The Journal of Pediatrics

Background Neonates with critical congenital heart disease (CCHD) are vulnerable to feeding-related complications including necrotizing enterocolitis (NEC). Human milk and direct breastfeeding (BF) may offer protection, but multisite evidence is limited. We aimed to determine relationships between the proportion of human milk received (ie, human milk percentage) or BF frequency during the neonatal period and NEC, sepsis, infectious complications, or length of stay (LOS). We also determined whether bovine-derived fortification or formula initiation was associated with NEC. Methods This retrospective study included neonates from 25 US pediatric centers who underwent surgery with cardiopulmonary bypass. Outcomes were NEC (modified Bell's Stages II-III), sepsis, infection, and LOS. Disease risk score case-control matching and energy balancing weighted regression balanced multiple relevant covariates. Results Among 822 neonates, the percentage of human milk received during the neonatal period was not associated with NEC, sepsis or infection. Initiation of fortification or formula was associated with 3-fold higher odds of developing NEC within 5 days (OR:3.10, 95%CI:1.10-8.12, p=0.025). In energy balancing weighted regression models, higher neonatal human milk percentage and more frequent BF were strongly associated with shorter LOS: 100% versus 0% human milk with 9.33 days shorter (4.47-14.19, p<0.001); each additional BF session with 0.48 days shorter (0.31-0.65, p<0.001). Conclusions In this multisite cohort, fortification or formula initiation was associated with increased odds of NEC; and neonatal human milk percentage and BF with shorter LOS. Given limited evidence to guide practice, caution in introducing bovine-derived formula for high-risk infants with CCHD may be warranted.

Objective: To identify factors associated with predischarge morbidity and mortality among small for gestational age infants. Study Design: We conducted a retrospective single-center cohort study of small for gestational age infants admitted to a level IV neonatal intensive care unit. We determined the association of clinical characteristics, congenital anomalies, and genetic disorders with the primary outcome of predischarge morbidity or mortality and characterized morbidity and mortality across congenital anomaly subgroups. Results: Among 293 small for gestational age infants, 18 (6.1%) had a genetic disorder and 103 (35.2%) had a major congenital anomaly, with congenital heart disease (CHD) representing the largest subgroup. The primary outcome of morbidity or mortality occurred in 93 infants (31.7%); 74 infants (25.3%) experienced morbidity and 19 (6.5%) died. CHD (adjusted odds ratio [aOR]: 16.5, 95% CI 6.44-45.7) and multiple congenital anomalies (aOR: 17.8, 95% CI 4.64-71.1) were found to be strongly associated with morbidity or mortality, after accounting for sex, maternal race, and intubation > 7 days. Statistically significant associations were also found with the presence of musculoskeletal anomalies as well as genetic disorders in infants without congenital anomalies, though in limited sample sizes. CHD was the largest contributor to morbidity, whereas multiple congenital anomalies accounted for the greatest proportion of mortality. Infants with abdominal wall defects and central nervous system anomalies experienced no morbidity or mortality. Conclusion: Congenital heart disease and multiple congenital anomalies were strongly associated with morbidity and mortality among SGA infants, whereas the degree of SGA alone was not. These findings suggest that risk is not explained by the degree of SGA alone and may be more strongly associated with congenital disease and other underlying factors.

Gastrointestinal (GI) conditions are common among children with neurodevelopmental disabilities (NDDs), and are associated with functional impairment, behavioral symptoms, and increased health care utilization. A unique relationship between autism and GI dysfunction has been proposed, leading to a focus on autism in GI research, management guidelines, and clinical tool development. Leveraging >20 years of electronic health record data and a cohort of 42,204 cases with attention-deficit/hyperactivity disorder, autism, cerebral palsy, epilepsy, or intellectual disability and 297,402 controls without NDDs, we quantified associations between NDDs and GI conditions in children. GI conditions were more common in cases than controls across all individual NDDs; intellectual disability and cerebral palsy were most strongly associated with having a GI condition. In this work, clinically recognized GI morbidity was elevated across all NDDs and not unique to autism, suggesting that a broader, transdiagnostic approach to GI dysfunction in children with NDDs is warranted.

