Long-term clinical and economic outcomes post birth hospitalization in preterm infants with neonatal respiratory distress syndrome: A real-world retrospective cohort study

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Abman, Alessia Colucciello, Natalia Meshchenkova, Laura Fabbri, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9141627/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Neonatal respiratory distress syndrome (nRDS) is a leading cause of morbidity among preterm infants. While short-term outcomes during birth hospitalization are well described, real-world evidence on long-term respiratory outcomes, healthcare resource utilization (HCRU), and economic burden following discharge remains limited. Methods This retrospective observational cohort study used linked IQVIA US Hospital Charge Data Master, Professional Fee Claims, and Longitudinal Prescription Claims databases from October 2015 to March 2024. Preterm infants (< 37 weeks’ gestation) diagnosed with nRDS between October 1, 2015, and March 31, 2022, and treated with surfactant or continuous positive airway pressure during birth hospitalization were included. Follow-up began at discharge and continued for ≥ 3 months. The outcomes included respiratory diseases during follow-up, respiratory-related HCRU, and costs standardized to 2023 USD per patient per month (PPPM). The results were reported overall and by gestational age (GA): very/extreme (< 32 weeks), moderate (32 to < 34 weeks), and late preterm (34 to < 37 weeks). Results The cohort comprised 7,532 preterm infants with nRDS; 43.6% were late preterm, 23.7% moderate preterm, and 32.3% very/extreme preterm (median follow-up: 1 year). Respiratory morbidity persisted across all GA categories: upper respiratory tract infection (URTI; 49.6%), cough (32.4%), lower respiratory tract infection (LRTI; 31.5%), and bronchiolitis (28.6%). Acute respiratory conditions, including URTI, LRTI, bronchiolitis, and cough, were more frequent among moderate and late preterm infants, whereas asthma, pulmonary hypertension, obstructive sleep apnea, pneumonia, and wheeze occurred most often in very/extreme preterm infants. Respiratory-related HCRU was common, including outpatient pharmacy use (62.2%), physician office visits (40.3%), and emergency room visits (30.8%), with similar patterns across GA subgroups. Mean respiratory-related costs were $ 347 PPPM overall, driven primarily by inpatient care (77.5%). Costs increased markedly with lower GA, averaging $ 684 PPPM in very/extreme preterm infants versus $ 164 PPPM in late preterm infants. Conclusions Preterm infants with nRDS experience substantial long-term respiratory morbidity and healthcare costs following discharge, even in the absence of BPD. Persistent burden across all GAs highlights the need for structured long-term respiratory follow-up and preventive strategies that extend beyond the neonatal period. Neonatal respiratory distress syndrome (nRDS) preterm infants respiratory morbidity healthcare resource utilization (HCRU) Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Respiratory disease remains a major contributor to short and long-term morbidity and mortality in preterm infants [ 1 ]. Neonatal respiratory distress syndrome (nRDS), driven by surfactant deficiency and pulmonary immaturity, is one of the most frequent and severe causes of respiratory failure in this vulnerable population. Globally, nRDS affects about 1% of all newborns, accounting for nearly 20,000 − 30,000 cases annually and approximately 860 infant deaths each year in the United States (US) [ 2 ]. The incidence of nRDS is inversely correlated with gestational age (GA) and birth weight, affecting up to 60%–80% of infants born before 28 weeks, 30% of those born between 28–34 weeks, and approximately 5% of late preterm neonates [ 1 , 3 ]. Importantly, all preterm infants, including moderate and late preterm, remain at significant risk of developing nRDS. Prior studies have predominantly emphasized post-discharge outcomes of infants with bronchopulmonary dysplasia (BPD); however, many preterm infants without the added diagnosis of BPD remain at high risk for late respiratory and non-respiratory sequelae [ 1 , 4 ]. Current literature indicates that infants with chronic lung disease resulting from nRDS are at heightened risk of rehospitalization due to respiratory illness compared to GA-matched controls. Furthermore, evidence also suggests that respiratory morbidity may persist throughout childhood and into adulthood, with abnormal respiratory function recorded years after the initial neonatal phase [ 1 , 5 ]. Recent randomized controlled trials with long-term follow-up have further highlighted the burden of respiratory sequelae in infants with BPD, demonstrating meaningful differences in outcomes such as asthma and respiratory hospitalizations that persist well beyond infancy [ 6 , 7 ]. However, real-world data are limited on clinical outcomes and related healthcare utilization and cost impacts in preterm infants with nRDS following discharge from neonatal intensive care unit (NICU) discharge. Despite significant therapeutic advances, the economic burden of nRDS remains substantial [ 8 ]. The primary cost drivers during initial hospitalization include invasive ventilation, longer hospitalization duration, and nRDS-associated complications such as BPD, with mean initial hospitalization costs ranging from $ 27,000 for 1,500–2,000g infants to over $ 100,000 for those < 1,000g [ 9 ]. More recent analyses further highlight this impact: preterm infants experience significantly longer inpatient stays (54.1 vs 29.0 days), extended neonatal intensive care unit stays (34.1 vs 17.5 days), increased time on ventilation (4.7 vs 2.2 days), and higher total hospitalization charges ( $ 613,350 vs $ 422,558) compared with term or near-term infants (all P < 0.001) [ 10 ]. Early surfactant administration is more effective and less expensive than delayed intervention, leading to shorter hospital stays, fewer complications and reduced overall downstream treatment costs. While many studies have examined short-term outcomes during the initial hospital stay [ 11 ], there exists a paucity of research investigating long-term clinical and economic consequences following hospital discharge [ 3 , 12 ]. Overall, a major gap exists in understanding the comprehensive real-world burden associated with nRDS, which is critical to guide evidence-based clinical decision making, health care resource allocation and economic planning. The objective of this real-world study was to describe long-term clinical respiratory outcomes and economic burden in a large US-based cohort of preterm infants by various GA categories. By examining hospitalizations, medication utilization, diagnosis of subsequent respiratory diseases, and related healthcare costs, this research aims to generate crucial insights into the progression of respiratory health outcomes, patterns of healthcare utilization, and the overall societal burden of this critical condition across all preterm categories. Methods Study design and data sources The study was a retrospective observational cohort analysis utilizing three linked IQVIA US databases: Hospital Charge Data Master (CDM), Professional Fee Claims (Dx), and Longitudinal Prescription Claims (LRx), covering the period October 1, 2015, to March 31, 2024 ( Figure 1 ). The CDM database provides patient-level service order records from over 500 hospitals, encompassing 7 million annual inpatient stays and 60 million annual