The Journal of Pediatrics

Using electronic health record data combined with primary chart review, we identified 7 children across 8 pediatric medical centers with a diagnosis of Multisystem Inflammatory Syndrome in Children (MIS-C) who were managed as outpatients. These findings should prompt a discussion about modifying the case definition to allow for such a possibility.

Objective To examine group differences and continuity in caregiving environments of infants born preterm from Spanish- and English-speaking families. Study Design We conducted a prospective cohort study of Spanish- (n = 17) and English-speaking (n = 23) families of infants born preterm (< 32 weeks gestation). Caregiver-infant engagement was assessed neonatally via hospital visitation and skin-to-skin (STS) care, and at home via child-directed adult word counts/hour (CD-AWC/hour) from all-day audio recordings. Result No significant group differences were observed in family visitation, neonatal STS care, or in-home verbal engagement, although STS care rates varied considerably, especially within Spanish-speaking families. Across both groups, greater STS care was associated with higher CD-AWC/hour at home. Conclusion Spanish- and English-speaking families showed comparable patterns of caregiver-infant engagement, as a group, however, many Spanish-speaking families engaged in less STS than English-speaking families. STS care predicted caregiver-infant verbal engagement at home, highlighting continuity from hospital to home.

ObjectiveTo examine differences in infant-directed talk activities (e.g., reading) before and after introduction of a NICU book cart. Study DesignWe retrospectively analyzed medical record data of infants born <32 weeks gestational age (n = 147) whose NICU stay occurred in the year before or after book cart implementation (6/1/2022). Talk rates and frequencies were calculated from clinically charted family and staff talk data; talk amounts were compared across pre- and post-book cart cohorts, adjusting for covariates. ResultsCohorts displayed equivalent clinical/demographic variables, except for higher bronchopulmonary dysplasia rates in the post-book cart cohort. Post-book cart family and staff engaged in more talk than those in the pre-book cart cohort, with staff showing higher talk rates and frequencies than family across both cohorts. ConclusionFamily and staff with access to a NICU book cart engaged in more talk, suggesting a strategy to support infant speech exposure.

AbstractO_ST_ABSBackgroundC_ST_ABSThe increasing clinical use of combining structural MRI (sMRI) with General Movements Assessment (GMA) or Hammersmith Infant Neurological Exam (HINE) before five months corrected age (CA) for early diagnosis of cerebral palsy (CP) lacks sufficient prognostic data for children with CP, especially those with Gross Motor Function Classification System (GMFCS) I. ObjectiveEvaluate the predictive value of sMRI, GMA, and HINE individually and in combination for early CP diagnosis and assess accuracy across varying GMFCS levels in a regional cohort of preterm infants. MethodsWe performed sMRI between 39-44 weeks postmenstrual age and GMA and HINE between 12-18 weeks CA in 395 preterm infants born at [&le;]32 weeks gestation across five NICUs in Greater Cincinnati. Brain abnormalities on sMRI included white matter injuries, cortical and deep gray matter lesions, or extensive cerebellar hemorrhage. Absent fidgety movements constituted abnormal GMA; abnormal HINEs were scores <56. The primary outcome was CP diagnosis at 22-26 months CA, classified by the GMFCS. We calculated sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios for individual tests and combinations. ResultsOf 338 (86%) infants with complete follow-up, 48 (14.2%) showed sMRI abnormalities, 15 (4.6%) had abnormal GMA, and 69 (20.9%) had abnormal HINE. Thirty-nine children (11.5%) developed CP at age 2, of which 28 had GMFCS level I and 11 had GMFCS >II. The combination of sMRI and GMA achieved 100% specificity but only 22% sensitivity while the combination of abnormal sMRI and HINE demonstrated sensitivity of 32% and specificity of 98% for prediction of CP. Individual or combined tests showed far higher sensitivity (78-100%) for predicting CP in children with GMFCS levels II-V. ConclusionsThe combination of sMRI with GMA or HINE demonstrated high specificity but low sensitivity for early CP diagnosis in a regional cohort of preterm infants. This approach appears effective for early detection of CP levels II-V but not for level I cases, the most prevalent type, underscoring the need for continued developmental follow-up for all very preterm infants and need for more sensitive diagnostic tools for early detection of CP. Key PointsO_ST_ABSQuestionsC_ST_ABSWhat is the individual and combined prognostic accuracy of sMRI, GMA, and HINE for early diagnosis of CP in preterm infants? FindingsIn our prospective, regional study of preterm infants born at [&le;]32 weeks gestation, we found that combining brain abnormalities on sMRI with abnormal GMA achieved 100% specificity but 22% sensitivity for diagnosing CP. Individual or combined tests showed far higher sensitivity (78-100%) for predicting CP in children with GMFCS levels II-V. Both individual and combined tests were poor predictors of GMFCS level I CP, the most common type. MeaningWhile sMRI combined with GMA or HINE is effective for diagnosing CP with GMFCS levels II-V, this approach falls short for children with GMFCS level I.

