinosis, or nephrolithiasis were rare and showed no relationship with furosemide exposure in logistic regression analysis. These data contributed to the October 2024 FDA label update to include pediatric popPK data and improve dosing in preterm infants.

Methadone is used in hospitalized children to treat pain and iatrogenic opiate withdrawal. Optimal pediatric dosing for both enteral and intravenous methadone is unknown. We conducted two prospective, multi-center, open-label studies to characterize the pharmacokinetics of methadone in the pediatric population. These studies were conducted at a total of 23 US children's hospitals. Ninety-nine children with a median (range) age of 2.3 (0-19.0) years and weight of 13.0 (0.72-159) kg were prescribed methadone per standard of care for treatment of pain or iatrogenic opiate withdrawal. Ninety-nine children received median (range) methadone doses of 0.11 (0.01-0.39) mg/kg intravenously and 0.10 (0.01-0.61) mg/kg enterally. Ten participants received only intravenous doses; 78 received only enteral doses; and 11 received intravenous and enteral doses. We analyzed 263 pharmacokinetic samples with a median (range) methadone plasma concentration of 42.2 (0.9-729.2) ng/mL. A one-compartment population pharmacokinetic model described the methadone data well. Median (range) empiric Bayesian estimates of clearance, volume of distribution, and half-life were 0.17 (0.009-1.50) L/h/kg, 4.99 (0.97-20.6) L/kg, and 20.5 (3.0-86.2) h, respectively. Dosing simulations showed that doses of 0.1 mg/kg every 8 h (intravenous) and 0.2 mg/kg every 8 h (enteral) achieved exposures associated with pain control and reduction in withdrawal symptoms. Based on observed exposures and model simulations, we recommend a starting dose of 0.1 mg/kg intravenous or 0.2 mg/kg enterally (max 10 mg) every 8 h. Because of wide interindividual variability, this dose should be titrated to effect.

OBJECTIVE:Determine if preterm infants have prolonged therapeutic post-discontinuation antibiotic exposures (PDAE) following empiric ampicillin. STUDY DESIGN:Prospective study of 27 infants ≤7 days and <37 weeks gestational age (GA) receiving ampicillin (200 mg/kg/day); 49 post-discontinuation PK samples were collected. Exposures were predicted using PK simulations and a prior ampicillin PK model. The probability of target attainment 24- and 36-h after the final ampicillin dose for various minimum inhibitory concentrations (MICs) and the duration of therapeutic PDAE was calculated. RESULT:At 24- and 36-h after ampicillin, the probability of exposures ≥1 μg/mL was 95% and 60%, respectively. PDAE (≥1 μg/mL) lasted a median 33 h (95% confidence interval: 15, 79), and varied with GA, from median 53 h (<28 weeks GA) to 27 h (34-36 weeks GA). CONCLUSION:Many preterm infants experience therapeutic exposures at least 24 h after the final ampicillin dose. Shorter courses could be considered.

OBJECTIVE:Describe caffeine use in late preterm infants (LPIs) in neonatal intensive care units (NICUs) over time METHODS: Cohort study of infants born 34-36 weeks gestation discharged from Pediatrix Medical Group NICUs from 2011-2022. RESULTS:Of 233,804 LPIs, 3.7% (n = 8633) were exposed to caffeine. Caffeine-exposed LPIs had a lower gestational age (GA), were more likely to receive surfactant, had higher and longer respiratory support needs, and longer length of stay (all p < 0.001). Compared to epoch 1 (2011-2016), LPIs in epoch 2 (2017-2022) were exposed to caffeine at an earlier postnatal age (2 vs. 3 days), shorter duration (1 vs. 6 days) and had discontinued at an earlier postmenstrual age (35 vs. 35.4 weeks) (all p < 0.001). CONCLUSION:Caffeine was used more often in LPIs requiring respiratory support and with lower GA. Although incidence of caffeine use was stable over time, details of prescribing practices differed across sites and over time.