outpatient visits. Key data elements include patient demographics, diagnoses, procedures, medications, devices, and both inpatient and outpatient encounters. The Dx database contributes approximately 1 billion professional fee claims annually from over 800,000 office-based physicians and specialists, representing 60–70% of physician activity in the United States. The Dx database captures detailed diagnostic, procedural, and service-level information, enabling the identification of respiratory events and healthcare utilization through linked diagnosis, procedure, and billing data. The LRx database includes over 1.6 billion retail or mail-order prescription claims, representing approximately 85% of all pharmacies nationwide, including, but not limited to retail, mail, and specialty pharmacies. The LRx database captures comprehensive dispensing-level information, including National Drug Codes (NDCs), fill dates, days’ supply, quantities, payer types, and paid or allowed amounts, which were used to quantify outpatient medication utilization and respiratory-related pharmacy costs during follow-up. Patient-level linkage across databases was accomplished through IQVIA's proprietary deterministic encryption algorithm, which utilized actual patient-level information (first name, last name, date of birth, gender, and five-digit ZIP code) to create unique patient identifiers [13]. This approach ensured the continuity of patient records while maintaining compliance with the Health Insurance Portability and Accountability Act (HIPAA) through source-level de-identification. Figure 1. Study design a Linkage to LRx and Dx was assessed during the study period. b Infants with age >0 at index (CDM/Dx/LRx) or those with records before index date or evidence of data quality issues or evidence or nRDS treatment or death during birth hospitalization were also excluded. c Censoring events: death, loss of follow-up, end of study period. Abbreviations: CDM, hospital charge data master; Dx, professional fee claims; HCRU, healthcare resource utilization; LRx, longitudinal prescription claims; nRDS, neonatal respiratory distress syndrome. Study population and patient selection The cohort included preterm infants diagnosed with nRDS during their birth hospitalization, recorded in CDM between October 1, 2015, and March 31, 2022. The index date was defined as the day after discharge from the birth hospitalization. This analysis used existing HIPAA-compliant de-identified data and was therefore exempt from human subjects' protection requirements under 45 Code of Federal Regulations (CFR) 46.101(b). Inclusion criteria Infants were included if they met the following criteria: inpatient admission for preterm birth (GA <37 weeks) based on diagnosis codes in CDM during the selection window (between October 1, 2015, and March 31, 2022; Figure 1 ); nRDS diagnosis (International Classification of Diseases, tenth revision, Clinical Modification (ICD-10-CM available in Supplementary Table 1 ) during the birth hospitalization; linkage to both Dx and LRx databases with at least one record during the study period; evidence of nRDS treatment (surfactant or continuous positive airway pressure [CPAP] only) during birth hospitalization; at least one Dx record and one LRx record after birth hospitalization discharge; at least one month of pharmacy stability after discharge; and at least three months of follow-up post-birth hospitalization discharge in both Dx and LRx databases. Exclusion criteria Infants with any records in Dx, LRx, or CDM database before the birth hospitalization admission date and age >0 years in the year of birth hospitalization admission were excluded to ensure a valid neonatal cohort where the birth hospitalization was the first documented encounter to capture incident cases. To ensure data integrity and validity, those with missing critical demographics (e.g., sex) were excluded. Given this study focused on outcomes specific to nRDS after birth hospitalization, infants with evidence of death during the birth hospitalization and those with evidence of severe congenital malformations (e.g., diaphragmatic hernia, major congenital heart disease [ICD-10-CM available in Supplementary Table 1 ]) during the first year of life were excluded. Finally, infants with records of surfactant treatment after hospital discharge (and treated with CPAP and no surfactant during birth hospitalization) were excluded to maintain the integrity of the neonatal cohort since surfactant is typically administered within first hours of life during the birth hospitalization. Study periods and follow-up The study period was October 1, 2015, to March 31, 2024; the selection window was October 1, 2015, to March 31, 2022. The baseline period extended from the admission date of birth hospitalization to the discharge date. The follow-up period began on the index date (birth hospitalization discharge date) and continued for a minimum of three months, censored at the earliest of: evidence of death, loss of activity in Dx/LRx, loss of pharmacy stability or end of the study period (March 31, 2024). Death was identified based on a discharge status of "expired" in CDM or through application of a claims-based death proxy algorithm [14]. Infants were assumed to have died if they had evidence during the month preceding the latest observed Dx claim date of: critical care transport current procedural terminology (CPT) procedure; an inpatient, emergency room, or hospice claim with acute myocardial infarction diagnosis, major thoracostomy with cardiac massage, direct repair of aneurysm or excision, cardiac event including resuscitation, defibrillation, cerebral death, cardiac arrest or failure diagnosis, sudden death diagnosis, injection given to stimulate the heart, emergency room visit with high-urgent severity, emergency transport, or critical care. Outcome measures Clinical outcomes The primary clinical outcomes included the frequency, number of events, and incidence rate of respiratory diseases. Chronic respiratory conditions (asthma, chronic bronchitis, pulmonary hypertension, obstructive sleep apnea) were limited to one event per patient during the follow-up period, while acute respiratory conditions (upper respiratory tract infection [URTI], lower respiratory tract infection [LRTI], bronchiolitis, pneumonia, cough, wheeze) included multiple events per patient. Each patient contributed at most one event for a chronic respiratory condition. For acute respiratory conditions, patients can contribute multiple events and are at risk for the event again after a 14-day washout period. Healthcare resource utilization and cost outcomes Medical healthcare resource utilization (HCRU) and costs were considered respiratory disease-related if they had an ICD-10-CM diagnosis code for the respiratory disease of interest in CDM or Dx in any position, or respiratory disease-related drugs (oxygen therapy, long-acting beta-agonists, long-acting muscarinic antagonists, short-acting beta-agonists, inhaled corticosteroids, antibiotics, diuretics, anticoagulants) based on Healthcare Common Procedure Coding System (HCPCS) codes or billing descriptions. The respiratory diseases of interest included nRDS, bronchopulmonary dysplasia, chronic lung disease, asthma, chronic bronchitis, URTI, LRTI, bronchiolitis, pneumonia, cough, wheeze, pulmonary hypertension, and obstructive sleep apnea. Pharmacy HCRU and costs were considered respiratory disease-related if the NDC on the claim corresponded to a respiratory disease-related drug. Outpatient