OBJECTIVE: Deep medullary vein thrombosis (DMVT) is increasingly recognized on neonatal brain MRI, but its predisposing factors and clinical characteristics remain poorly defined. This study aims to evaluate the clinical...OBJECTIVE: Deep medullary vein thrombosis (DMVT) is increasingly recognized on neonatal brain MRI, but its predisposing factors and clinical characteristics remain poorly defined. This study aims to evaluate the clinical characteristics and associated imaging features of DMVT in neonates. STUDY DESIGN: We performed a retrospective single-center study of infants admitted to the neonatal intensive-care unit who underwent brain MRI between 2015 and 2023. RESULT: Over the study period, 23 infants had medullary vein abnormalities on brain MRI; of them, 10 (five preterm and five term) were identified as DMVT. Among preterm infants, four (80%) had intraventricular hemorrhage (IVH). All term infants demonstrated extensive (bilateral) DMVT. CONCLUSION: Medullary vein abnormalities are not uncommon on neonatal brain MRI. In preterm infants, they are often associated with IVH, whereas term infants typically exhibit bilateral extensive DMVT. Larger studies are needed to further explore the pathogenesis and long-term outcomes.
OBJECTIVE: Evaluate Neonatal Intensive Care Unit (NICU) interpreter access and utilization, unit-based interpreter policies and initiatives, staff awareness and confidence in understanding language-access laws, and perce...OBJECTIVE: Evaluate Neonatal Intensive Care Unit (NICU) interpreter access and utilization, unit-based interpreter policies and initiatives, staff awareness and confidence in understanding language-access laws, and perceptions of language-based inequities. STUDY DESIGN: An exploratory national survey of NICU staff was distributed via the National Association of Neonatal Nurses and the American Academy of Pediatrics (AAP) (10/2024-4/2025). Descriptive statistics and qualitative analysis were used for survey results. RESULT: The 189 respondents represented all ten AAP districts. Most were aware of NICU-based interpreter policies (76%). 81% were not aware of additional state laws/provisions and many lacked confidence understanding federal (43%) or state (63%) language-access laws. Many respondents disagreed that language-discordance resulted in worse quality of care (40%) and outcomes (59%) in their NICU. CONCLUSION: Results highlight the need for additional education on federal and state laws and provisions as well as the broad and systemic nature of language-based healthcare inequities across institutions.
Perinatal opioid exposure is increasingly studied, though our understanding of xylazine, a veterinary sedative-turned-fentanyl adulterant, is less robust. The majority of published xylazine data is animal-derived, despit...Perinatal opioid exposure is increasingly studied, though our understanding of xylazine, a veterinary sedative-turned-fentanyl adulterant, is less robust. The majority of published xylazine data is animal-derived, despite broader drug testing that identifies increased incidental human exposure and prolonged sedation. Xylazine's clinical sequelae are often underrecognized, especially in pregnant populations. We systematically reviewed five databases for literature on xylazine exposure in human pregnancy. We identified eleven discrete reports, where seven described clinical outcomes, and four measured toxicology data indicating xylazine exposure. In both categories, most studies focused on fetal outcomes and umbilical cord tissue testing, which highlighted xylazine transmission to the fetus. Only three studies reported any data on maternal outcomes. Findings suggest that not only is human-derived data on xylazine exposure limited, but maternal outcomes are particularly understudied despite evidence of prevalent exposure.