Bronchopulmonary dysplasia (BPD) is an inflammatory disease stemming from premature birth and iatrogenic lung injury. BPD is relatively common and frequently fatal; despite this, there are no FDA-approved therapies. Montelukast is increasingly used to treat developing BPD despite scant safety and efficacy data. Infants with developing BPD have high levels of inflammatory leukotrienes; montelukast blocks the cysteinyl leukotriene receptor. Montelukast shows promise due to results from several small BPD studies. For this Pharmacokinetic and pharmacodynamic study of montelukast in infants with developing BPD (PRISM) trial, we chose the smallest dose and shortest treatment duration that maintained a prospect for direct benefit. PRISM is a randomized, double-blind, placebo-controlled trial (5 sites, n = 28) of 0.75 mg/kg enteral montelukast dosed every 24 h for up to 7 days. Eligible infants (<28 weeks’ gestation, birthweight <1000 g) require mechanical ventilation and supplemental oxygen (FiO2 ≥30%) at age 7 to 28 days of life. The primary outcome will be apparent clearance of montelukast from a population pharmacokinetic analysis; we will also estimate the apparent volume of distribution, half-life, and exposure metrics. Safety will be assessed by comparing all-cause and neuropsychiatric adverse events and laboratory evaluations between treatment and placebo groups. Comprehensive neurodevelopmental evaluations will occur periodically to 24 months of age. Preliminary efficacy will be measured by oxygen saturation index and time on respiratory supports. These data are intended to demonstrate a reassuring initial risk-benefit profile to justify a dose-escalating PRISM2 trial involving a larger cohort of infants with developing BPD.

Effective design and execution of multicenter clinical trials remain critical yet challenging for advancing clinical care. The Trial Innovation Network (TIN) Comprehensive Consultation process was established to improve the feasibility and success of investigator-initiated trial proposals by offering structured, multidisciplinary support across 60+ Clinical and Translational Science Award (CTSA) institutions. We report outcomes from 75 trial proposals that underwent Comprehensive Consultation between 2016 and 2024. The process follows a phased Assess-Design-Compose model that integrates expertise in trial design, operations, recruitment, and informatics to generate robust, fundable grant applications. Here we demonstrate 66% of our submitted grants receive funding. This consultation framework demonstrates a scalable, high-impact approach to enhancing the rigor, efficiency, and success of multicenter clinical trials and offers a model for national and global networks seeking to improve clinical research translation.

BACKGROUND:eSource technologies that exchange patient data from electronic health records (EHR) to clinical study electronic data capture (EDC) systems can reduce data quality errors and decrease data collection time. However, the availability of site-specific EHR data to support pediatric studies has not been evaluated. METHODS:We used a previously developed data element mapping procedure to evaluate the HL7® FHIR® standard's coverage in multi-center pediatric clinical studies. Four study sites independently mapped three pediatric studies' case report forms (CRFs) to their site's EHR and FHIR® server data elements. RESULTS:Site investigators mapped 4152 total and 2070 distinct data elements. Only 33.8 % of total CRF data elements (n = 1402) and 27.4 % of distinct data elements (n = 568) were able to be mapped in FHIR® at the four sites. However, the percent of total data elements mapped varied by pediatric study (55.3 %, 30.8 %, and 26.2 %) and study site (46.4 %, 32.3 %, 27.8 %, and 26.6 %). The percent of total CRF data elements mapped was higher in domains containing standard of care data (e.g., Concomitant Medications, Demographics, Diagnosis/Procedures, Medical History, and Vital Signs) and lower in domains containing protocol-specific data (e.g., Adverse Events, Concomitant Medications, Enrollment/Eligibility/Consent, and study treatment-related Labs, and Vital Signs). CONCLUSIONS:There is substantial between-study and between-site variability in the percentage of pediatric study data elements available in FHIR® at study sites. These results suggest that mapping solutions for pediatric studies utilizing eSource technologies will need to be site-specific.

Multicenter clinical trials are essential for evaluating interventions but often face significant challenges in study design, site coordination, participant recruitment, and regulatory compliance. To address these issues, the National Institutes of Health's National Center for Advancing Translational Sciences established the Trial Innovation Network (TIN). The TIN offers a scientific consultation process, providing access to clinical trial and disease experts who provide input and recommendations throughout the trial's duration, at no cost to investigators. This approach aims to improve trial design, accelerate implementation, foster interdisciplinary teamwork, and spur innovations that enhance multicenter trial quality and efficiency. The TIN leverages resources of the Clinical and Translational Science Awards (CTSA) program, complementing local capabilities at the investigator's institution. The Initial Consultation process focuses on the study's scientific premise, design, site development, recruitment and retention strategies, funding feasibility, and other support areas. As of 6/1/2024, the TIN has provided 431 Initial Consultations to increase efficiency and accelerate trial implementation by delivering customized support and tailored recommendations. Across a range of clinical trials, the TIN has developed standardized, streamlined, and adaptable processes. We describe these processes, provide operational metrics, and include a set of lessons learned for consideration by other trial support and innovation networks.