medical HCRU measures included physician office visits, emergency room visits, laboratory and pathology visits, radiology visits, HCPCS codes administrations, and other outpatient visits. Inpatient hospitalization measures included the number of inpatient visits, average length of stay, total inpatient days, NICU/pediatric intensive care unit (PICU) admissions and length of stay, and discharge disposition. Both Dx and CDM reported charges, while LRx reported allowed or paid amounts. A cost-to-charge ratio was applied for charges in Dx and CDM. All costs were converted to 2023 United States dollars using the medical component of the Consumer Price Index and standardized as per patient per month (PPPM). All-cause and respiratory disease-related inpatient admissions were assessed during specific time periods: 30 days, 90 days, and 180 days following birth hospitalization discharge. Covariates Patient characteristics assessed during the birth hospitalization included demographic variables (sex, birth year, geographic region, payer type) and clinical characteristics (GA, birth weight, intrauterine growth restriction or small for GA). Birth hospitalization characteristics included: hospital length of stay, ICU visits and length of stay, NICU/PICU length of stay, premature birth complications identified based on ICD-10-CM diagnosis codes ( Supplementary Table 1 ) from the CDM database (bronchopulmonary dysplasia, intraventricular hemorrhage, retinopathy of prematurity, air leak syndrome, pulmonary hemorrhage, sepsis, necrotizing enterocolitis), electrocardiogram use identified based on procedure codes and billing descriptions from the CDM database, and treatments observed for nRDS identified based on NDC codes, procedure codes and billing descriptions from the CDM database (CPAP, surfactant therapy, mechanical ventilation [MV]). Data analysis All study measures were summarized descriptively. Continuous variables were summarized by mean, standard deviation (SD), minimum, median, first quartile, third quartile, and maximum. Categorical variables were summarized by frequency and percentage. For chronic respiratory conditions, the incidence rate was calculated by dividing the total events with a respiratory diagnosis of interest by the total person-years at risk for such events. For acute respiratory conditions, patients could contribute multiple events with a 14-day washout period between events. All study measures were reported for the overall nRDS cohort and GA categories (extremely [<28 weeks] and very preterm [28 to <32 weeks], moderate preterm [32 to <34 weeks], late preterm [34 to <37 weeks]). Results Study cohort identification and patient selection A total of 200,533 infants with an inpatient admission containing at least one diagnosis code for preterm birth were identified between October 1, 2015, and March 31, 2022. Of these, 86,695 infants (43.2%) had a diagnosis code for nRDS during the birth hospitalization, and 17,229 had evidence of treatment for nRDS (surfactant or CPAP) during the birth hospitalization. After applying all study selection criteria, including follow-up activity requirements, the overall nRDS cohort comprised of 7,532 preterm infants. A schematic of the patient identification process is presented in Figure 2 . Additionally, by GA distribution, the nRDS cohort included 43.6% late preterm infants (34 to <37 weeks), 23.7% moderately preterm infants (32 to <34 weeks), and 32.3% were very or extremely preterm (<32 weeks); 0.4% infants had an unspecified GA. Figure 2. Patient identification and flow diagram showing stepwise selection of preterm infants with nRDS Abbreviations: CMD, hospital charge data master; CPAP, continuous positive airway pressure; Dx, professional fee claims; ICD-10-CM, International Classification of Diseases, tenth revision, Clinical Modification; LRx, longitudinal prescription claims; nRDS, neonatal respiratory distress syndrome. Demographic and clinical characteristics The nRDS cohort was 54.0% males and 46.0% females, with the majority of infants located in the South (64.6%) followed by West (15.5%), Northeast (12.6%) and the Midwest (7.2%). Commercial insurance was the most common primary payer (41.3%), followed by Medicaid (15.6%). Sex distribution varied slightly across GA subgroups with very/extreme preterm subgroup comprised 52.1% female, 47.9% male; moderate preterm subgroup comprised 44.8% female, 55.2% male; late preterm subgroup comprised 42.1% female, 57.9% male ( Table 1 ). Geographical and payer distribution remained consistent across GA subgroups. Additionally, among infants with documented birth weight (68.8% of the overall nRDS cohort), 33.9% weighed 2,000g – 2,499g, 17.1% weighed 1,750g – 1,999g, 15.6% weighed 1,500g – 1,749g, 13.9% weighed 1,250g – 1,499g, 10.4% weighed 1,000g – 1,249g, and 9.0% weighed <1,000g. Intrauterine growth restriction or small for GA status was documented in 5.1% infants. The mean inpatient length of stay during the birth hospitalization was 26.7 days (SD 22.8), which decreased progressively as GA increased, ranging from 49.0 days in very/extreme preterm infants to 11.9 days in late preterm infants. Overall, birth complications occurred in 24.5% of the cohort, with retinopathy of prematurity (11.3%) and sepsis (9.4%) being the most prevalent. Complication rates were substantially higher in infants with lower GA. Among very/extreme preterm, moderate preterm, and late preterm infants, the observed rates were as follows: retinopathy of prematurity - 33.1%, 2.1%, and 0.6%; sepsis - 13.7%, 8.0%, and 7.0%; intraventricular hemorrhage - 13.3%, 2.5%, and 0.6%; air leak syndrome - 2.3%, 1.6%, and 3.5%; necrotizing enterocolitis - 2.7%, 0.6%, and 0.1%, respectively. BPD was documented in 5.1% of very/extreme preterm infants and 0.1% of the moderate and late preterm infants. Respiratory support modalities during birth hospitalization in the overall cohort included CPAP (91.5%), MV (34.2%), and surfactant therapy (29.5%). The use of CPAP remained consistently high (>89%) across all GA subgroups. MV and surfactant use was more frequent in lower GA subgroups and less frequent in higher GA subgroups. Electrocardiogram use was documented in 2.5% of infants. Table 1. Baseline demographic, gestational, and birth hospitalization characteristics of preterm infants with nRDS Demographics Overall nRDS cohort N=7532 Subgroups by GA Very or extreme preterm (N=2435) Moderate preterm (N=1784) Late preterm (N=3285) Sex, female, n (%) 3466 (46.0) 1269 (52.1) 799 (44.8) 1383 (42.1) US region a , n (%) Northeast 950 (12.6) 276 (11.3) 224 (12.6) 449 (13.7) Midwest 544 (7.2) 187 (7.7) 109 (6.1) 247 (7.5) South 4862 (64.6) 1623 (66.7) 1153 (64.6) 2068 (63.0) West 1171 (15.5) 345 (14.2) 297 (16.6) 521 (15.9) Payer type, n (%) Commercial 3107 (41.3) 975 (40.0) 737 (41.3) 1385 (42.2) Medicare (including Part D coverage) 72 (1.0) 20 (0.8) 16 (0.9) 36 (1.1) Medicaid (including managed Medicaid) 1176 (15.6) 445 (18.3) 263 (14.7) 465 (14.2) Other Medicaid/Medicare/state assistance b 1146 (15.2) 358 (14.7) 260 (14.6) 523 (15.9) Cash payments 7 (0.1) 1 (0.0) 6 (0.3) 0 (0.0) Unknown 2024 (26.9) 636 (26.1) 502 (28.1) 876 (26.7) Birth weight, n (%) c <1000g 466 (9.0) 457 (20.4) 6 (0.4) 2 (0.1) 1000-1249g 541 (10.4) 508 (22.7) 26 (1.7) 7 (0.5) 1250-1499g 720 (13.9) 593 (26.5) 109 (7.3) 16 (1.1) 1500-1749g 810 (15.6) 427 (19.1) 314 (21.0) 69 (4.8) 1750-1999g 888 (17.1) 188 (8.4) 460 (30.8) 235 (16.4) 2000-2499g 1757 (33.9) 68 (3.0) 580 (38.8) 1101 (77.0) With IUGR/SGA diagnosis code, n (%) 