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.

ImportanceNeonatal intensive care units (NICUs) care for a vulnerable population with suboptimal research recruitment rates. Understanding NICU parents motivations and recommendations may improve recruitment efforts. ObjectiveIdentify key factors influencing NICU parents decisions to enroll their newborns in research and gather recommendations to enhance engagement. DesignSemi-structured interviews were conducted with 24 parents from three NICU study populations: NSR-RISE, TRANSIT-CHD, and PROMPT. Using a grounded theory approach, data was analyzed prior to developing hypotheses, allowing themes to emerge organically during data analysis. Transcripts were coded through multiple rounds of data analysis until thematic saturation was reached. SettingInterviews occurred virtually with previous research participants at UCSF hospitals. Participants65 parents of NICU patients were invited; 24 participated. Inclusion criteria included 1) parent age older than 18 years, 2) NICU admission history, 3) prior participation in NSR-RISE, TRANSIT-CHD, or PROMPT, and 4) child aged 18-36 months at time of interview. Main Outcome(s) and Measure(s)Using a grounded theory approach, data was analyzed prior to developing hypotheses, allowing themes to emerge organically during data analysis. ResultsParents of 8 NSR-RISE, 8 TRANSIT-CHD, and 8 PROMPT-enrolled neonates participated. Three primary themes emerged: 1) parents lived experiences during an emotionally intense NICU period fostered parental resilience and newfound support systems, 2) decision-making regarding NICU research participation included factors such as prognosis, emotional state, desire to aid future families, and perceived risks versus benefits, and 3) recommendations for improving NICU research recruitment, such as timely, empathic communication from trusted researchers, sensitivity to emotions, concise language, and early emphasis of altruistic goals. Conclusions and RelevanceAltruism is a key motivator for NICU parents research participation. Recruitment strategies should emphasize empathetic, well-timed communication from trusted persons, clearly addressing risks and altruistic outcomes. Sensitivity to the emotionally charged NICU environment is essential for improving engagement and enhancing the NICU experience.