Objectives: To observe the mean daily dose of fentanyl required for adequate sedation in critically ill, mechanically ventilated children randomized to receive dexmedetomidine or placebo. Methods: We conducted Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multicenter, double-blind, randomized, placebo-controlled, dose-escalating trial. We enrolled children aged 35 weeks post-menstrual to 17 years (inclusive) admitted across 13 pediatric multidisciplinary and cardiac intensive care units. Adequate sedation was based on a State Behavioral Score and Richmond Agitation-Sedation Scale of-1 or lower. Only the first two dexmedetomidine dosing cohorts opened for enrollment, due to early trial closure during the coronavirus 2019 pandemic. Thirty children were randomized over 13 months and included in the analyses. Results: Demographic and baseline characteristics were not different between dexmedetomidine and placebo cohorts. Similarly, mean daily fentanyl use was not different, using an unadjusted mixed regression model that considered treatment, time, and a treatment-by-time interaction. Adverse events and safety events of special interest were not different between cohorts. Conclusions: The DOSE trial revealed that dexmedetomidine added to fentanyl does not impact safety and may not spare fentanyl use in critically ill children, although the trial did not meet its recruitment goals, due to early closure during the coronavirus 2019 pandemic. More rigorous inpatient pediatric trials like DOSE that study critically ill, mechanically ventilated children are needed. Despite the many obstacles faced, the DOSE trial presents challenges from which the greater research community can learn and use to optimize future therapeutic trials in children.

ABSTRACT Purpose Increases in adult stimulant prescribing pose a potential risk due to the higher prevalence of contraindicated conditions among this population. We sought to identify patient, provider, and visit characteristics predictive of potentially inappropriate adult stimulant prescriptions. Methods We conducted a repeated cross‐sectional study using the National Ambulatory Medical Care Survey, a nationally representative weighted sample of 5 453 702 723 ambulatory care visits from 2012 to 2019. Potentially inappropriate prescriptions were defined as prescriptions to patients with potentially contraindicated conditions, as determined by US Food and Drug Administration stimulant labels. Results Of the 5 453 702 723 visits, stimulant use was prevalent at 121384694 (2.23%) visits and newly prescribed at 18880152 (0.34%) visits. Of these, 4 620 138 (24.47%) new stimulant prescriptions and 28 055 947 (23.11%) prevalent prescriptions were potentially inappropriate. Potentially inappropriate prescribing increased over time and with age. Visits to primary care providers (relative risk [RR] 1.65, 95% CI 1.05–2.59) were predictive of inappropriate prescribing. Non‐Hispanic Black (RR 0.48, 95% CI 0.33–0.70) and Hispanic race/ethnicity (RR 0.46, 95% CI 0.35–0.60), coronary artery disease (RR 0.54, 95% CI 0.33–0.86), pregnancy (RR 0.05, 95% CI 0.03–0.11), hypertension (RR 0.69, 95% CI 0.56–0.84), and glaucoma (RR 0.07, 95% CI 0.02–0.24) were predictive of decreased prevalent stimulant prescriptions; substance abuse was predictive of new stimulant prescribing (RR 2.14, 95% CI 1.07–4.27). Conclusions The proportion of potentially inappropriate adult stimulant prescriptions increased over time and with patient age. Visits to primary care providers were predictive of potentially inappropriate prescribing, and a history of substance abuse was predictive of new stimulant prescriptions; therefore, quality improvement interventions regarding safe stimulant prescribing practices may be warranted.

This study aimed to characterize the cerebrospinal fluid (CSF) of infants with stroke and compare those findings to the CSF of infants with bacterial meningitis and neither condition in the first 14 postnatal days. Cohort study of 30,092 infants who received a lumbar puncture in the first 14 postnatal days discharged from >400 neonatal intensive care units from 1997 to 2020. CSF parameters were compared between infants with stroke and bacterial meningitis using non-parametric hypothesis testing and quantile regression. Compared to infants with bacterial meningitis, infants with stroke had a significantly lower median protein concentration, higher median glucose concentration, higher median red blood cell count, and higher median monocyte count. Using quantile regression at the 75th percentile, infants with stroke had a significantly lower white blood cell count, segmented neutrophil count, and lymphocyte count than infants with bacterial meningitis. This study addresses the paucity of literature describing the CSF of infants with ischemic stroke. Knowledge of the differences in CSF parameters between infants with stroke and meningitis may allow for faster recognition and intervention before CSF culture results are available. · Neonatal stroke is a serious and morbid event.. · Neonatal stroke and meningitis can present similarly.. · The CSF of neonatal stroke is poorly described..