Objectives: Using a nationally representative database of U.S. hospitalizations, we aimed to (1) characterize contemporary trends in hypoxic-ischemic encephalopathy (HIE) prevalence by severity, therapeutic hypothermia (TH) utilization, and associated in-hospital mortality; and (2) examine the association between TH and mortality by HIE severity and gestational age (GA), focusing on 35- and 36-weeks GA. Methods: We analyzed newborn hospitalizations from the National Inpatient Sample, 2016-2023. Unspecified, mild, moderate, and severe HIE were identified using ICD-10-CM diagnosis codes P91.60-P91.63; and 35- and 36-weeks GA using codes P07.38-P07.39. TH was identified using ICD-10-PCS codes 6A4Z0ZZ and 6A4Z1ZZ. Survey-weighted multivariable generalized linear models with marginal standardization were used to estimate adjusted mortality risk differences (RD) with surprisal (S) values, and assess whether associations between TH and mortality differed by HIE severity across GA strata. Results: Among 29,767,238 hospital discharges, HIE was identified in 66,535 neonates (2.24 per 1,000), and TH used in 19.2% of HIE cases. In-hospital mortality was 9.74% among all HIE cases and 6.65% among TH-treated neonates. From 2016-23, HIE prevalence nearly doubled (1.58 to 3.01 per 1,000; p-for-trend <0.001) and TH utilization more than doubled (0.33 to 0.74 per 1,000; p-for-trend <0.001), while TH use as a proportion of HIE remained stable (17.8%-20.8%; p-for-trend=0.39). HIE severity distribution was: mild (15%), moderate (29.4%), severe (18.3%), and unspecified (37.3%), with moderate HIE increasing over time (22.3%-33.5%). Crude mortality was consistently highest for severe HIE (range: 33.65%-35.25%). Among infants with severe HIE, TH was associated with reduced mortality overall (RD -10.12%; 95% CI -14.86, -5.39; p<0.001; S=15.12), and specifically at 36-weeks GA (RD -21.98%; 95% CI -35.85, -8.12; p=0.002; S=9.06), but not at 35-weeks (RD -1.83%; 95% CI -21.2, 17.55; p=0.86; S=0.22). Conclusions: TH was associated with mortality reduction in severe HIE overall and at 36-weeks GA, but this benefit remains uncertain at 35-weeks GA.

Importance: Expectant management for preterm prelabor rupture of membranes (PPROM) is guided primarily by gestational age (GA), yet whether the association between latency duration and neonatal outcomes varies among pregnancies remains uncertain. Objective: To characterize heterogeneous associations between latency duration and neonatal outcomes after PPROM and identify maternal and fetal characteristics associated with the largest estimated benefit. Design: Nationwide registry-based retrospective cohort study using restricted cubic spline regression and causal forest analysis. Data were analyzed from July 2025 to July 2026. Setting: The Korean Neonatal Network (KNN), a nationwide registry of infants born before 32 weeks' gestation or with a birth weight less than 1,500g, from 2013 to 2023. Participants: A total of 7,057 neonates born after PPROM were included. Exposures: Latency duration, defined as the number of days from PPROM diagnosis to delivery (0-118 days). Main Outcomes and Measures: Neonatal Health Index (NHI), an ordinal composite from 0 (death) to 8 (survival free of 7 major neonatal morbidities: intraventricular hemorrhage grades 3-4, periventricular leukomalacia, retinopathy of prematurity stage [&ge;]3, bronchopulmonary dysplasia, pulmonary hypertension, necrotizing enterocolitis stage [&ge;]2, and sepsis). Results: Among 7,057 neonates (median [IQR] maternal age, 34.0 [31.0-36.0] years; GA at PPROM, 27.0 [24.0-29.0] weeks; latency duration, 2.0 [0.0-8.0] days), longer latency was associated with better neonatal health, reflected by higher NHI (n = 6,872), in a non-linear, GA-dependent pattern (overall P < .001; nonlinearity P < .001). Causal forest analysis estimated an average partial effect of a 0.078-point increase in NHI per additional day of latency (P < .001), with significant heterogeneity across individuals (P < .001). GA at PPROM, oligohydramnios, and maternal age were the strongest modifiers; neonates with GA at PPROM of 26 weeks or less, no oligohydramnios, and maternal age younger than 30 years had an estimated treatment effect 28.0% greater than the rest of the cohort (0.121 vs 0.094 NHI points per latency-day). Conclusions and Relevance: Associations between neonatal outcomes and prolonged latency after PPROM were positive overall but heterogeneous in magnitude, varying by GA at PPROM, oligohydramnios status, and maternal age. These findings support tailoring expectant management after PPROM according to individual patient characteristics rather than a uniform, GA-based strategy.