BackgroundMulti-system inflammatory syndrome in children (MIS-C) represents one of the most severe post-acute sequelae of SARS-CoV-2 infection in children, and there is a critical need to characterize its disease patterns for improved recognition and management. Our objective was to characterize subphenotypes of MIS-C based on presentation, demographics and laboratory parameters. MethodsWe conducted a retrospective cohort study of children with MIS-C from March 1, 2020 - April 30, 2022 and cared for in 8 pediatric medical centers that participate in PEDSnet. We included demographics, symptoms, conditions, laboratory values, medications and outcomes (ICU admission, death), and grouped variables into eight categories according to organ system involvement. We used a heterogeneity-adaptive latent class analysis model to identify three clinically-relevant subphenotypes. We further characterized the sociodemographic and clinical characteristics of each subphenotype, and evaluated their temporal patterns. FindingsWe identified 1186 children hospitalized with MIS-C. The highest proportion of children (44{middle dot}4%) were aged between 5-11 years, with a male predominance (61.0%), and non- Hispanic white ethnicity (40{middle dot}2%). Most (67{middle dot}8%) children did not have a chronic condition. Class 1 represented children with a severe clinical phenotype, with 72{middle dot}5% admitted to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 represented a mild presentation, with fewer organ systems involved, lower CRP, troponin values and less cardiac involvement. Class 1 initially represented 51{middle dot}1% of children early in the pandemic, which decreased to 33{middle dot}9% from the pre-delta period to the omicron period. InterpretationMIS-C has a spectrum of clinical severity, with degree of laboratory abnormalities rather than the number of organ systems involved providing more useful indicators of severity. The proportion of severe/critical MIS-C decreased over time. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and preprint articles from December 2019, to July 2022, for studies published in English that investigated the clinical subphenotypes of MIS-C using the terms "multi-system inflammatory syndrome in children" or "pediatric inflammatory multisystem syndrome" and "phenotypes". Most previous research described the symptoms, clinical characteristics and risk factors associated with MIS-C and how these differ from acute COVID-19, Kawasaki Disease and Toxic Shock Syndrome. One single-center study of 63 patients conducted in 2020 divided patients into Kawasaki and non-Kawasaki disease subphenotypes. Another CDC study evaluated 3 subclasses of MIS-C in 570 children, with one class representing the highest number of organ systems, a second class with predominant respiratory system involvement, and a third class with features overlapping with Kawasaki Disease. However, this study evaluated cases from March to July 2020, during the early phase of the pandemic when misclassification of cases as Kawasaki disease or acute COVID-19 may have occurred. Therefore, it is not known from the existing literature whether the presentation of MIS-C has changed with newer variants such as delta and omicron. Added value of this studyPEDSnet provides one of the largest MIS-C cohorts described so far, providing sufficient power for detailed analyses on MIS-C subphenotypes. Our analyses span the entire length of the pandemic, including the more recent omicron wave, and provide an update on the presentations of MIS-C and its temporal dynamics. We found that children have a spectrum of illness that can be characterized as mild (lower inflammatory markers, fewer organ systems involved), moderate (4-6 organ involvement with clinical overlap with acute COVID-19) and severe (higher inflammatory markers, critically ill, more likely to have cardiac involvement, with hypotension/shock and need for vasopressors). Implications of all the available evidenceThese results provide an update to the subphenotypes of MIS-C including the more recent delta and omicron periods and aid in the understanding of the various presentations of MIS-C. These and other findings provide a useful framework for clinicians in the recognition of MIS-C, identify factors associated with children at risk for increased severity, including the importance of laboratory parameters, for risk stratification, and to facilitate early evaluation, diagnosis and treatment.

BACKGROUND AND OBJECTIVESex chromosome trisomies (SCT), including XXY, XYY, and XXX syndromes, have been historically underdiagnosed. Noninvasive prenatal cell-free DNA screening has significantly increased identification of these conditions, leading to a need for pediatric care for a growing population of newborns with SCT. Our goal was to analyze and compare perinatal features, medical diagnoses, and physical features in infants with prenatal identification of SCT conditions through the first year of life. METHODSThe eXtraordinarY Babies Study is an ongoing, prospective natural history study of prenatally identified children with SCT conducted by interdisciplinary teams in Colorado and Delaware. Participants were enrolled prior to 12 months of age and had pregnancy, birth, medical histories, and physical exams completed by board-certified pediatricians at 2, 6, and/or 12-month visits. Descriptive statistics were followed by comparisons between SCT groups using t-tests or ANOVA, Fisher exact, and correlations between medical features with alpha of 0.05. Relative risks were calculated compared to general population rates. RESULTS327 infants were included in the analysis (XXY=195, XXX=79, XYY=53). Major congenital anomalies were rare (1.7%). Relative risk compared to general population was elevated for breastfeeding difficulties (51.7%;RR 2.7), positional torticollis (28.2%;RR 7.2), eczema (48.0%;RR 3.5), food allergies (19.3%;RR 2.4), constipation requiring intervention (33.9%;RR 7.6), small cardiac septal defects (7.7%;RR 17.2), and structural renal abnormalities (4.4%;RR 9.7). Inpatient hospitalization was required for 12.4%, with 59.5% of hospitalizations attributable to respiratory infections. DISCUSSIONThese findings of medical conditions with a higher prevalence can inform anticipatory guidance and medical management for pediatricians caring for infants with SCT. Article SummaryMedical findings in largest cohort of prenatally identified infants with XXY, Trisomy X, and XYY from birth to 12 months and implications for pediatric care. Whats Known on This SubjectOne in [~]500 individuals have an extra X or Y chromosome, or sex chromosome trisomy (SCT). Prenatal screening is now routinely identifying SCT, however there are few studies to guide perinatal and infant care for these individuals. What This Study AddsThis prospective observational study presents medical features for 327 infants with prenatally identified SCT from birth through the first year of life. Results identify where proactive screenings and/or interventions may be warranted for infants with SCT.