OBJECTIVE: To compare the effect of skin-to-skin contact (SSC) initiation at three different time points on exclusive breastfeeding (EBF) rates at 6 weeks among healthy term infants delivered via cesarean section. STUDY...OBJECTIVE: To compare the effect of skin-to-skin contact (SSC) initiation at three different time points on exclusive breastfeeding (EBF) rates at 6 weeks among healthy term infants delivered via cesarean section. STUDY DESIGN: In this open-label randomized controlled trial, neonates were assigned to three groups: Group 1 (immediate SSC in the delivery room), Group 2 (SSC after transfer to the recovery room), and Group 3 (breastfeeding initiation followed by SSC in the recovery room). The primary outcome was the percentage of mothers exclusively breastfeeding (EBF) at 6 weeks. Secondary outcomes included duration of SSC, early initiation of breastfeeding (EIBF) rates, exclusive breastfeeding rates at 6 months, and challenges during implementation of SSC. RESULTS: Baseline characteristics were similar across 750 enrolled infants (250 per group). In Group 1, 46 babies (18.4%) faced challenges in SSC initiation and were reallocated. No significant difference in 6-week EBF rates (RR 0.98, 95% CI: 0.77-1.25, p = 0.90). Group 3 was associated with the highest EIBF rates (RR 0.5, 95% CI 0.3-0.8, p = 0.013) and the longest duration of SSC. CONCLUSION: Given the challenges of immediate intraoperative SSC after a C-section, our study found that initiating SSC in the recovery room is a practical and effective alternative, having a similar impact on breastfeeding rates. While the timing of SSC does not significantly impact EBF rates at 6 weeks or 6 months, it remains a critical factor for EIBF. Our findings show that immediate SSC significantly optimizes EIBF. Furthermore, the high EBF rates sustained across all cohorts suggest that robust institutional support is a primary driver of long-term breastfeeding success.
The shortages in pediatric subspecialist workforce are threatening care of children in the US. A prolonged residency plus fellowship of 6 years and relatively low salaries may discourage medical students from choosing pe...The shortages in pediatric subspecialist workforce are threatening care of children in the US. A prolonged residency plus fellowship of 6 years and relatively low salaries may discourage medical students from choosing pediatric fellowship training. To address this "subspecialty shortage," the American Board of Pediatrics (ABP) recently announced a fundamental shift toward competency-based medical education (CBME). This proposal reduces fellowship training duration to a two-year clinical track option. This change is likely to start as early as 2028. We propose an alternate approach that is similar in length (5-years) but with a shorter residency (2-years) and a three-year fellowship for procedural-based subspecialties in pediatrics, cardiology and intensive care fields, such as neonatal-perinatal medicine (NPM), and pediatric critical care medicine (PCCM).
Kumar NK, Phillips A, Gootenberg DB
… +2 more, Vesoulis ZA, Viehl LT
J Perinatol
· 2026 May · PMID 42192159
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INTRODUCTION: NICU sepsis evaluation balances rapid antibiotic administration for mortality reduction against unnecessary treatment. Objective risk stratification optimizes resource allocation. METHODS: We retrospectivel...INTRODUCTION: NICU sepsis evaluation balances rapid antibiotic administration for mortality reduction against unnecessary treatment. Objective risk stratification optimizes resource allocation. METHODS: We retrospectively studied 191 sepsis evaluations from 136 NICU patients. Sepsis was defined as positive blood culture or clinical sepsis with ≥5 days of antibiotics. A machine learning score (POWS) used cardiorespiratory data 1 h prior to evaluation to quantify sepsis risk. We performed ROC analysis, identified optimal thresholds by Youden Index, and assessed postmenstrual age (PMA) and gestational age (GA) as effect modifiers. RESULTS: POWS was higher in sepsis versus no sepsis (4.53 vs. 2.14, p < 0.005; AUC 0.744 [95% CI: 0.608-0.870]). A POWS threshold of 2.9 provided 71% sensitivity and 81% specificity for detection, stratifying into groups with a sepsis incidence of 4.2% vs. 31.9%. PMA, but not GA, modulated POWS (-0.054 points/week, p < 0.0001). CONCLUSION: POWS discriminates sepsis risk at the time of evaluation. IMPACT: A machine learning-developed score (POWS) provides real-time risk stratification during sepsis evaluations, distinguishing a truly low-risk group (4.2% sepsis rate) from a high-risk group (31.9% sepsis rate), among infants with clinical concern for infection. Postmenstrual age at evaluation significantly modulates POWS's performance but birth gestational age does not, suggesting that current developmental maturity is more important than historical prematurity when interpreting and utilizing POWS. Prospective implementation with real-time POWS display may enable risk-based triage thereby prioritizing resources to pursue urgent workup and early antibiotic administration in high-risk infants.