Background: Vitamin K prophylaxis is universally recommended for newborns to prevent life threatening vitamin K deficiency bleeding. Although not on the immunization schedule, vitamin K prophylaxis is often coadministered with hepatitis B birth dose and erythromycin ophthalmic ointment, and rising hesitancy around vaccines/preventive care may spill over into vitamin K administration. Methods: We conducted a retrospective cohort study using Truveta electronic health record data with linked mother-child dyads. Live births to mothers aged 15-49 from January 1, 2019 through June 30, 2026 were included. Vitamin K administration was defined as documentation on the birth date or following day. Logistic regression assessed sociodemographic predictors of non-receipt, and interrupted time series analysis evaluated changes after January 2026. Results: Among 1,026,375 infants, 995,628 (96.97%) had documented vitamin K administration. Non-receipt increased from an average of 2.1% during 2019-2022 to 4.3% in 2025 and 6.1% in 2026, reaching 8.10% in June 2026. Older maternal age, non-Hispanic or Latino ethnicity, Medicaid or unknown insurance, and year of delivery were associated with greater odds of non-receipt. After January 2026, there was no immediate step change, but the odds of vitamin K receipt declined an additional 10% per month (OR: 0.90; 95% CI, 0.88-0.91). Conclusions: Vitamin K non-receipt increased over the study period and accelerated after January 2026. Because vitamin K recommendations were not changed by the January vaccine schedule, this association may reflect broader impacts to confidence in newborn preventive care. Future studies should examine causal mechanisms, parental decision-making, and associated clinical outcomes.

Background: Rapid genome sequencing (rGS) is a first-tier test in the neonatal intensive care unit (NICU). Implementation strategies to scale rGS for clinical care may change clinician roles. We analyzed the NICU rGS workflow to understand challenges rGS poses for clinical roles and responsibilities. Methods: The study took a qualitative approach to understanding the rGS workflow in Level III and Level IV NICUs. The five workflow phases studied included: i) identification of a patient with a suspected genetic disorder, ii) subspecialist consultation, iii) test selection and ordering, iv) return of results, and v) disclosure. Data were collected via job task journals, interviews, and workflow diagram construction with clinicians involved in rGS. Analysis included participant-guided workflow diagram refinement, qualitative thematic analysis, and identification of rGS workflow challenges. Results: We documented issues related to decision-making authority and scope of responsibility for clinicians, with the majority relating to complexities of subspecialist consultations. Issues included differences in: criteria for triggering consultations, expectations of consulted subspecialists' roles, test selection preferences, and responsibility for documenting clinical interpretations and disclosure. Conclusion: Subspecialist consultations in clinical rGS involved significant role ambiguity and communication challenges, requiring intentional implementation efforts to ensure clear clinical roles and responsibilities.

AIM: To evaluate whether selective motor control quantified from spontaneous infant movement recordings provides diagnostic and prognostic information for cerebral palsy (CP) beyond established movement-based assessments. METHOD: This multicenter diagnostic and prognostic accuracy study included 302 infants (151 with CP) with spontaneous movement recordings obtained between 10 and 20 weeks corrected age from cohorts in Australia and the United States. All eligible infants with CP were included, and a comparison sample without CP was randomly selected. Recordings were scored using the Baby Observational Selective Control Appraisal (BabyOSCAR), Motor Optimality Score Revised (MOS-R), and General Movements Assessment (GMA). Outcomes at 2 years or older included CP diagnosis, Gross Motor Function Classification System (GMFCS) level, and motor distribution. RESULTS: BabyOSCAR discriminated CP diagnosis (area under the curve [AUC] 0.98), including children later classified in GMFCS level I. Among infants with CP, BabyOSCAR discriminated GMFCS levels I - II from III - V (AUC 0.89). BabyOSCAR absolute asymmetry also discriminated unilateral CP from all other infants (AUC 0.90). Diagnostic discrimination was also observed for MOS-R (AUC 0.94) and GMA (AUC 0.86). INTERPRETATION: Quantifying selective motor control from brief infant movement recordings may provide complementary early information about CP diagnosis, functional level, and motor distribution.