BackgroundChildren born very preterm (< 32 weeks gestational age), are at risk for poor growth and adverse neurodevelopmental outcomes. Poor outcomes in preterm children have been attributed to the aversive sounds and relative speech paucity of the neonatal intensive care unit (NICU). Experimental studies that directly expose preterm infants to speech sounds in the NICU find significant improvements in health factors relevant for neurodevelopment. Few studies have examined whether natural variations in the speech environment of the NICU are related to short-term health outcomes in preterm infants. Such data are important for optimizing the sound environment of the NICU. ObjectiveExamine relations between the NICU speech environment and rate of weight gain during hospitalization, an important determinant of physical health and neurodevelopmental outcomes for preterm infants. MethodsParticipants were infants born very preterm (n = 20). The speech environment of each infant was assessed at 32-36 weeks postmenstrual age using a speech-counting device known as a Starling. Speech rates were averaged for each infant over the 4-week period. Average rates of weight gain (g/kg/day) were ascertained over the same period. Calories were derived from charted intake (kcals/kg/day). Linear regressions examined associations between weight gain and both caloric intake and speech counts. Control analyses explored whether effects remained after controlling for family visitation, time in incubator, and health acuity. ResultsInfants who received more calories gained more weight, accounting for more than 30% of the variance. Importantly, speech counts accounted for nearly 29% additional variance (p < .001). These effects were not reduced when controlling for family visitation, time in incubator, or health acuity. ConclusionsEnhancing speech exposure in the NICU may be beneficial for physical growth. NICU infant care plans should consider opportunities to increase speech exposure.

Background and ObjectivesRecurrent acute otitis media (rAOM; defined as [&ge;]3 AOM episodes in 6 months or [&ge;]4 episodes in 12 months) affects 10-15% of children in the United States and is a leading cause of healthcare utilization and antibiotic prescriptions. Prospective identification of children at risk of rAOM could help target interventions and identify new risk factors to guide preventive approaches. We therefore sought to develop predictive models to identify children at risk of rAOM using electronic health records (EHR) data. MethodsWe extracted retrospective EHR data for children who were born at Duke University Health System (DUHS) hospitals between January 1, 2014, and June 30, 2022, and who had at least one AOM episode during the study period. We used LASSO to build predictive models for development of rAOM at each episode and identified factors associated with rAOM. ResultsWe identified 6,566 children who met the study criteria, including 1,634 (24.8%) who met criteria for rAOM. A model using only data available at the first AOM episode had an area under the curve (AUC) of 0.75 (0.73, 0.77) and an Area Under the Precision Recall Curve (AUPRC) of 0.41 (95% CI 0.37, 0.46), indicating moderate discriminative ability. At the time of the first AOM episode, features associated with subsequent rAOM development included age, number of prior antibiotic prescriptions, and diagnosis of gastroesophageal reflux disease (GERD). Further, children who developed rAOM were more likely to experience treatment failure than children who did not meet rAOM criteria across all episodes. ConclusionsOur findings indicate that clinical exposures and patient characteristics documented in the EHR distinguish children who are at risk of developing rAOM. Such models could be deployed within EHR systems to identify children who would benefit from early evaluation by an otolaryngologist and audiologist.