OBJECTIVE: Describe nutrition type/route at the first oral feed (FOF) for infants with critical congenital heart disease (CCHD); identify supportive/limiting factors. STUDY DESIGN: Retrospective cohort; adjusted regressi...OBJECTIVE: Describe nutrition type/route at the first oral feed (FOF) for infants with critical congenital heart disease (CCHD); identify supportive/limiting factors. STUDY DESIGN: Retrospective cohort; adjusted regression estimated associations between parental/clinical factors and human milk or breastfeeding at the FOF. RESULT: For 1355 infants across 15 sites, human milk was used in 78.5% of FOFs, with 34.5% breastfeeding. Human milk was associated with parent presence (OR: 5.32, p < 0.001) and with feeding/lactation consults (2.49, p < 0.001). Private insurance predicted human milk (1.87, p < 0.001) and breastfeeding (1.82, p < 0.001). Younger age (<2 days; 2.23, p < 0.001) and preoperative status (3.66, p < 0.001) were associated with breastfeeding. CONCLUSION: This is the first description of human milk/breastfeeding at the FOF in CCHD. Parent presence and feeding/lactation support were potentially modifiable factors.
OBJECTIVE: Neonatal sepsis remains a leading cause of neonatal mortality, yet comprehensive evaluations of its current and future burden are limited. This study assessed global, regional, and national trends and projecte...OBJECTIVE: Neonatal sepsis remains a leading cause of neonatal mortality, yet comprehensive evaluations of its current and future burden are limited. This study assessed global, regional, and national trends and projected mortality through 2050. STUDY DESIGN: Data from the UN child mortality database (2000-2021) across 194 countries were analyzed. Neonatal sepsis was defined using ICD-10 codes P35-P39, excluding P37.3-P37.4. Trends were assessed using annual percentage change, and mortality was projected under three scenarios: continuation of current trends, convergence to high-income country trends, and attainment of the greatest observed national reduction. RESULTS: In 2021, the global neonatal sepsis mortality rate was 129.34 per 100,000 live births, a 41.6% reduction since 2000. West and Central Africa had the highest mortality and slowest decline. By 2050, mortality is projected to decline to 61.49 per 100,000. CONCLUSIONS: Despite progress, substantial regional disparities persist, highlighting the need for targeted interventions in high-burden regions.
INTRODUCTION: Early-onset neonatal sepsis (EOS) carries significant mortality, prompting the initiation of empiric antibiotics pending blood culture results, which increases neonatal antibiotic exposure. In 2022, our ins...INTRODUCTION: Early-onset neonatal sepsis (EOS) carries significant mortality, prompting the initiation of empiric antibiotics pending blood culture results, which increases neonatal antibiotic exposure. In 2022, our institution shortened antibiotic coverage of EOS rule-outs from 36 to 24 h. We evaluated the safety of this change and its impact on antibiotic use. METHODS: This single hospital retrospective cohort study (2018-2023) compared infants <72 h of life who underwent EOS evaluation under 36- vs. 24-h protocols. Demographics, causative organisms, time to positivity (TTP), and antibiotic utilization for EOS were compared. RESULTS: Among 1491 blood cultures, 17 had positive cultures and all had a TTP < 24 h. Cohorts were clinically similar. Mean antibiotic days initiated in the first 72 h of life decreased from 1.8 to 1.5 following the protocol change (Standard Deviations 0.29 and 0.25). CONCLUSIONS: Reducing antibiotic coverage from 36 to 24 h lowered antibiotic exposure without inappropriate discontinuation of antibiotics.
OBJECTIVE: Reduce the proportion of eligible infants who leave the NICU with a decline in weight-for-age z-score >1.0 SD by 20%. STUDY DESIGN: Designed to engage NICUs with an average daily census ≤10.9, the California P...OBJECTIVE: Reduce the proportion of eligible infants who leave the NICU with a decline in weight-for-age z-score >1.0 SD by 20%. STUDY DESIGN: Designed to engage NICUs with an average daily census ≤10.9, the California Perinatal Quality Care Collaborative conducted a quality improvement collaborative titled Growth Advancement in the NICU (GAIN) Ten Point Nine (10.9) among seven NICUs between 05/2021 and 07/2023. Inborn infants with a birthweight between 1500 and 2500 g and a minimum NICU stay of seven days were included. NICU teams took part in virtual monthly meetings and three half-day Learning Sessions. RESULTS: GAIN 10.9 achieved a 41.6% relative reduction in infants with z-score declines > 1.0 SD. All seven NICUs adopted weight-based feeding guidelines and implemented weekly nutrition rounds. CONCLUSIONS: A quality improvement initiative among low volume NICUs successfully reduced growth restriction in moderate or late preterm infants.