Background: Socioeconomic deprivation is associated with childhood morbidity, but nationwide evidence on critical illness and death in a health system with universal insurance coverage is scarce. We assessed the association between area-level deprivation and the population-level incidence of hospital admission, complex intensive care treatment (CICT), and CICT-related mortality in German children, and changes over time. Methods: Population-based analysis of complete German hospital discharge data, 2016 to 2023, covering all cases aged > 28 days to < 18 years. Cases were linked to the German Index of Socioeconomic Deprivation (GISD) via the municipality of residence and grouped into quintiles (Q1 least, Q5 most deprived). Incidence rates were calculated per 100,000 child years. Negative binomial regression adjusted for calendar year, with population as offset, yielded adjusted incidence rate ratios (aIRR) per one-quintile increase in deprivation; sensitivity analyses additionally adjusted for age group. Excess cases were estimated by applying Q1 incidence rates to Q2 to Q5. Results: Of 8,890,103 pediatric cases, 140,509 (1.6 %) received CICT and 3,386 (2.40 %) of these died. Incidence rose with deprivation from Q1 to Q5: admissions 6,191 to 9,255 per 100,000 child years, CICT 97 to 128, mortality 2.54 to 2.96. Each one-quintile increase was associated with higher risk of admission (aIRR 1.10, 95 % CI 1.10-1.11), CICT (1.07, 1.05-1.08), and mortality (1.04, 1.01-1.06); estimates were unchanged after age adjustment. Relative to Q1 rates, Q2 to Q5 accounted for 1,295,896 excess admissions (20.8 %), 11,254 excess CICT cases (12.6 %), and 194 excess deaths (8.7 %). Case fatality among CICT cases was lower in more deprived quintiles (2.35 % in Q5 versus 2.64 % in Q1), as were organ dysfunction and chronic conditions. Disparities in admission and CICT narrowed over time, whereas the mortality gradient persisted. Conclusions: Universal health insurance did not eliminate socioeconomic inequalities in pediatric critical illness. Deprivation increased the population burden of admission, intensive care, and death, but did not worsen outcomes once intensive care had begun, indicating that inequalities arise before pediatric intensive care and that prevention upstream in the care continuum is the primary target.

Formula-fed infants have altered gut microbiota and immune development relative to breastfed infants. Human milk oligosaccharides (HMOs) and microbes able to ferment these, like Bifidobacterium infantis, promote healthy immune-microbiome interactions in breastfed infants. In this randomized trial, 240 healthy term infants in the Philippines received a synbiotic blend formula (SynF; seven HMOs, bovine milk oligosaccharides, and B. infantis LMG11588) or control formula (CtrlF) for 6 months. SynF supported growth non-inferior to CtrlF and near universal B. infantis colonization (vs <10% in CtrlF). Markers of intestinal inflammation were lower in children fed SynF while secretory IgA was higher. SynF fed infants showed lower markers of systemic inflammation in plasma, slower immune cell maturation, and fewer upper respiratory tract infections (URTI) during their first 6 months of life. These findings suggest that synbiotic formula can dampen inflammatory responses to colonizing microbes and mild infections in fully formula-fed, term infants. Trial registration: NCT06073652.

Background and Objectives: Dozens of projects around the world are sequencing the genomes of healthy babies near birth. Genomic information becomes actionable across infancy, childhood and adulthood, making timing of return a design choice for programs. We report the first study of health care professionals' views on timing. Methods: We conducted a qualitative interview study of US-based clinical geneticists, genetic counselors, laboratory personnel, pediatric primary care clinicians and genomic screening implementers. Participants responded to three strategies: staged throughout childhood when information becomes actionable, all at birth with adult-actionable results deferred, and all at birth. Transcripts were analyzed using framework analysis. Results: We interviewed 52 individuals; 39 were asked directly about timing. Giving parents a choice, raised by participants rather than presented, was the most endorsed position (18), ahead of staging across childhood (12). Many viewed staging as preferable in theory, but feasibility concerns weighed against it, including that 'actionability' was not a robust enough concept. A further concern was that parents would not grasp the distinction between data generated and data examined, on which staging depends. Where information is staged, participants saw a role for adolescent assent; where it is not, disclosure to the developing child becomes important, and participants identified a lack of support for parents. Conclusions: Tying the return of information to the age of actionability is intuitive but hard to operationalize. Parental choice was the most endorsed position but will only be viable with decision support and guidance for disclosure to children.