Genome-wide association studies (GWAS) have discovered thousands of replicable genetic associations, guiding drug target discovery and powering genetic prediction of human phenotypes and diseases. However, genetic associations can be affected by gene-environment correlations and non-random mating, which can lead to biased inferences in downstream analyses. Family-based GWAS (FGWAS) uses the natural experiment of random assignment of genotype within families to separate out the contribution of direct genetic effects (DGEs) - causal effects of alleles in an individual on an individual - from other factors contributing to genetic associations. Here, we report results from an FGWAS meta-analysis of 34 phenotypes from 17 cohorts. We found evidence that factors uncorrelated with DGEs make substantial contributions to genetic associations for 27 phenotypes, with population stratification confounding - a form of gene-environment correlation - likely the major cause. By estimating SNP heritability and genetic correlations using DGEs, we found evidence that assortative mating has led to overestimation of SNP heritability for 5 phenotypes and overestimation of the degree of shared genetic effects (pleiotropy) between 22 pairs of phenotypes. Polygenic predictors constructed from DGEs are particularly useful for studying natural selection, assortative mating, and indirect genetic effects (effects of relatives' genes mediated through the family environment). We validate our meta-analysis results by predicting phenotypes in hold-out samples using polygenic predictors constructed from DGEs, achieving statistically significant out-of-sample prediction for 24 phenotypes with little attenuation of predictive power within-families. We provide FGWAS summary statistics for 34 phenotypes that can be used for downstream analyses. Our study provides both a template for performing FGWAS and an argument for its value for debiasing inferences and understanding the impact of environment and mating patterns.

The nitroimidazole antibiotic, metronidazole, is frequently prescribed to infants with serious intra-abdominal infections, and multiple dosing recommendations exist. We sought to evaluate the extent to which metronidazole doses and associated exposures achieved desired efficacy and safety in infants enrolled in the Antibiotic Safety in Infants with Complicated Intra-abdominal Infections (SCAMP) trial (NCT01994993). SCAMP participants received intravenous metronidazole as part of multimodal antimicrobial therapy. Participants received a 15 mg/kg loading dose and a 7.5 mg/kg maintenance dose at 24 h. A subsequent 7.5 mg/kg maintenance dose was administered every 12 h for participants of postmenstrual age (PMA) 23 to <34 weeks; 8 h for PMA 34-40 weeks; and 6 h for PMA >40 weeks. We evaluated associations between simulated metronidazole exposures and pre-specified surrogate pharmacodynamic targets and clinical outcomes of efficacy and safety. Nearly 100% of pharmacodynamic targets were met. Infants with therapeutic success (a composite efficacy outcome, defined as the absence of death, negative bacterial blood cultures, and presumptive clinical cure at 30 days) had higher Cmin,ss, Cmax,ss, AUC00-24,ss, and AUCcum compared with infants without therapeutic success. However, the relationships between these exposure measures and therapeutic success were not significant in logistic regression analysis adjusting for gestational age. Despite generally high simulated exposures, no relationships were observed between exposures and prespecified safety events (necrotizing enterocolitis, intestinal strictures, intestinal perforation, positive blood culture, seizures, death, and intraventricular hemorrhage). Findings support metronidazole dosing as administered in term and preterm infants in the SCAMP trial.

This qualitative study describes the Trial Innovation Network's initial consultation process, which provides researchers with resources and recommendations to address complex aspects of planning and conducting clinical trials.