BACKGROUND: Infant mortality disparities, with prematurity among the leading causes of death, make it critical for neonatal intensive care units (NICUs) to assess internal demographic and outcomes data. Assessment of a d...BACKGROUND: Infant mortality disparities, with prematurity among the leading causes of death, make it critical for neonatal intensive care units (NICUs) to assess internal demographic and outcomes data. Assessment of a delivery hospital NICU within a large children's hospital system revealed "Unavailable" infant race among the top demographic categories. OBJECTIVE: To decrease the rate of "Unavailable" infant race in the electronic health record by 10% in a level III NICU by December 2023 and sustain for 1-year. DESIGN/METHODS: We developed a multidisciplinary team, completed Gemba walks, conducted Plan-do-study-act (PDSA) cycles, and analyzed outcomes in process control charts. RESULTS: "Unavailable" infant race decreased from 97% to 49% and was sustained. Modifying hospital registration processes, updating caregiver questionnaires, engaging and educating staff contributed to success and sustainment. CONCLUSIONS: We reduced "Unavailable" data by 48% with 6-months sustainment prior to project expansion. Emulating this process can improve demographic data accuracy nationally.
Maeda T, Tanahashi Y, Asada H
… +15 more, Ueda K, Taniguchi A, Tanaka R, Miura R, Suzuki T, Muramatsu Y, Kato E, Hayashi S, Yamamoto H, Takemoto K, Kato Y, Oshiro M, Kidokoro H, Takahashi Y, Sato Y
OBJECTIVE: To evaluate the relationship between postnatal growth by term and high-performing neurodevelopment in infants born at less than 28 weeks of gestational age. METHODS: This retrospective study examined associati...OBJECTIVE: To evaluate the relationship between postnatal growth by term and high-performing neurodevelopment in infants born at less than 28 weeks of gestational age. METHODS: This retrospective study examined associations between anthropometric Z-scores (length, weight, head circumference) at 32, 36, and 40 weeks postmenstrual age (PMA) and neurodevelopment at age 3 categorized into four groups (delay, subnormal, normal, high-performing). RESULTS: A total of 287 infants were evaluated. Body length at 40 weeks PMA was significantly associated with high-performing neurodevelopment (adjusted OR = 1.86, 95% CI = 1.49-2.32), followed by head circumference (adjusted OR = 1.32, 95% CI = 1.04-67). Changes in body length Z-scores from 36 to 40 weeks PMA were significantly associated with high-performing neurodevelopment, whereas body weight and earlier changes in Z-scores were not. CONCLUSIONS: In extremely preterm infants, body length growth by 40 weeks PMA was an independent predictor for high-performing neurodevelopment at age 3, whereas body weight and earlier growth changes did not.
BACKGROUND/OBJECTIVES: Birth plans include preferences for neonatal care in prenatally diagnosed complex medical conditions. This study aimed to determine how neonatal providers interpret birth plans for those with prena...BACKGROUND/OBJECTIVES: Birth plans include preferences for neonatal care in prenatally diagnosed complex medical conditions. This study aimed to determine how neonatal providers interpret birth plans for those with prenatally diagnosed life-limiting conditions. SUBJECTS/METHODS: This single-site study of neonatal attendings, fellows, advance practice providers, and pediatricians assessed provider actions to prompts associated with potential limitations of care identified in birth plans via three case scenarios developed by palliative care and neonatal providers, with expert review. Data analysis included descriptive statistics and Chi-square or Fisher's exact test, to assess associations between responses and demographics. RESULTS: Seventy-five providers completed the survey (54% response rate). We identified high degree of variability in responses, including high-risk interventions. Previous palliative care training had little impact on interpretation of birth plans. CONCLUSION: High degrees of variability in birth plan interpretation supports their utility to guide discussion with families, rather than a step-by-step guide for care.