Background Pontocerebellar hypoplasia Type 2A (PCH2A) is a rare, autosomal recessive disorder with reduced life expectancy. Clinical features include profound developmental delay, microcephaly, and a dyskinetic movement disorder. Additional symptoms frequently observed are feeding difficulties, vomiting, dystonic attacks, and seizures. Compared to parents of typically developing children, parents of children with PCH2A experience decreased health-related quality of life. The aim of this study was to provide a follow-up on survival, symptoms, and perceived disease burden. Methods Patients were primarily recruited via the German patients' organization (PCH-Familie e.V.). Inclusion required genetic confirmation of PCH2A. Data were collected from 2020-2022 using parent questionnaires and medical reports; uncertainties were clarified during semi-standardized telephone interviews. Statistical analysis was quantitative, appropriate statistical tests were used, depending on the data distribution. Results Sixty-five patients participated, with a median age of 6.4 years and balanced gender distribution. Sixteen patients (25%) died at a median age of 5.5 years. Ten-year survival rate was 71.5%. Feeding difficulties, dyskinesia, and sleep disturbances were common and persistent symptoms. Seizures increased with age, whereas vomiting and dystonic attacks decreased over time. Perceived disease burden differed among families, but most reported overall impaired quality of life. The most burdensome symptoms were restlessness, sleep disorder, and gastrointestinal issues, while seizures/epilepsy were ranked as least impactful. With increasing age, perceived burden from feeding and swallowing disorders, gastrointestinal problems, episodic abdominal pain, and overall quality of life decreased significantly. Conclusions Life expectancy in PCH2A remains limited, but survival appears to have improved in more recent birth cohorts. Most symptoms persist with age, though a few, like reflux and dystonic attacks, improve in tendency. Conversely, respiratory symptoms and seizures tend to worsen. Notably, perceived disease burden generally decreases as patients age. Restlessness proved to be the most burdensome symptom, although it has not been clearly described before.

Background Despite cerebrospinal fluid (CSF) analysis being the gold standard for definitively diagnosing meningitis, its practical application has presented considerable difficulties, especially in environments with limited resources. Cranial ultrasound (CUS), while not a replacement for CSF analysis, provides rapid imaging to identify meningeal irregularities. Nevertheless, achieving a timely diagnosis of meningitis, particularly in its nascent stages, remains problematic, and healthcare professionals exhibit a notably low awareness of CUS's utility in diagnosing this condition. Methods This was a prospective cohort that recruited 273 term mother-neonate pairs. The neonates were initially divided into those with sepsis-meningitis (exposure group) and those with sepsis (non-exposure group) based on clinical assessment done by the admitting team. The research team further divided the participants into 4 diagnostic subgroups based on CUS findings: positive CUS for meningitis, positive clinical diagnosis for meningitis, positive CUS & clinical diagnosis for meningitis and those with negative CUS & clinical diagnosis for meningitis /sepsis only. Data on socio-demographics, clinical characteristics, blood works and CSF analysis reports, neurologic deficits and mortality outcomes were recorded for each neonate. Descriptive and inferential statistics were performed. Results The 4 diagnostic subgroups based on CUS findings were: positive CUS for meningitis (24.5%), positive clinical diagnosis for meningitis (4.4%), positive CUS & clinical diagnosis for meningitis (6.6%) and those with negative CUS & clinical diagnosis for meningitis /sepsis only (64.5%). Overall, duration of hospitalization was 11 days (range 2-45 days; interquartile range [IQR] 6,16) and the median chronological age of the neonates was 13 days (IQR 7, 21). Meningitis was suspected in 11% of neonates admitted with clinical sepsis. Uptake for lumbar puncture (LP) or ventricular tap (VT) was low at 4.4% (n = 12), underlining barriers to CSF-based diagnosis in this setting. Late-onset sepsis was associated with only 31.9% of NSM. The chronological age of the neonates at admission (p=0.002) and their duration of hospitalization (p=0.042) were significantly different across the 4 categories of neonates. Prominent sulci, hyperechoic brain lesions, ventriculitis, and lateral ventriculomegaly were the most common abnormal findings on CUS. Overall, neonates with meningitis presented later in age and stayed longer on the ward than those with sepsis: clinical meningitis diagnosis was likely to be made in older neonates and was associated with a shorter duration of hospitalization than CUS-diagnosed meningitis. Overall mortality rate was 2.2%. Mortality (16.7%) was highest amongst those with clinical & CUS diagnosed-NSM. Prevalence of Near-Miss cases of NSM was at least 27.6%. A neonate with clinical diagnosis of NSM was 3.94 times (95% CI 1.80, 8.62; p<0.001) more likely to have abnormal CUS at the time of admission. Percent agreement between the clinical and CUS diagnosis for NSM was 71.1%. Nine (75%) out of the 12 CSF reports was positive for meningitis; and the majority 55.6% (5) of the positive CSF report belonged to the category of neonates with sepsis only. Compared to CSF analysis, sensitivity of clinical diagnosis of NSM was 22.2%; specificity was 33.3%; positive predictive value (PPV) was 50%; negative predictive value (NPV) was 12.5% and likelihood ratio (LR) was 0.33. Whereas, sensitivity of CUS was 44.4%; specificity of CUS was 66.7%; PPV was 80%; NPV was 28.6% and LR was 1.33. Conclusion The CUS was only moderately effective at diagnosing meningitis whereas the presence of positive CSF among neonates with sepsis only within this study, further reaffirms the irreplaceability of CSF analysis in the diagnosis of NSM. Nevertheless, the integration of clinical assessment and CUS findings for diagnosing NSM emerged as possessing greater clinical significance in contexts characterized by limited resources. The systematic adoption of CUS for neonates exhibiting features suggestive of sepsis or meningitis (while exploring measures to improve on uptake of CSF analysis) could enhance the promptness of diagnosis, inform the selection of suitable therapeutic interventions, and potentially mitigate mortality rates and the occurrence of long-term neurological impairments, especially within environments facing resource limitations.