Infliximab may play an important role in reducing mortality in severe COVID-19, though optimal dosing is unknown. This secondary analysis of the ACTIV-1 IM trial characterized infliximab pharmacokinetics and outcomes in patients hospitalized with severe COVID-19. ACTIV-1 IM included patients admitted with COVID-19 pneumonia who received infliximab in addition to routine care. Infliximab was administered as a single 5-mg/kg intravenous dose. The primary exposure variable was predicted infliximab concentrations over 28 days (AUC0-28). Logistic regression modeling was used to relate AUC0-28 to the primary outcome of 28-day mortality, adjusted for age. The relationship between AUC0-28 and the secondary outcome of time to recovery was evaluated using a Fine-Gray model, adjusted for age, with death as a competing risk. AUC0-28 was higher in patients who did not die versus those who died, with a median (range) of 20,681 mg h/L (8379-60,322) versus 17,392 (9543-43,145), P < .001. A 5000-unit increase in AUC0-28 was associated with decreased mortality (OR 0.62, 95% CI 0.43-0.88, P = .008) and decreased composite safety events (OR 0.57, 95% CI 0.45-0.71, P < .001). Higher AUC0-28 was associated with a greater probability of recovery; an AUC0-28 ≤ 17,400 mg h/L was associated with a 3.45-fold higher (95% CI 2.23-5.34) probability of recovery at Day 28, as was an AUC0-28 >17,400 mg h/L, albeit at a lower rate (1.18-fold higher [95% CI 1.07-1.32]), P < .002 for both. Overall, 113/390 (29.0%) patients did not achieve an optimal predicted infliximab AUC0-28 of at least 17,400 mg h/L, particularly those <100 kg and those with the highest baseline disease severity.

The long-term effects of the novel coronavirus disease 2019 (COVID-19) infection during pregnancy are poorly characterized in mothers and their infants. The aim of this study was to assess the physical, mental, and emotional well-being of mothers and infants in the first year postpartum who were exposed to and/or diagnosed with COVID-19 infection.This direct-to-participant cohort study recruited 96 mother-infant pairs delivering at Pediatrix Medical Group sites, where mothers tested positive for COVID-19 during their pregnancy or birth hospitalization and/or infants tested positive for COVID-19 prior to hospital discharge. Main outcome measures included scored responses to surveys administered at 6 and 12 months postpartum and infant health status from newborn admission through the first year after birth.Mothers with COVID-19 infection during pregnancy often reported persistent physical, mental, and emotional stress affecting both themselves and their infants. Scores assessing infant temperament were higher than reported in prior literature. Infants were relatively healthy throughout their first year after birth.The experience of COVID-19 infection during pregnancy may create a unique set of circumstances that affects the well-being of infants and their mothers separately as well as the child-caregiver relationship. Early life events have the potential to generate lasting consequences; therefore, it is important to identify these issues to maximize support and intervene if indicated. · Experiencing COVID-19 in pregnancy is unique.. · Possible effects on temperament, and relationships.. · This impact may persist for at least 1 year postpartum..

This study aimed to evaluate the role of early effective antibiotic therapy in preventing secondary meningitis as a sequelae of bacterial bloodstream infections (BSI).In this multicenter cohort study, we identified blood cultures that were positive for Group B Streptococcus (GBS), Staphylococcus aureus, Escherichia coli, and other non-E. coli gram-negative bacteria that had a corresponding cerebrospinal fluid sample collected ≤7 days after the positive blood culture among infants discharged from a neonatal intensive care unit managed by the Pediatrix Medical Group 2002 to 2020. The odds of secondary meningitis for early effective antibiotic therapy versus delayed antibiotic therapy were compared using an adjusted logistic regression model. The odds of secondary meningitis following GBS BSI were compared for infections treated with empirical vancomycin versus β-lactam antibiotic.Secondary meningitis was identified in 11% of 5,967 BSI. Early effective antibiotic therapy was not associated with a reduced odds of secondary meningitis for GBS (adjusted odds ratio [aOR]: 1.17; 95% confidence interval [CI]: 0.82-1.66) or E. coli (aOR: 1.06; 95% CI: 0.82-1.38); however, was associated with decreased odds for non-E. coli gram-negative bacteria (aOR: 0.69; 95% CI: 0.49-0.98) and S. aureus (aOR: 0.51; 95% CI: 0.34-0.74). GBS BSIs were more often complicated by meningitis when vancomycin was used empirically compared with β-lactam antibiotic (aOR: 2.01; 95% CI: 1.28-3.14).Early effective antibiotic therapy for BSI in infants did not reduce the odds of secondary meningitis caused by GBS or E. coli; however, early effective antibiotic therapy did reduce episodes due to non-E. coli gram-negative bacteria and S. aureus. · Early effective antibiotic therapy in the setting of non-E. coli gram-negative bacteria and S. aureus BSI was associated with reduced odds of secondary meningitis.. · Early effective antibiotic therapy for BSI in infants was not found to reduce the odds of secondary meningitis caused by GBS or E. coli.. · GBS BSIs were more commonly complicated by meningitis when vancomycin was used empirically compared with a β-lactam antibiotic..