OBJECTIVE: To evaluate the ability of a tiered, risk-stratified postnatal management pathway to safely provide monitoring and postnatal care recommendations based on the prenatal Coarctation of Aorta (CoA) risk category....OBJECTIVE: To evaluate the ability of a tiered, risk-stratified postnatal management pathway to safely provide monitoring and postnatal care recommendations based on the prenatal Coarctation of Aorta (CoA) risk category. METHODS: Retrospective cohort study of fetuses with CoA concern on fetal echocardiogram. Postnatal recommendations were based on prenatal risk categories as follows: mild-concern (nursery, echo before discharge); moderate-concern (NICU, echo before 24 h); high-concern (PGE infusion, CICU, admission echo). RESULTS: For mild (40/87), moderate (13/87), and high (34/87) concern categories, 3%, 38%, and 82% had CoA repair before initial discharge. Eighty percent of mild-concern initially remained with parents. For moderate-concern, 6/13 transferred to CICU and 5 required surgery pre-discharge. Umbilical catheters placed if CICU transfer. CONCLUSIONS: A standardized risk-stratified postnatal CoA pathway can be effectively implemented in a delivery hospital and minimize medicalization of low-to-moderate-concern newborns. With appropriate safety nets, select patients can concurrently receive CoA evaluation and newborn care.
OBJECTIVE: To characterize dynamic changes in the weight-adjusted rapid shallow breathing index (RSBI) during a 60-min spontaneous breathing trial (SBT) in mechanically ventilated preterm infants and evaluate its predict...OBJECTIVE: To characterize dynamic changes in the weight-adjusted rapid shallow breathing index (RSBI) during a 60-min spontaneous breathing trial (SBT) in mechanically ventilated preterm infants and evaluate its predictive value for weaning outcomes. STUDY DESIGN: This retrospective study included preterm infants undergoing SBT in a neonatal intensive care unit. Patients were classified as successful or failed weaning based on reintubation or escalation of respiratory support within 48 h. Weight-adjusted RSBI [f/(Vt/kg)] was calculated, and parameters at multiple SBT time points were compared. Receiver operating characteristic analysis assessed predictive performance. RESULT: Eighty-six infants were enrolled (58 successful, 28 failed). Baseline characteristics were comparable. RSBI increased significantly after 30 min in the failed group. At 60 min, RSBI was higher in failed infants (16.31 ± 3.82 vs. 9.79 ± 2.15; P < 0.001). Predictive ability was high (AUC 0.892; sensitivity 85.7%; specificity 82.8%). CONCLUSION: Rising weight-adjusted RSBI during late SBT predicts weaning failure reliably.
OBJECTIVE: Examine neonatologists' perspectives on disclosing rapid genomic sequencing (rGS) results, including the barriers and facilitators they perceive. STUDY DESIGN: Neonatologists from 10 NICUs participating in the...OBJECTIVE: Examine neonatologists' perspectives on disclosing rapid genomic sequencing (rGS) results, including the barriers and facilitators they perceive. STUDY DESIGN: Neonatologists from 10 NICUs participating in the Virtual Genome Center (VIGOR) study were surveyed after each rGS disclosure and interviewed regarding their experience after 2 or more disclosures. Quantitative results were compared by result type, and qualitative results were iteratively coded for themes. RESULTS: 93% of neonatologists felt comfortable disclosing rGS results regardless of result type. Neonatologists utilized multiple resources to prepare for disclosures, including the VIGOR Clinical Interpretive Report, medical literature, and local genetics experts. They preferred to have a geneticist present during disclosure when possible. Neonatologists were motivated to participate in disclosures to help families and leverage existing trust. CONCLUSION: Neonatologists are important to the rGS disclosure experience, but a joint effort with genetics experts may be the ideal model to successfully expand access. TRIAL REGISTRATION NUMBER: NCT05205356/clinicaltrials.gov .
Resch-Poteralski E, Maurer-Fellbaum U, Eichberger J
… +6 more, Strenger V, Krause R, Pichler-Stachl E, Avian A, Resch B, Urlesberger B
J Perinatol
· 2026 May · PMID 42086726
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OBJECTIVE: This study aimed to determine the influence of nosocomial bacterial and viral infections of preterm very low birth weight (VLBW) infants on neurodevelopmental outcome and on rehospitalization rates during the...OBJECTIVE: This study aimed to determine the influence of nosocomial bacterial and viral infections of preterm very low birth weight (VLBW) infants on neurodevelopmental outcome and on rehospitalization rates during the first two years of life. STUDY DESIGN: Retrospective single-center cohort study including preterm infant born between 2010 and 2018 and followed until two years of age corrected for prematurity (Bayley scales). RESULTS: Of 620 study infants 418 without neurodevelopmental impairment (NDI). were compared to 202 infants with NDI. Single or multiple nosocomial infections were not risk factors for NDI in a multivariate logistic regression model checked for multicollinearity. Infants with NDI were of younger gestational age, had lower birth weights and higher rates of neonatal complications (ileus, periventricular leukomalacia, and bronchopulmonary dysplasia). Nosocomial infection were also not risk factors for rehospitalizations by infectious diseases. CONCLUSIONS: Nosocomial infections did not significantly influence NDI and rehospitalization rates in preterm VLBW infants. TRIAL REGISTRATION NUMBER: The study was registered at "Deutsches Register Klinischer Studien" DRKS00019000.