385 (5.1) 115 (4.7) 107 (6.0) 163 (5.0) Inpatient LOS, mean days (SD) 26.7 (22.8) 49.0 (24.8) 23.5 (11.4) 11.9 (7.9) Birth complications, n (%) Any of the below 1849 (24.5) 1233 (50.6) 244 (13.7) 366 (11.1) Retinopathy of prematurity 851 (11.3) 805 (33.1) 38 (2.1) 6 (0.2) Sepsis 709 (9.4) 334 (13.7) 142 (8.0) 229 (7.0) Intraventricular hemorrhage 390 (5.2) 324 (13.3) 45 (2.5) 20 (0.6) Air leak syndrome 200 (2.7) 57 (2.3) 28 (1.6) 115 (3.5) Bronchopulmonary dysplasia 129 (1.7) 124 (5.1) 4 (0.2) 1 (0.0) Necrotizing enterocolitis 78 (1.0) 65 (2.7) 11 (0.6) 2 (0.1) Pulmonary hemorrhage 22 (0.3) 17 (0.7) 2 (0.1) 3 (0.1) Treatments, n (%) CPAP 6895 (91.5) 2181 (89.6) 1639 (91.9) 3051 (92.9) Surfactant therapy 2219 (29.5) 1066 (43.8) 475 (26.6) 668 (20.3) MV 2574 (34.2) 1274 (52.3) 523 (29.3) 769 (23.4) With ECG use, n (%) 189 (2.5) 100 (4.1) 30 (1.7) 59 (1.8) a There were five infants in the overall nRDS cohort with an unknown US region. b Includes other managed Medicaid, Medicare supplement, Medigap, and state assistance. c The denominator is the number of infants with diagnosis codes indicating birth weight. There were 2,350 infants (31.2%) in the overall nRDS cohort with no diagnosis codes specifying the birth weight range. Abbreviations: BPD, bronchopulmonary dysplasia; CPAP, continuous positive airway pressure; ECG, electrocardiogram; GA, gestational age; IUGR, intrauterine growth restriction; LOS, length of stay; MV, mechanical ventilation; nRDS, neonatal respiratory distress syndrome; SD, standard deviation; SGA, small for gestational age. Long-term respiratory outcomes in the overall cohort and by gestational age During follow-up (median duration of 1 year, range up to 9 years), nearly half of infants in the overall cohort experienced URTI (49.6%), while more than one-fourth had cough (32.4%), LRTI (31.5%) or bronchiolitis (28.6%) [ Figure 3 ]. Among chronic respiratory outcomes, asthma occurred in 11.3% of infants, whereas chronic bronchitis (0.4%), obstructive sleep apnea (OSA; 1.0%), and pulmonary hypertension (0.1%) were infrequent. When stratified by GA, respiratory morbidity persisted across all subgroups. URTI was reported in 45.8% of very/extreme preterm, 50.4% of moderate preterm and 52.0% of late preterm infants. Patterns were similar for cough (30.8–33.5%), LRTI (30.3–32.3%) and bronchiolitis (27.1–29.4%). There was no consistent trend in disease incidence rates by GA; although chronic bronchitis, URTI, LRTI, bronchiolitis, and cough were more frequent in moderate or late preterm infants, whereas asthma, pulmonary hypertension, obstructive sleep apnea, pneumonia, and wheeze had the highest incidence in very/extreme preterm infants. Notably, zero infants in the late preterm subgroup developed pulmonary hypertension during follow-up. Rates of URTI (45.8%–52.0%), LRTI (30.3%–32.3%), and cough (30.8%–33.5%) were consistently high across all GA subgroups, exceeding 500 events per 1,000 person-years ( Table 2 ). In contrast, chronic conditions such as asthma (9.8%–13.5%), obstructive sleep apnea (0.5%–1.6%), and chronic bronchitis (0.2%–0.6%) occurred infrequently (<15 events per 1,000 person-years). Figure 3. Proportion of patients with acute and chronic respiratory events during follow-up (≥3-months), by GA Abbreviations: GA, gestational age; LRTI, lower respiratory tract infection; nRDS, neonatal respiratory distress syndrome; OSA, obstructive sleep apnea; URTI, upper respiratory tract infection. Table 2. Incidence rates of respiratory events anytime during the follow-up (≥3-months) Measures Overall nRDS cohort N=7532 Subgroups by GA Very or extreme preterm (N=2435) Moderate preterm (N=1784) Late preterm (N=3285) Asthma, n (%) 851 (11.3) 328 (13.5) 199 (11.2) 323 (9.8) Incidence rate per 1000 person-years, (95% CI) 97.3 (91.9–103.0) 114.9 (104.7–125.9) 100.6 (89.1–113.1) 83.1 (75.7–91.2) Chronic bronchitis, n (%) 31 (0.4) 5 (0.2) 11 (0.6) 15 (0.5) Incidence rate per 1000 person-years, (95% CI) 3.1 (2.3–4.2) 1.5 (0.6–3.2) 4.9 (2.7–8.1) 3.5 (2.1–5.4) Pulmonary hypertension, n (%) 6 (0.1) 4 (0.2) 2 (0.1) 0 (0.0) Incidence rate per 1000 person-years, (95% CI) 0.6 (0.3–1.2) 1.2 (0.4–2.8) 0.9 (0.2–2.8) 0.0 (NA–NA) Obstructive sleep apnea, n (%) 73 (1.0) 38 (1.6) 18 (1.0) 17 (0.5) Incidence rate per 1000 person-years, (95% CI) 7.4 (6.0–9.0) 11.6 (8.7–15.2) 8.0 (5.2–11.9) 3.9 (2.5–5.9) Upper respiratory tract infection, n (%) 3736 (49.6) 1116 (45.8) 900 (50.4) 1707 (52.0) Incidence rate per 1000 person-years, (95% CI) 1581.2 (1557.8–1605.0) 1369.0 (1331.6–1407.2) 1651.2 (1600.8–1702.9) 1711.8 (1674.7–1749.6) Lower respiratory tract infection, n (%) 2373 (31.5) 738 (30.3) 569 (31.9) 1060 (32.3) Incidence rate per 1000 person-years, (95% CI) 557.4 (543.5–571.6) 522.7 (499.6–546.7) 600.4 (570.2–631.9) 563.2 (542.0–585.1) Bronchiolitis, n (%) 2152 (28.6) 661 (27.1) 519 (29.1) 967 (29.4) Incidence rate per 1000 person-years, (95% CI) 462.9 (450.3–475.8) 431.1 (410.3–452.8) 505.1 (477.5–533.9) 467.3 (448.0–487.3) Pneumonia, n (%) 597 (7.9) 233 (9.6) 115 (6.4) 246 (7.5) Incidence rate per 1000 person-years, (95% CI) 89.7 (84.7–95.0) 107.5 (98.0–117.8) 96.1 (85.3–108.0) 72.8 (66.0–80.2) Cough, n (%) 2443 (32.4) 750 (30.8) 582 (32.6) 1102 (33.5) Incidence rate per 1000 person-years, (95% CI) 680.3 (665.2–695.7) 625.2 (600.4–650.8) 726.5 (693.8–760.4) 696.7 (673.6–720.4) Wheeze, n (%) 1043 (13.8) 390 (16.0) 241 (13.5) 409 (12.5) Incidence rate per 1000 person-years, (95% CI) 199.2 (191.5–207.2) 240.4 (225.6–255.9) 198.6 (182.5–215.6) 169.2 (158.5–180.4) Abbreviations: CI, confidence interval; GA, gestational age; nRDS, neonatal respiratory distress syndrome. Healthcare resource utilization and costs in the overall cohort and by gestational age Resource utilization During the follow-up period, the most common categories of respiratory-related healthcare utilization in the overall nRDS cohort were outpatient pharmacy use (62.2%), physician office visits (40.3%), and emergency room (ER) visits (30.8%). Other categories included HCPCS drug administration (25.4%), other outpatient medical services (22.3%), and laboratory/pathology visits (19.8%), while inpatient (5.5%) and radiology (4.9%) encounters were infrequent ( Figure 4 ). Patterns of utilization were consistent across GA subgroups. Outpatient pharmacy use was nearly identical among very/extreme preterm (62.1%), moderate preterm (62.9%), and late preterm (61.9%) infants. Similarly, rates of physician office visits ranged from 35.8% in very/extreme preterm infants to 43.5% in late preterm infants, and ER visits occurred in approximately 30–32% of infants across all subgroups. Inpatient visits were uncommon following discharge, with 2.8% of the overall cohort hospitalized within 30 days and 5.2% within 90 days. Rates of respiratory-related inpatient readmission were lower, occurring in 1.5% of infants within 30 days and 3.3% within 90 days. Early readmissions within 90 days occurred in 6.3% of very/extreme preterm infants, 4.6% of moderate preterm and 4.7% of late preterm infants. Figure 4. Commonly-reported HCRU categories overall and across GA subgroups during follow-up (≥3-months) Abbreviations: ER, emergency room; GA, gestational age; HCPCS, Healthcare Common Procedure Coding System; HCRU, healthcare resource utilization; nRDS, neonatal respiratory distress syndrome. Healthcare costs Mean (SD) monthly respiratory-related costs during follow-up were $347 ($5,366) PPPM in the overall cohort, with inpatient costs accounting for 77.5% (mean [SD]: $269 [$5,312] PPPM) of total costs ( Figure 5 ). Outpatient medical services accounted for 19.8% (mean [SD]: $69 [$680] PPPM), while outpatient pharmacy costs contributed 2.7% (mean [SD]: $9 [$38] PPPM), respectively. When stratified by GA, mean monthly respiratory-related costs increased markedly with lower GA. Very/extreme preterm infants incurred the highest average costs (mean [SD]: $684 [$9,239] PPPM), with inpatient care representing 85.3% (mean [SD]: $583 [$9,171] PPPM) of the total. Moderate preterm infants averaged a mean (SD) of $228 ($1,754) PPPM, with 70.0% (mean [SD]: $160 [$1,680] PPPM) attributable to inpatient care. Late preterm infants had the lowest mean costs (mean [SD]: $164 [$987] PPPM), of which 59.0% (mean [SD]: $97 [$860] PPPM) were inpatient-related. Figure 5. Mean PPPM respiratory-related healthcare costs by GA during follow-up (≥3-months) Respiratory-related medical costs were identified from claims with an ICD-10-CM diagnosis code for nRDS, BPD, or a respiratory disease of interest (asthma, chronic bronchitis, pulmonary hypertension, obstructive sleep apnea, upper and lower respiratory tract infection, bronchiolitis, pneumonia, cough, wheeze) in CDM or Dx in any position or HCPCS for respiratory disease-related drugs. Respiratory disease-related outpatient pharmacy costs were identified from claims with an NDC for respiratory disease-related drugs. Abbreviations: BPD, bronchopulmonary dysplasia; CDM, hospital charge data master; Dx, professional fee claims; ER, emergency room; GA, gestational age; HCPCS, Healthcare Common Procedure Coding System; NDC, National Drug Code; nRDS, neonatal respiratory distress syndrome; PPPM, per patient per month. COVID-19 sensitivity analysis The study period coincided with the Coronavirus disease-19 (COVID-19) pandemic, introducing potential confounding due to altered healthcare utilization patterns. To account for the likely reduction in outpatient respiratory encounters, we performed sensitivity analyses excluding infants whose follow-up overlapped with the pandemic. The sensitivity analysis was limited to infants with all follow-up before December 31, 2019 (preceding the COVID-19 pandemic) [n=3,660]. Respiratory-related healthcare costs were relatively lower than in the overall cohort (n=7,532). The mean (SD) costs declined from $347 ($5,366) PPPM in the overall cohort to $247 ($2,092) PPPM among those with all follow-up preceding the COVID-19 pandemic. By GA, very/extreme preterm infants had the highest mean costs in both groups, decreasing from mean (SD) $684 ($9,239) PPPM overall to $438 ($3,416) PPPM pre–COVID-19. Corresponding mean (SD) costs were $228 ($1,754) versus $190 ($1,157) PPPM for moderate preterm infants and $164 ($1,754) versus $144 ($916) PPPM for late preterm infants ( Supplementary Figure 1 ). These findings suggest that future adjusted analysis is warranted to account for variation in costs attributable to COVID-19 or other factors. Discussion To our knowledge, this study represents the first retrospective study of a large US cohort assessing long-term respiratory-related clinical and economic outcomes beyond the birth hospitalization among preterm infants treated for nRDS. Importantly, our cohort primarily includes preterm infants with nRDS, and very few infants carried a BPD diagnosis; this allows us to characterize long-term burden faced by preterm infants who do not have a documented diagnosis of BPD but who experience substantial respiratory morbidity, healthcare use, and economic burden throughout childhood. All preterm infants with nRDS, including moderate and late preterms without a formal diagnosis of BPD, were at risk of long-term respiratory morbidity and high rates of health care utilization during early childhood. The overall costs remained high, with inpatient care representing the primary driver; however, inpatient admissions were observed in only 5.5% of infants. The most common respiratory-related HCRU components were outpatient pharmacy, physician office visits, and ER visits. All preterm infants with nRDS, require long-term pulmonary follow-up extending beyond the neonatal period. Healthcare providers should maintain heightened vigilance for respiratory infections during early childhood, as hospitalization for respiratory illness during this period is associated with increased risk of persistent airway dysfunction. Efforts to optimize neonatal management, including universal antenatal corticosteroids, early surfactant therapy, and minimization of MV duration, may have lasting benefits for long-term respiratory health. Long-term respiratory outcomes and gestational age Persistent respiratory morbidity was reported across all GA categories. During the follow-up period (mean 1.3 years; maximum 9 years), nearly half of all infants (49.6%) experienced URTI, with additional high rates of cough (32.4%), LRTI (31.5%), and bronchiolitis (28.6%). These observations are in line with other literature showing that preterm birth predisposes infants to more severe respiratory infections. For example, Wang et al. demonstrated that preterm birth significantly impacts the detection of bacterial pathogens in pediatric pneumonia, with preterm birth being a risk factor for severe pneumonia (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.24 –1.78) and early-preterm infants showing even greater risk (OR 1.89, 95% CI 1.41 –2.53) [15]. These findings support the observed pattern in which very or extreme preterm infants demonstrated higher readmission rates within 90 days (6.3%) than moderate-to-late preterm infants (4.6%–4.7%). Our findings extend prior evidence from longitudinal studies by showing that respiratory morbidity is not confined to extremely preterm infants. Moderate and late preterm infants have fewer complication rates (13.7% and 11.1%) than very/extreme preterm infants (50.6%), but they still experience respiratory morbidity throughout childhood. In the current study, the rates of URTI, LRTI, and cough were consistently high across all GA subgroups, ranging between 45.8%–52.0%, 30.3%–32.3%, and 30.8%–33.5%, respectively. The PREMATURITAS 20 cohort provides insights into pulmonary outcomes extending into young adulthood [5] among survivors born at <32 weeks. Walicka-Serzysko et al. found that 28.0% of young adults born prematurely had airway obstruction (forced expiratory volume in 1 second/forced vital capacity [FEV₁/FVC] ≤-1.646 z-score), with current asthma affecting 11.5% of subjects [5]. Leps et al. demonstrated that infants born at <32 weeks of gestation were more likely to be associated with all wheezing trajectories (early-remittent, late-onset, and persistent-relapsing wheeze), with the persistent-relapsing wheeze pattern showing the strongest association (OR 4.30, 95% CI 2.33 –7.91), suggesting early and long-lasting damage to lung tissue [16]. Healthcare utilization and economic burden The economic burden of nRDS identified in this study reveals substantial long-term costs driven predominantly by inpatient hospitalizations. Mean respiratory-related healthcare costs during follow-up were $684 PPPM for very/extreme preterm infants and $164 PPPM for late preterm infants. Inpatient care emerged as the primary cost driver in our cohort. Despite the highest absolute costs occurring among very/extreme preterm infants, moderate and late preterm infants demonstrated notable use of healthcare resources, particularly outpatient and physician services. During follow-up, the most frequent categories of respiratory-related healthcare utilization were outpatient pharmacy use (62.2%), physician