Purpose: Outcome consequences of critically ill children treated outside of pediatric intensive care units (PICU) are unknown. We assessed case fatality of children receiving complex intensive care treatment (CICT) by treating department in Germany and explored reasons for admission to adult intensive care units (AICU). Methods: Retrospective study using the German nationwide hospital discharge dataset 2016 to 2023. Cases aged [&ge;] 28 days and < 18 years receiving CICT were classified as PICU, AICU, or interdisciplinary by department codes. Odds ratios (OR) for in-hospital case fatality were estimated in generalized linear mixed models with the hospital as random effect, adjusted for age, acute organ dysfunction, and chronic conditions. Excess deaths were estimated and a survey among pediatric and adult intensivists was analyzed qualitatively. Results: Of 143,034 cases, 67.8 % were treated in PICUs, 14.0 % in AICUs, and 18.2 % were interdisciplinary. The crude OR for death in PICUs versus AICUs was 1.14 (95 % CI 1.03 to 1.26), reversing to 0.73 (0.63 to 0.84) after adjustment. For PICU and interdisciplinary cases combined versus AICU, the fully adjusted OR was 0.61 (0.54 to 0.70). Estimated excess deaths across the study period were 100, rising to 191 when interdisciplinary cases counted as pediatric. Capacity constraints, organizational factors, and clinical expertise were the main domains underlying AICU admissions. Conclusions: Children treated outside of PICUs had higher risk-adjusted case fatality, while crude figures pointed in the opposite direction. The findings support treating critically ill children in settings with routine pediatric intensive care experience.