OBJECTIVE:To evaluate the safety of furosemide in preterm infants at the risk of developing bronchopulmonary dysplasia (BPD). STUDY DESIGN:This multicenter, randomized, dose-escalating, placebo-controlled trial enrolled infants born <29 weeks gestational age at 7-28 days postnatal age and at risk for BPD. Infants were randomized 3:1 (furosemide:placebo) into 2 cohorts with escalating doses of furosemide to a maximum of 1 mg/kg intravenous (IV; or 2 mg/kg enteral) every 24 hours (cohort 1; n = 40) or 1 mg/kg IV (or 2 mg/kg enteral) every 6 hours (cohort 2; n = 40) for 28 days. Effects of furosemide on total adverse events (AEs; primary outcome), BPD, death, hearing loss, serum electrolyte AEs, and nephrocalcinosis were estimated using logistic regression adjusted for gestational age. RESULTS:We found 293 AEs in 74 of 80 (93%) infants, including 223 AEs among 56 of 61 (92%) infants who received furosemide and 70 AEs among 18 of 19 (95%) infants who received placebo (P > .99). Adjusted analysis among all groups showed no difference in the odds of having moderate-to-severe BPD or death at 36 weeks post-menstrual age (P = .32), hearing loss (P = .78), or nephrocalcinosis (P = .39). For serum electrolyte AE, OR (furosemide vs placebo) was 4.46 (95% CI, 1.06-21.70; P = .048) for cohort 1 and 7.89 (95% CI, 1.50-61.91; P = .023) for cohort 2. CONCLUSIONS:In preterm infants, furosemide did not increase the overall incidence of AEs, hearing loss, or nephrocalcinosis, but did increase the incidence of electrolyte abnormalities. Furosemide given for 28 consecutive days was not associated with a difference in moderate-to-severe BPD or death at 36 weeks postmenstrual age. CLINICALTRIALS:GOV: NCT02527798.

Importance Historically, Staphylococcus aureus has been a leading cause of morbidity and mortality in the neonatal intensive care unit (NICU). The current incidence and attributable mortality of late-onset invasive S aureus infection in hospitalized infants is unknown. Objective To estimate the incidence and attributable mortality of late-onset S aureus infection among hospitalized infants in the US. Design, Setting, and Participants This retrospective cohort study included an emulated trial among a national convenience sample of 315 NICUs within the US between 2016 and 2021. Participants were infants aged at least 4 postnatal days who were hospitalized in a participating NICU. Data were analyzed from May to August 2024. Exposures The primary exposures were birth weight and postnatal age. Main Outcomes and Measures The outcomes were the incidence and attributable mortality of late-onset invasive S aureus infection. Methicillin-resistant and methicillin-sensitive S aureus classification was not universally available; thus, all invasive S aureus infections were pooled. Results From 468 201 infants (260 491 [55.6%] male; median [IQR] gestational age, 36 [33-38] weeks) eligible for analysis, 1724 infants experienced 1762 infections for an overall incidence of 37.6 (95% CI, 35.9-39.4) invasive S aureus infections per 10 000 infants. Most infants with invasive infections were 32 weeks’ gestational age or younger (1394 infants [80.9%]), very low birth weight (VLBW; ie, <1500 g) (1318 infants [76.5%]), and/or had a central line during their hospital stay (1509 infants [87.5%]). Invasive infections mostly included bloodstream infections (1505 infections [85.4%]), and 1160 infections (65.8%) occurred within 4 to 28 postnatal days. Birth weight inversely correlated with incidence: infants with VLBW experienced a more than 20-fold higher incidence relative to infants born weighing at least 1500 g (227.1 [95% CI, 215.3-239.4] vs 10.1 [95% CI, 9.1-11.1] infections per 10 000 infants). Most deaths following invasive infection occurred among VLBW infants (189 of 209 deaths [90.4%]). Compared with matched infants without a late-onset invasive S aureus infection, infected infants had an absolute difference in mortality rate of 5.3% (95% CI, 3.8%-6.8%). Conclusions and Relevance This cohort study found late-onset invasive S aureus infection and subsequent attributable mortality disproportionally affected infants with VLBW. Targeted infection prevention and control measures are necessary to reduce morbidity and mortality from invasive S aureus infections in this vulnerable population.