Valles-Murcia N, Aguar M, Pinilla-González A
… +9 more, Torrejón-Rodriguez L, Cayuela-Hernández A, Sáenz-González P, Escrig-Fernández R, González-Timoneda A, Collados-Gómez L, Cernada M, Vento M, Solaz-García Á
BACKGROUND: Immediate Kangaroo Mother Care (iKMC) after delivery and delayed cord clamping (DCC), both improve cardiorespiratory stability in newborns. METHODS: This prospective observational study included 96 moderate t...BACKGROUND: Immediate Kangaroo Mother Care (iKMC) after delivery and delayed cord clamping (DCC), both improve cardiorespiratory stability in newborns. METHODS: This prospective observational study included 96 moderate to late preterm (MLPT) neonates. Preductal pulse oximetry (SpO₂) and heart rate (HR) were recorded during the first 10 min after birth. Neonates who received iKMC and DCC were compared to those who did not receive iKMC. RESULTS: iKMC was performed in 64.6% of the infants. The iKMC group showed a non-significant trend toward higher SpO₂ levels. Mean SpO₂ was 76.06% in the iKMC group versus 70.98% in the non-iKMC group; at 420 s, it was 95.13% versus 93.77%. HR was significantly higher in the iKMC group at all time points, averaging 102.2 bpm at 120 s compared to 87.1 bpm in the non-iKMC group. CONCLUSIONS: Combining iKMC with DCC improves hemodynamic stability and oxygenation in MLPT infants, with higher HR and earlier stabilization of SpO₂ levels.
OBJECTIVE: To Improve timely administration of the first antibiotic dose in the neonatal intensive care unit (NICU) through a quality improvement (QI) initiative. STUDY DESIGN: Conducted in a 53- bed NICU over 3 years in...OBJECTIVE: To Improve timely administration of the first antibiotic dose in the neonatal intensive care unit (NICU) through a quality improvement (QI) initiative. STUDY DESIGN: Conducted in a 53- bed NICU over 3 years involving 1094 neonates who received antibiotics for suspected sepsis. Using the Institute for Healthcare Improvement (IHI) methods, three interventions were made: NICU staff education; developed order sets for stat antibiotic doses and implementation of a secure code medication delivery system. Outcomes included the infants receiving their first antibiotic dose within 60 min of ordering and average time from order to administration. RESULTS: Infants receiving antibiotics within 60 min improved from baseline 32.7% to 84.4% over a 3 year period and has been sustained over 2 years. The average time to administration decreased from 93.3 min to 44.7 min. CONCLUSION: A systematic multidisciplinary approach decreased the time from antibiotic order to administration time in the NICU.
The earliest clinical sign of pulmonary vascular disease in neonates is persistent pulmonary hypertension of the newborn (PPHN), traditionally classified as World Symposium on Pulmonary Hypertension (WSPH) Group 1. Typic...The earliest clinical sign of pulmonary vascular disease in neonates is persistent pulmonary hypertension of the newborn (PPHN), traditionally classified as World Symposium on Pulmonary Hypertension (WSPH) Group 1. Typical PPHN is defined by the delayed transition from intra- to extra- uterine life with failure of pulmonary artery pressures to fall after delivery. This results in sustained elevation of pulmonary vascular resistance and contributes to hypoxemic respiratory failure (HRF). However, early HRF can also arise from atypical PPHN phenotypes that may persist beyond the expected resolution of typical PPHN and are often classified within WSPH Groups 2, 3 and 5. In addition, a history of PPHN can be associated with the childhood and adulthood PH. In this perspective, we highlight the diverse etiologies contributing to the PPHN phenotype, with a focus on Group 3 disease, and propose a physiology-based framework to classify PPHN and delineate disease trajectories.