Abstract Background: Having a usual source of care (USC) supports continuity and access to health services. Recent national trends among U.S. children have not been comprehensively characterized. We examined changes in USC prevalence, subgroup heterogeneity, and reported reasons for not having a USC using the 2015-2024 Medical Expenditure Panel Survey. Methods: We analyzed the 2015-2024 Medical Expenditure Panel Survey Household Full-Year Consolidated Data. Annual prevalence rates were estimated for children aged 0 to 17 years overall and by sex, age group, race and ethnicity, and insurance status. The reported reasons for not having a USC were grouped to low perceived need, preference or self-management, access or continuity barrier, and other reasons. The distribution of grouped reasons was analyzed for each study year. Temporal differences in yearly estimates were evaluated using two-sample z-tests between 2015 and 2019 and between 2015 and 2024, and average annual changes were estimated using generalized linear regression. Results: Overall USC prevalence declined from 92.9% (95% confidence interval [CI], 91.9%, 93.8%) in 2015 to 87.2% (95% CI, 85.1%, 89.2%) in 2024. The estimated average annual change was -0.8 percentage points (95% CI, -1.0 to -0.6). Declines were observed across most subgroups and were largest among uninsured children, whose prevalence decreased from 78.4% to 53.6%. Low perceived need remained the most common reported reason for not having a USC, while the proportion reporting access or continuity barriers decreased and the proportion classified as other reasons increased. Conclusions: Estimates based on the Medical Expenditure Panel Survey indicated a substantial decline in the prevalence of having a USC among U.S. children, with notable heterogeneity by insurance status and race and ethnicity. Further research is needed to determine whether the decline reflects changing access, organization and use of pediatric care, survey measurement, or a combination of these factors.

Introduction: The TREOCAPA (Prophylactic TREatment Of the duCtus Arteriosus in Preterm infants by Acetaminophen) trial was a pan-European, multi-centre, phase II/III trial investigating the impact of prophylactic paracetamol (also known as acetaminophen) given during the first 5 days of life for children born before 29 weeks' gestational age (GA) on survival to 36 weeks' post-menstrual age without severe neonatal morbidities. However, due to time restrictions, long-term follow-up was not planned as part of the initial trial despite recommendations for neonatal trials to include endpoints measuring efficacy after discharge from the neonatal unit and on-going debate about the long-term effects of paracetamol in the neonatal period. This protocol describes a study to follow-up participants in the TREOCAPA trial at 2 years corrected age initiated after the trial's onset. Methods and analysis: The TREOCAPA Long Term (TREOCAPA-LT) study population consists of all children included in the TREOCAPA phase III trial in centres in countries participating in the follow-up study who are aged between 23.5 and 27.5 months corrected age during the study period. Families are contacted by the clinical teams and a parent or guardian is invited to complete an internet-based (online) questionnaire. The primary outcome is cognition, as measured by the non-verbal Cognitive Scale standard score from the Parent Report of Children's Abilities-Revised (PARCA-R) questionnaire. Secondary outcomes are moderate to severe neurodevelopment, health service use and costs. Data will be analysed according to the study groups to which children were randomised in the original TREOCAPA RCT. Ethics and Dissemination: The TREOCAPA-LT protocol was first approved by ethics' committees in France (the study's sponsor) and subsequently by all participating countries. Results from TREOCAPA-LT will be published in open access journals in accordance with the funder's regulations. Registration: https://clinicaltrials.gov/study/NCT06064825

Background: Genetic conditions are common in congenital heart disease (CHD) and affect care, but are often missed or diagnosed late. We asked whether routine clinical data can shortlist the most likely genetic conditions. Methods: Retrospective single-center cohort of children with CHD and an echocardiogram who had either a confirmed genetic diagnosis or negative cytogenetic testing and CHD gene sequencing. Echocardiogram images and serial medical record data were added as model inputs in the order they become clinically available. Class balanced logistic regression (LR) and a multimodal deep learning fusion network were fitted to the same inputs at each step. The primary metric was balanced top-3 accuracy (correct diagnosis among the top three, averaged across conditions), with bootstrap intervals. Results: The cohort included 1,720 children (988 with common CHD-associated genetic conditions, 231 rare diagnoses, 501 negative testing). Using only inputs generated at the echocardiogram visit, LR reached a balanced top-3 accuracy 0.758 (chance 0.429). Serial records, radiology notes and ICD-10 codes, raised this to 0.809. Multimodal fusion performed similarly at each stage. With a genetic condition withheld from training, the fusion embedding placed affected children nearest to others sharing a gene group in 0.37 of cases versus 0.10 without the embedding (+0.268 [95% CI +0.242, +0.295]). Conclusions: Routine clinical data available at first echocardiogram can help identify likely genetic diagnoses, and later coded inputs ceiling. Multimodal fusion added no accuracy over LR, but places children sharing a genetic cause near one another, making nearest-neighbor retrieval informative for undiagnosed children.