office visits (40.3%), and emergency room visits (30.8%). Of note, physician office visits were numerically higher in infants with higher GA, suggesting that these infants remain active users of outpatient care despite having milder neonatal courses. The high per-episode cost of hospitalizations explains why inpatient care remains the dominant cost driver, even though these visits are relatively infrequent (5.5% within 90 days). This finding aligns with established cost-effectiveness literature showing that interventions reducing hospitalization duration and complications yield significant cost savings [4]. Our findings are consistent with the European multinational cohort study by Kim et al., who reported incremental societal costs of €2,755 (p<0.001) for children born at ≤26 weeks compared to those born at 30–31 weeks. Importantly, Kim et al. found that indirect costs, such as parental work loss, accounted for more than half of total societal costs, whereas our study captured only direct medical costs, including inpatient, outpatient, emergency room, and pharmacy expenses. The absence of indirect cost data in our analysis likely underestimates the true societal economic burden of nRDS, as families of preterm infants with ongoing respiratory morbidity face substantial productivity losses and caregiving demands not reflected in healthcare claims [12]. Our results add to the existing literature by providing real-world evidence of long-term costs beyond the birth hospitalization in a large US cohort, an area where data have been limited. Broader literature shows that survivors of preterm nRDS frequently exhibit persistent respiratory symptoms, neurodevelopmental delays, and abnormal lung function into childhood, irrespective of initial respiratory management [3, 17, 18]. The persistent high costs observed in our cohort, particularly among the most premature infants, underscore the need for strategies that not only optimize initial neonatal management but also address long-term respiratory health through preventive care, early intervention for respiratory infections, and coordinated follow-up to reduce costly hospitalizations [5]. Limitations Several limitations should be acknowledged. As with all observational analyses using administrative claims data, there is potential for misclassification of exposures and outcomes, and clinical details such as ventilation parameters and surfactant dosing were unavailable. The databases are open-source, potentially resulting in incomplete capture of healthcare encounters outside participating facilities/providers/pharmacies. The study period overlapped with the COVID-19 pandemic, which may have impacted healthcare utilization and costs. Important confounders were unavailable, including surfactant timing, maternal risk factors, RSV prophylaxis, breastfeeding duration, and social determinants of health. Conclusion Although adverse short and long-term respiratory outcomes in preterm children after NICU discharge are well known, there are only limited data on specific diagnoses, and quantification of HCRU and economic costs beyond the NICU course. Based on rigorous analyses of an extensive database, we report new insights into the long-term clinical and economic burdens in a large real-world cohort of infants with nRDS. Regardless of GA and even in only rare the absence of a formal diagnosis of BPD at 36 weeks postmenstrual age (PMA), preterm newborns with nRDS face ongoing risk for respiratory disease and the need for frequent use of health care resources throughout childhood. Interestingly, incidence rates for specific respiratory conditions (chronic bronchitis, URTI, LRTI, bronchiolitis, and cough) were higher among moderate- and late-preterm infants than among those with lower GA While outpatient pharmacy and ER visits were similar across GA subgroups, physician office visits were higher in moderate and late preterm infants. These findings underscore the need for structured long-term follow-up programs and preventive strategies across all GA, independent of the traditional diagnosis of BPD. Abbreviations BPD: Bronchopulmonary dysplasia CCR: Cost charge ratio CDM: Hospital charge data master CE: Continuous enrollment CFR: Code of Federal Regulations CI: Confidence interval COVID-19: Coronavirus disease-19 CPAP: Continuous positive airway pressure CPT: Current Procedural Terminology Dx: Professional fee claims ECG: Electrocardiogram ER: Emergency room FEV₁/FVC: Forced expiratory volume in 1 second/forced vital capacity HCPCS: Healthcare Common Procedure Coding System HCRU: Healthcare resource utilization HIPAA: Health Insurance Portability and Accountability Act ICD-10-CM: International Classification of Diseases, tenth revision, Clinical Modification ICD-9-CM: International Classification of Diseases, ninth revision, Clinical Modification ICS: Inhaled corticosteroids ICU: Intensive care unit IUGR: Intrauterine growth restriction LOS: Length of stay LRTI: Lower respiratory tract infection LRx: Longitudinal prescription claims MV: Mechanical ventilation NDC: National Drug Code NICU: Neonatal intensive care unit nRDS: Neonatal respiratory distress syndrome OR: Odds ratio OSA: Obstructive sleep apnea PICU: Pediatric intensive care unit PPPM: Per patient per month SD: Standard deviation SGA: Small for gestational age URTI: Upper respiratory tract infection US: United States USD: United States dollar Visual abstract Abbreviations: CPAP, Continuous positive airway pressure; GA, gestational age; HCRU, Healthcare resource utilization; LRTI, lower respiratory tract infection; PPPM, Per patient per month; nRDS, neonatal respiratory distress syndrome; URTI, upper respiratory tract infection. Declarations Ethics declarations This observational study was exempt from Institutional Review Board (IRB) informed consent stipulations. The researchers accessed a de-identified limited dataset, and only summary statistics were reported. This work is fully compliant with all relevant provisions of the US Federal Health Insurance Portability and Accountability Act of 1996 (HIPAA). Clinical trial number Not applicable. Consent for publication Not applicable. This study does not contain data from any individual person. Data availability statement IQVIA analysed the data on behalf of Chiesi and provided summarized insights; however, because of data confidentiality, the supporting raw data cannot be made publicly available. IQVIA has direct access to the data and clarification could be provided upon reasonable request Competing interests The authors declare the following: SA is an employee at the Department of Pediatrics at University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO, USA and also serves as an advisor to Chiesi. AC, NM, LF, TM are employees of Chiesi Farmaceutici S.p.A., Via Palermo, 26/A, 43122, Parma, Italy. XS and JM are employees of Chiesi USA, Inc.175 Regency Woods Place, Suite 600, Cary, NC, USA. MD, JT, SM were employees of IQVIA, Inc, Falls Church, VA, USA* whose activities on research projects are funded by various pharmaceutical/biotech/medical device companies *At the time of the conduct of this study Funding This study was sponsored and funded by Chiesi. Author contributions All the authors contributed substantially to the conceptualization and design of this study. Authors MD, JT, and SM, were employees of IQVIA, Inc. at the time of this study, engaged in data acquisition and analysis. All the authors contributed to the study design, interpretation of the results, critically reviewed the manuscript and approved the final manuscript and take responsibility for its content. Acknowledgments We thank Abhilasha Verma, PhD, for providing medical writing assistance on this manuscript in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). References Fraser J, Walls M, McGuire W. Respiratory complications of preterm birth. BMJ. 2004;329(7472):962-965. Hermansen CL, Mahajan A: Newborn respiratory distress. Am Fam Physician. 