Background and ObjectivesPreterm infants (<34 weeks gestation) experience high rates of morbidity and mortality before hospital discharge. Genetic disorders substantially contribute to morbidity and mortality in related populations. The prevalence and clinical impact of genetic disorders is unknown in this population. We sought to determine the prevalence of commonly diagnosed genetic disorders in preterm infants, and to determine the association of disorders with morbidity and mortality. MethodsThis was a retrospective multicenter cohort study of infants born from 23 to 33 weeks gestation between 2000 and 2020. Genetic disorders were abstracted from diagnoses present in electronic health records. We excluded infants transferred from or to other health care facilities prior to discharge or death when analyzing clinical outcomes. We determined the adjusted odds of pre-discharge morbidity or mortality after adjusting for known risk factors. ResultsOf 320,582 infants, 4196 (1.3%) had genetic disorders. Infants with trisomy 13, 18, 21, or cystic fibrosis had greater adjusted odds of severe morbidity or mortality. Of the 17,427 infants who died, 566 (3.2%) had genetic disorders. Of the 65,968 infants with a severe morbidity, 1319 (2.0%) had genetic disorders. Conclusions Genetic disorders are prevalent in preterm infants, especially those with life-threatening morbidities. Clinicians should consider genetic testing for preterm infants with severe morbidity and maintain a higher index of suspicion for life-threatening morbidities in preterm infants with genetic disorders. Prospective genomic research is needed to clarify the prevalence of genetic disorders in this population, and the contribution of genetic disorders to preterm birth and subsequent morbidity and mortality. Article SummaryGenetic disorders were found in 1.3% of preterm infants and at a higher rate (2.0%) in infants who died or developed severe morbidity. Whats Known on This SubjectPrevious research described the prevalence and associated short-term morbidity and mortality of trisomy 13, 18, and 21 in preterm infants. The prevalence of other commonly diagnosed genetic disorders and associated short-term morbidity and mortality in preterm infants is unknown. What This Study AddsIn a multicenter, retrospective cohort of 320,582 preterm (<34 weeks gestation) infants, we found that 1.3% had genetic disorders diagnosed through standard care. Multiple disorders were associated with increased adjusted odds of morbidities or mortality prior to hospital discharge. Contributors Statement PageSelin S. Everett conceptualized and designed the study, conducted analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript. Dr. Thomas Hays conceptualized and designed the study, drafted the initial manuscript, and critically reviewed and revised the manuscript. Miles Bomback conceptualized and designed the study and critically reviewed and revised the manuscript. Drs. Veeral N. Tolia and Reese H. Clark coordinated and supervised data collection and critically reviewed and revised the manuscript. Dr. Rakesh Sahni conceptualized and designed the study and critically reviewed and revised the manuscript. Dr. Alex Lyford conducted analyses and critically reviewed and revised the manuscript. Dr. Ronald J. Wapner reviewed and critically revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

ObjectiveTo evaluate whether combining abdominal ultrasound with radiography improves diagnostic accuracy and surgical risk prediction in neonates with suspected necrotising enterocolitis (NEC) compared with radiography alone. Design, setting, patientsProspective cohort study conducted in two tertiary neonatal intensive care units. Sixty-seven neonates with suspected NEC underwent concurrent abdominal radiography and ultrasound assessments. Imaging studies were independently reviewed by masked investigators using pre-specified criteria to classify each study as reassuring or non-reassuring. Main outcome measuresThe primary outcome was the need for surgical intervention. Imaging data were analysed using unsupervised k-means clustering (k = 2); logistic regression - testing associations with surgery and Principal component analysis (PCA) - to identify imaging features most contributing to group separation. ResultsUltrasounds were reassuring in all cases subsequently diagnosed with non-NEC, i.e feeding intolerance, whereas most radiographs in this group were non-reassuring. Clustering based on radiographs alone did not significantly discriminate surgical risk (58.8% vs 39.4%; p = 0.11). Combined model (radiograph + ultrasound) produced two distinct clusters with significantly different surgical rates (78.3% vs 34.1%; OR 6.96, 95% CI 2.29-24.58). PCA highlighted complex ascites, absent peristalsis, and abnormal bowel perfusion as key discriminating features. ConclusionIn suspected NEC, combining ultrasound with radiography significantly improves surgical risk stratification compared with radiography alone. A reassuring ultrasound reliably identified infants with feeding intolerance, suggesting potential to reduce unnecessary transfers and treatments. Larger multicentre studies are needed to validate these findings and inform development of a unified multimodal imaging score for NEC diagnosis. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LINEC is an acquired intestinal disease mainly affecting preterm infants with the potential risk of serious life-long co-morbidities. C_LIO_LIPlain abdominal radiography remains the standard initial investigation for suspected NEC but provides limited information on bowel perfusion and viability. C_LIO_LIEmerging evidence supports the role of bowel ultrasound in NEC, in assessing bowel wall thickness, perfusion, peristalsis, and intra-abdominal fluid collections. C_LI What this study addsO_LIUsing a multi-modal imaging approach (combining ultrasound and radiography) improved surgical risk stratification in neonates with suspected NEC compared with using radiography alone. C_LIO_LIA reassuring ultrasound may identify benign conditions initially suspected as early NEC, supporting earlier de-escalation of care. C_LIO_LIThe study findings lay the foundation for a standardised imaging-based score combining radiograph and ultrasound findings in cases with suspected NEC, to better guide diagnosis and predict the need for surgical intervention. C_LI