BACKGROUND: Adverse consequences of neonatal hyperbilirubinemia disproportionately affect babies in low- and middle-income countries. Laboratory measurement of total serum bilirubin is limited in low-resource settings, necessitating simpler alternatives. Our study aimed to evaluate the diagnostic accuracy of visual inspection of jaundice via the World Health Organization Integrated Management of Childhood Illnesses algorithm compared to transcutaneous bilirubinometry for the identification of hyperbilirubinemia in community settings. METHODS: Hyperbilirubinemia was assessed by visual inspection for jaundice and transcutaneous bilirubinometry at 0-72 hours, 3-5 days, and 5-14 days postnatal in the PRISMA prospective cohort study in six sites in Asia and Africa. We assessed sensitivity, specificity, and positive and negative percent agreement. RESULTS: We analyzed data from 14,331 infants, including 1,852 preterm infants. 15% had hyperbilirubinemia, as defined by transcutaneous bilirubin values and the NICE nomograms, at 3-5 days postnatal. Visual inspection had a sensitivity of 16%, specificity of 96%, positive percent agreement of 56%, and negative percent agreement of 86% at 3-5 days postnatal age, pooled across all sites and gestational ages, versus transcutaneous bilirubin defined by NICE nomograms. CONCLUSION: The poor sensitivity of visual inspection underscores an urgent need for accurate, affordable screening tools to improve screening for hyperbilirubinemia.

Background: Infants <30 weeks gestational age (very preterm (VPT)), are at risk of experiencing multiple serious neonatal morbidities. These morbidities impart serious biological stress, which may be reflected in dysregulated protein expression even after the morbidities have resolved. Recent studies suggest that DNA methylation-based predictors of circulating proteins may reflect the molecular effects of neonatal adversity. The objective of this study is to examine associations between DNA methylation-derived EpiScores, which are externally trained methylation signatures that proxy circulating protein levels, and neonatal morbidity burden in children born VPT. Buccal DNA methylation was obtained at NICU discharge in 537 infants from the NOVI cohort. A total of 111 EpiScores were calculated and tested for association with multimorbidity (0-1 vs. [&ge;] 2 morbidities) using adjusted linear regression models. Cross-tissue analyses in an external paired blood-buccal dataset (n=21) were used to identify EpiScores with moderate-to-strong correlations across tissues. Results: Eighteen EpiScores were nominally associated with multimorbidity (p < 0.05), with Melanoma-derived growth regulatory protein (MIA) with FDR < 0.05 (beta = 0.0023, p = 0.0004). In cross-tissue analyses, 35 EpiScores yielded r > 0.50 (p<0.05), 11 of which showed nominal associations with multimorbidity, including MIA. Overall, the morbidity-associated EpiScores reflected immune, inflammatory, metabolic, and growth-related pathways. Conclusions: Buccal DNA methylation-derived EpiScores capture biological signatures associated with neonatal morbidity burden in very preterm infants.

Background Congenital heart disease is the most common congenital anomaly and a major public health concern. No single cause has been identified, and its aetiology is most likely to be multifactorial, determined by a combination of genetic and environmental factors. Congenital heart disease can have a significant and lasting impact on childrens health and development with well documented neurodevelopmental difficulties experienced by some children with CHD. However, evidence linking early environmental factors to developmental outcomes remains limited, despite growing recognition of their importance. The Northern Ireland BabyHearts 2 Study provides an opportunity to investigate these relationships in a longitudinal cohort with extensive prospectively collected preconceptional and antenatal data. Aim To investigate the associations between preconceptional and antenatal environmental factors and the birth outcomes, physical health, neurodevelopment and academic achievement of children with and without congenital heart disease. Methods This is a longitudinal matched cohort follow-up study of children with and without congenital heart disease recruited to the NI BabyHearts 1 case-control study (2014-2017), with controls matched 1:1 by age and sex. Data sources include the existing NI BabyHearts 1 dataset of prospectively collected preconceptional and antenatal environmental exposures, together with linked routine maternity and prescribing data. Follow-up data collected at 8-11 years of age include parental questionnaires assessing child executive function and behavioural development, standardised child-completed assessments of neurodevelopment, language and educational attainment, and clinical information. Impact This study will provide evidence on the long-term health and developmental outcomes in children born with and without congenital heart disease and improve understanding of how early environmental factors influence these outcomes. Findings will inform clinical care and service provision for children with congenital heart disease, strengthen preconception and antenatal guidance, and contribute to public health policy aimed at improving long-term outcomes for children living with congenital heart disease.