2015;92(11):994-1002. Magni T, Ragni C, Pelizzi N, et al. Health economic studies of surfactant replacement therapy in neonates with respiratory distress syndrome: A systematic literature review. Pharmacoecon Open. 2023;7(3):359-371. Hannan KE, Hwang SS, Bourque SL. Readmissions among NICU graduates: Who, when and why? Semin Perinatol. 2020;44(4):151245. Walicka-Serzysko K, Postek M, Borawska-Kowalczyk U, et al. Long-term pulmonary outcomes of young adults born prematurely: a Polish prospective cohort study PREMATURITAS 20. BMC Pulm. Med. 2024;24(1):126. Dargaville PA, Kamlin COF, Orsini F, et al. Two-year outcomes after minimally invasive surfactant therapy in preterm infants: Follow-up of the OPTIMIST-A randomized clinical trial. JAMA. 2023;330(11):1054-1063. Hascoet JM, Deforge H, Demoulin S, et al. Outcomes at 7 Years of age of former very preterm neonates with repeated surfactant treatment for prolonged respiratory distress in the neonatal period. J Clin Med. 2023;12(19):6220. Cheah IGS. Economic assessment of neonatal intensive care. Transl Pediatr. 2019;8(3):246-256. Neil N, Sullivan SD, Lessler DS. The economics of treatment for infants with respiratory distress syndrome. Medical Decis Making. 1998;18(1):44-51. Pandya S, Baser O, Wan GJ, et al. The burden of hypoxic respiratory failure in preterm and term/near-term infants in the United States 2011-2015. J Health Econ Outcomes Res. 2019;6(3):130-141. Wang N, Lu K-Y, Jiang S-Y, et al. The current clinical landscape of neonatal respiratory failure in Jiangsu Province of China: patient demographics, NICU treatment interventions, and patient outcomes. BMC Pediatr. 2024;24(1):272. Kim SW, Andronis L, Seppänen AV, et al. Economic costs at age five associated with very preterm birth: multinational European cohort study. Pediatr Res. 2022; 92(3):700-711. Huse D RP, Vasey J. Expanding the evidence base in outcomes research: linking electronic medical records and claims data. ISPOR Connect. 2013;19(3):5-7. Pelletier EM, Shim B, Goodman S, et al. Epidemiology and economic burden of brain metastases among patients with primary breast cancer: results from a US claims data analysis. Breast Cancer Res Treat. 2008;108(2):297-305. Wang XR, Du J, Zhang SS, et al. Preterm birth and detection of common respiratory pathogens among pediatric pneumonia. iScience. 2023; 26(9):107488. Leps C, Carson C, Quigley MA. Gestational age at birth and wheezing trajectories at 3-11 years. Arch Dis Child. 2018;103(12):1138-1144. Marlow N, Hennessy EM, Bracewell MA, et al. Motor and executive function at 6 years of age after extremely preterm birth. Pediatrics. 2007;120(4):793-804. Telford K, Waters L, Vyas H, et al. Respiratory outcome in late childhood after neonatal continuous negative pressure ventilation. Arch Dis Child Fetal Neonatal Ed. 2007;92(1):F19-24. Additional Declarations Competing interest reported. The authors declare the following: SA is an employee at the Department of Pediatrics at University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO, USA and also serves as an advisor to Chiesi. AC, NM, LF, TM are employees of Chiesi Farmaceutici S.p.A., Via Palermo, 26/A, 43122, Parma, Italy. XS and JM are employees of Chiesi USA, Inc.175 Regency Woods Place, Suite 600, Cary, NC, USA. MD, JT, SM were employees of IQVIA, Inc, Falls Church, VA, USA* whose activities on research projects are funded by various pharmaceutical/biotech/medical device companies *At the time of the conduct of this study Supplementary Files SupplementaryFigure1.pptx SupplementaryTable1.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 09 May, 2026 Reviewers agreed at journal 03 May, 2026 Reviewers invited by journal 01 Apr, 2026 Editor invited by journal 23 Mar, 2026 Editor assigned by journal 22 Mar, 2026 Submission checks completed at journal 22 Mar, 2026 First submitted to journal 16 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9141627","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":618469299,"identity":"7670d44a-7a72-4e26-b057-d55d3746a994","order_by":0,"name":"Steven H. 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Dx, professional fee claims; HCRU, healthcare resource utilization; LRx, longitudinal prescription claims; nRDS, neonatal respiratory distress syndrome.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9141627/v1/fc3694b083a791ec5a370097.png"},{"id":106350059,"identity":"70b03ad4-a53e-4a44-bc67-2074420ec129","added_by":"auto","created_at":"2026-04-07 16:56:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":65710,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient identification and flow diagram showing stepwise selection of preterm infants with nRDS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: CMD, hospital charge data master; CPAP, continuous positive airway pressure; Dx, professional fee claims; ICD-10-CM, International Classification of Diseases, tenth revision, Clinical Modification; LRx, longitudinal prescription claims; nRDS, neonatal respiratory distress syndrome.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-9141627/v1/6d482a8f5d0042f5c2c6f04e.png"},{"id":106350057,"identity":"0ef693c7-7ba9-4490-8c51-57e8e9180382","added_by":"auto","created_at":"2026-04-07 16:56:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":26787,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProportion of patients with acute and chronic respiratory events during follow-up (≥3-months), by GA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: GA, gestational age; LRTI, lower respiratory tract infection; nRDS, neonatal respiratory distress syndrome; OSA, obstructive sleep apnea; URTI, upper respiratory tract infection.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-9141627/v1/af0cf14e2a7b4b9ddae2549f.png"},{"id":106404472,"identity":"31d6a3ab-64a6-4f68-9b5a-e448feb5b64f","added_by":"auto","created_at":"2026-04-08 09:16:05","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":31470,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCommonly-reported HCRU categories overall and across GA subgroups during follow-up (≥3-months)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: ER, emergency room; GA, gestational age; HCPCS, Healthcare Common Procedure Coding System; HCRU, healthcare resource utilization; nRDS, neonatal respiratory distress syndrome.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-9141627/v1/763b255dc5101055eb42877c.png"},{"id":106350060,"identity":"ac20d169-27ea-4841-802f-acdb06450da5","added_by":"auto","created_at":"2026-04-07 16:56:40","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":41958,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean PPPM respiratory-related healthcare costs by GA during follow-up (≥3-months)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRespiratory-related medical costs were identified from claims with an ICD-10-CM diagnosis code for nRDS, BPD, or a respiratory disease of interest (asthma, chronic bronchitis, pulmonary hypertension, obstructive sleep apnea, upper and lower respiratory tract infection, bronchiolitis, pneumonia, cough, wheeze) in CDM or Dx in any position or HCPCS for respiratory disease-related drugs. Respiratory disease-related outpatient pharmacy costs were identified from claims with an NDC for respiratory disease-related drugs.