Background: 48,XXYY syndrome is a rare sex chromosome aneuploidy (SCA) characterized by neurodevelopmental deficits and medical comorbidities. The limited information available in the literature is almost exclusively limited to postnatally diagnosed cases. This study aims to describe the early medical and developmental features of prenatally identified 48,XXYY infants, with comparisons to 47,XYY, 47,XXY cohorts, and typical populations, as well as previously reported postnatally diagnosed 48,XXYY cases. Methods: The eXtraordinarY Babies Study prospectively follows children prenatally identified to be at high risk for SCA with annual medical and neurodevelopmental evaluations. Data presented herein include the prevalence of medical conditions, developmental milestones, developmental and adaptive functioning assessment scores, and therapy utilization in participants confirmed to have 48,XXYY. Comparisons were made between this cohort and the typical population, infants with 47,XYY and 47,XXY also enrolled in the eXtraordinarY Babies Study, and a 2008 cohort of individuals postnatally identified 48,XXYY. Results: Infants with 48,XXYY exhibited a range of early medical features, including high rates of feeding and GI disorders (breastfeeding difficulties, gastroesophageal reflux, and eosinophilic esophagitis), allergic disorders (food allergies and environmental allergies), and hypotonia. Developmental and adaptive functioning scores indicated delays in motor, communication, and social domains, with nearly all infants receiving speech therapy, physical and/or occupational therapy. Comparisons with the 47,XYY and 47,XXY cohorts revealed more medical and developmental challenges in the 48,XXYY group, however there was variability and some overlap with both the general population and sex chromosome trisomy conditions. Additionally, comparison to the 2008 postnatally identified 48,XXYY cohort indicated that while prenatal diagnosis allowed for earlier intervention, developmental outcomes in the first years of life were similar between the two groups. Conclusions: 48,XXYY diagnosed prenatally facilitates early monitoring, anticipatory guidance, and proactive referrals for medical evaluations and intervention, given developmental delays and medical challenges are more common in infancy and early childhood compared to the general population and trisomy SCAs. These findings provide valuable insights for genetic counselors and healthcare providers, emphasizing the spectrum of medical and developmental findings and importance of early and proactive care to support individual outcomes. Prospective study of this prenatally identified cohort will provide important natural history and phenotypic variability in XXYY, as well as identification of predictors of health and developmental outcomes.

ObjectiveTo examine the association of admission NICU strain with neonatal mortality and morbidity. Study Design2008-2021 South Carolina cohort using linked vital statistics and discharge data of 22-44 weeks GA infants, born at hospitals with [&ge;] level 2 unit and [&ge;]5 births of infants <34 weeks GA/year. The exposure was tertiles of admission NICU strain, defined as the sum of infants <44 weeks GA with a congenital anomaly plus all infants born <33 weeks GA at midnight on the day of birth. We used Poisson generalized linear mixed models to examine the association of exposure to strain with the primary outcome of a composite of mortality and term and preterm morbidities adjusting for patient and hospital characteristics. ResultsWe studied 64,647 infants from 30 hospitals. High strain was associated with increased risk of mortality and morbidity adjusting for patient/hospital factors (aIRR 1.07, 95% CI 1.01 - 1.12). ConclusionNICU strain is associated with increased adverse outcomes.

Perinatal transmission of COVID-19 is poorly understood and many neonatal intensive care units (NICU) policies minimize mother-infant contact to prevent transmission. We present our units approach and ways it may impact neonatal microbiome acquisition. We attended COVID-19 positive mothers deliveries from March-August 2020. Delayed cord clamping and skin-to-skin were avoided and infants were admitted to the NICU. No parents visits were allowed and discharge was arranged with COVID-19 negative family members. Maternal breast milk was restricted in the NICU. All twenty-one infants tested negative at 24 and 48 hours and had average hospital stays of nine days. 40% of mothers expressed breastmilk and 60% of infants were discharged with COVID-19 negative caregivers. Extended hospital stays, no skin-to-skin contact, limited maternal milk use, and discharge to caregivers outside primary residences, potentially affect the neonatal microbiome. Future studies are warranted to explore how ours and other centers similar policies influence this outcome.

ObjectivesThe purpose of this study was to examine how the treatment and severity of multisystem inflammatory syndrome in children (MIS-C) has changed over more than two years of the COVID-19 pandemic in the United States. MethodsElectronic health record data were retrieved from the PEDSnet network as part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative. The study included data for children ages 0 to 20 years hospitalized for MIS-C from March 1, 2020 through July 20, 2022. Descriptive statistics for MIS-C treatments and laboratory results were computed for three time periods of interest: March 1, 2020 - May 31, 2021 (pre-Delta); June 1 - December 31, 2021 (primarily Delta); January 1 - July 20, 2022 (primarily Omicron). Standardized differences measured the effect size of the difference between Omicron and pre-Omicron cohorts. ResultsThe study included 946 children with a diagnosis of MIS-C. The largest differences in the Omicron period compared to prior years were decreases in the percentage of children with abnormal troponin (effect size = 0.40), abnormal lymphocytes (effect size = 0.33), and intensive care unit (ICU) visits (effect size = 0.34). There were small decreases in the Omicron period for the majority of treatments and abnormal laboratory measurements examined, including infliximab, anticoagulants, furosemide, aspirin, IVIG without steroids, echocardiograms, mechanical ventilation, platelets, ferritin, and sodium. ConclusionsThis study provides the first evidence that the severity of MIS-C declined in the first half of the year 2022 relative to prior years of the COVID-19 pandemic in the United States. Article SummaryUsing electronic health record data for 946 children, we found evidence that the severity of MIS-C declined during the first half of the year 2022. Whats Known on This SubjectThe clinical management of multisystem inflammatory syndrome in children (MIS-C) has commonly included intravenous immune globulin, steroids, and non-steroidal anti-inflammatory agents. Many children with MIS-C have required intravenous fluids, inotropes and vasopressors, and in some cases, mechanical ventilation. What This Study AddsRecent decreases in the percentage of children with MIS-C that have abnormal troponin, abnormal lymphocytes, or intensive care unit visits provide evidence that the severity of MIS-C has declined in the first half of the year 2022.

ObjectivesDevelop a digital phenotyping algorithm (PheIndex) using electronic medical records (EMR) data to identify children aged 0-3 who have been diagnosed with genetic disorders or present with illness with an increased risk for genetic disorders from a mother-child cohort. MethodsWe established 13 criteria for the algorithm where two metrics - a quantified score and a classification - were derived. The criteria and the classification were validated by chart review from a pediatrician and clinical geneticist. To demonstrate the utility of our algorithm in real-world evidence applications, we examined the association between size of carrier screening panel (small/[&le;]4 genes [CS-S] vs large/[&ge;]100genes [CS-L]) undertaken by mothers prior to delivery, and children classified as presenting with illness with an increased risk for genetic disorders by our algorithm. ResultsThe PheIndex algorithm identified 1,088 such children out of 93,154 live births and achieved 90% sensitivity, 97% specificity, and 94% accuracy by chart review. We found that children whose mothers received CS-L were less likely to be classified as presenting with illness with an increased risk for genetic disorders and a decreased need to have multiple specialist visits and multiple ER visits, compared to children whose mothers received CS-S. ConclusionsThe PheIndex algorithm can help identify when a rare genetic disorder may be present, and has the potential to improve healthcare delivery by alerting providers to consider ordering a diagnostic genetic test and/or referring a patient to a medical geneticist or other specialists. Article SummaryAlgorithm using EMR data to identify children who have been diagnosed with a genetic disorder or present with illness with increased risk of genetic disorders. Whats known on this subjectWith over 7000 Mendelian disorders, identifying children with a specific rare genetic disorder diagnosis through structured EMR data is challenging given incompleteness of records, inaccurate medical diagnosis coding, as well as heterogeneity in clinical symptoms and procedures for specific disorders. What this study addsWe developed a digital phenotyping algorithm using electronic medical records (EMR) data to identify children aged 0-3 who have been diagnosed with genetic disorders or present with illness with an increased risk for genetic disorders from a mother-child cohort.

ObjectiveWe previously identified Paenibacillus species in the cerebrospinal fluid of 44% of infants presenting for neurosurgical evaluation with findings consistent with postinfectious hydrocephalus (PIH) in Eastern Uganda. Here we sought to compare outcomes among hydrocephalic infants with and without Paenibacillus detection at the time of hydrocephalus surgery. MethodsIn a prospective observational study, 78 infants with PIH who underwent a cerebrospinal fluid (CSF) diversion prior to 90 days of age had a positive CSF polymerase chain reaction result for Paenibacillus species (PP), and 111 had a negative result (PN). The primary outcome was diversion failure-free survival defined as being alive without diversion failure at last patient contact. Secondary outcomes included overall survival and diversion success. ResultsAfter a median follow-up period of 35.7 months, the primary outcome was observed in 42 PP patients (54%) and in 76 PN patients (68%) (adjusted hazard ratio (aHR), 2.45; 95% confidence interval [CI], 1.42 to 4.22; P=0.001). PP patients who underwent endoscopic diversion had the worst primary event rate (aHR, 6.47; 95% CI, 2.40 to 17.42; P<0.001). Death from any cause occurred in 16 PP patients (20%) and 9 PN patients (8%) (aHR, 3.47; 95% CI, 1.44 to 8.37; P=0.006). Diversion failure occurred in 28 PP patients (36%) and in 29 PN patients (26%) (aHR, 2.24; 95% CI, 1.31 to 3.85; P=0.003). ConclusionsIn this study, Paenibacillus detection in the CSF at the time of hydrocephalus surgery was associated with a significantly increased rate of the composite of diversion failure or death, death, and diversion failure, and was particularly increased for patients who had an endoscopic diversion.

IntroductionRapid genome sequencing (rGS) provides high diagnostic yield for critically ill infants with suspected genetic disorders, but has high upfront costs and insufficient insurance coverage. Assessing the downstream costs and health outcomes associated with rGS is important for guiding coverage decisions. This study compares 1-year healthcare costs and quality-adjusted life years (QALYs) for: 1) early rGS (within 7 days of admission) for all infants, and 2) early targeted neonatal gene sequencing (NewbornDx) for all infants, followed by later rGS (after 7 days) for undiagnosed infants. Study DesignThe Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a multicenter, prospective study that enrolled 400 hospitalized infants under one year of age with suspected genetic disorders. All participants underwent both rGS and NewbornDx. Using GEMINI data and 2023 Medicare rates, we developed a decision tree to compare total costs and QALYs over a 1-year period for the two testing strategies. ResultsThe diagnostic yield and upfront testing costs were higher for rGS (49%; $12,297) than NewbornDx (27%; $2,449; p<0.05). As neither early testing nor diagnosis significantly affected QALYs, we conducted a cost-minimization analysis, focusing solely on cost differences between strategies. Over one year, early rGS was estimated to save $158,592 per patient (95% CI: $63,701-$253,292) compared to early NewbornDx with later rGS if necessary. ConclusionsEarly rGS results in substantial healthcare cost savings, highlighting the need to expand reimbursement to improve access early in a hospitalization for critically ill infants.

ScreenPlus is a consented pilot program that aims to screen 100,000 babies for a panel of rare disorders. Given its size, ScreenPlus provides a unique opportunity to learn about optimal recruitment practices. ScreenPlus recruitment strategy includes recruiter-initiated Active and Hybrid modes and parent-initiated Independent mode. Active recruitment occurs in-person at the postpartum bedside, whereas Hybrid recruitment includes other attempt types. In Independent recruitment, parents access online educational and e-consent forms. Analysis of 47,642 completed recruitment profiles from May 2021 through April 2025 showed that Active recruitment was used in 72.2% and had the highest percentage of parents consenting (65.5%) in an average of 1.2 days. Hybrid recruitment was used in 27.1% of profiles and resulted in a 44.5% consent rate in an average of 8.6 days, with electronic medical record messaging being the attempt type most likely to lead to a consent. Independent recruitment was used in less than 1% of profiles. In Active and Hybrid Recruitment, non-English speakers were more likely to consent compared with English speakers. Collectively, these findings emphasize that although optimal pilot NBS recruitment is multi-modal, direct communication between parents and study team has the highest consent yield.