\u003c/p\u003e\n\u003cp\u003eAbbreviations: BPD, bronchopulmonary dysplasia; CDM, hospital charge data master; Dx, professional fee claims; ER, emergency room; GA, gestational age; HCPCS, Healthcare Common Procedure Coding System; NDC, National Drug Code; nRDS, neonatal respiratory distress syndrome; PPPM, per patient per month.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-9141627/v1/62b31b2143d44fc6552d79ea.png"},{"id":106405649,"identity":"c58471bb-8e7f-4c66-aad8-f17c2de9b822","added_by":"auto","created_at":"2026-04-08 09:28:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1664176,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9141627/v1/c483213a-232f-45ec-a189-f0203cb344fb.pdf"},{"id":106350056,"identity":"e4332aa4-3eef-4ee2-8483-f6b9630c3bec","added_by":"auto","created_at":"2026-04-07 16:56:40","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4567728,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1.pptx","url":"https://assets-eu.researchsquare.com/files/rs-9141627/v1/1f85b0b73a19814e8b69d58b.pptx"},{"id":106404370,"identity":"9e0b1d05-f994-4027-9133-6ee0f2bb33e5","added_by":"auto","created_at":"2026-04-08 09:15:53","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":19660,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9141627/v1/c8987c6e0ca8c6fca6c2c63f.docx"}],"financialInterests":"Competing interest reported. The authors declare the following: SA is an employee at the Department of Pediatrics at University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO, USA and also serves as an advisor to Chiesi. AC, NM, LF, TM are employees of Chiesi Farmaceutici S.p.A., Via Palermo, 26/A, 43122, Parma, Italy. XS and JM are employees of Chiesi USA, Inc.175 Regency Woods Place, Suite 600, Cary, NC, USA. MD, JT, SM were employees of IQVIA, Inc, Falls Church, VA, USA* whose activities on research projects are funded by various pharmaceutical/biotech/medical device companies\n*At the time of the conduct of this study","formattedTitle":"Long-term clinical and economic outcomes post birth hospitalization in preterm infants with neonatal respiratory distress syndrome: A real-world retrospective cohort study","fulltext":[{"header":"Background","content":"\u003cp\u003eRespiratory disease remains a major contributor to short and long-term morbidity and mortality in preterm infants [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Neonatal respiratory distress syndrome (nRDS), driven by surfactant deficiency and pulmonary immaturity, is one of the most frequent and severe causes of respiratory failure in this vulnerable population. Globally, nRDS affects about 1% of all newborns, accounting for nearly 20,000\u0026thinsp;\u0026minus;\u0026thinsp;30,000 cases annually and approximately 860 infant deaths each year in the United States (US) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The incidence of nRDS is inversely correlated with gestational age (GA) and birth weight, affecting up to 60%\u0026ndash;80% of infants born before 28 weeks, 30% of those born between 28\u0026ndash;34 weeks, and approximately 5% of late preterm neonates [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Importantly, all preterm infants, including moderate and late preterm, remain at significant risk of developing nRDS.\u003c/p\u003e \u003cp\u003ePrior studies have predominantly emphasized post-discharge outcomes of infants with bronchopulmonary dysplasia (BPD); however, many preterm infants without the added diagnosis of BPD remain at high risk for late respiratory and non-respiratory sequelae [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Current literature indicates that infants with chronic lung disease resulting from nRDS are at heightened risk of rehospitalization due to respiratory illness compared to GA-matched controls. Furthermore, evidence also suggests that respiratory morbidity may persist throughout childhood and into adulthood, with abnormal respiratory function recorded years after the initial neonatal phase [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Recent randomized controlled trials with long-term follow-up have further highlighted the burden of respiratory sequelae in infants with BPD, demonstrating meaningful differences in outcomes such as asthma and respiratory hospitalizations that persist well beyond infancy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, real-world data are limited on clinical outcomes and related healthcare utilization and cost impacts in preterm infants with nRDS following discharge from neonatal intensive care unit (NICU) discharge.\u003c/p\u003e \u003cp\u003eDespite significant therapeutic advances, the economic burden of nRDS remains substantial [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The primary cost drivers during initial hospitalization include invasive ventilation, longer hospitalization duration, and nRDS-associated complications such as BPD, with mean initial hospitalization costs ranging from \u003cspan\u003e$\u003c/span\u003e27,000 for 1,500\u0026ndash;2,000g infants to over \u003cspan\u003e$\u003c/span\u003e100,000 for those\u0026thinsp;\u0026lt;\u0026thinsp;1,000g [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. More recent analyses further highlight this impact: preterm infants experience significantly longer inpatient stays (54.1 vs 29.0 days), extended neonatal intensive care unit stays (34.1 vs 17.5 days), increased time on ventilation (4.7 vs 2.2 days), and higher total hospitalization charges (\u003cspan\u003e$\u003c/span\u003e613,350 vs \u003cspan\u003e$\u003c/span\u003e422,558) compared with term or near-term infants (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Early surfactant administration is more effective and less expensive than delayed intervention, leading to shorter hospital stays, fewer complications and reduced overall downstream treatment costs. While many studies have examined short-term outcomes during the initial hospital stay [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], there exists a paucity of research investigating long-term clinical and economic consequences following hospital discharge [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOverall, a major gap exists in understanding the comprehensive real-world burden associated with nRDS, which is critical to guide evidence-based clinical decision making, health care resource allocation and economic planning. The objective of this real-world study was to describe long-term clinical respiratory outcomes and economic burden in a large US-based cohort of preterm infants by various GA categories. By examining hospitalizations, medication utilization, diagnosis of subsequent respiratory diseases, and related healthcare costs, this research aims to generate crucial insights into the progression of respiratory health outcomes, patterns of healthcare utilization, and the overall societal burden of this critical condition across all preterm categories.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and data sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was a retrospective observational cohort analysis utilizing three linked IQVIA US databases: Hospital Charge Data Master (CDM), Professional Fee Claims (Dx), and Longitudinal Prescription Claims (LRx), covering the period October 1, 2015, to March 31, 2024 (\u003cstrong\u003eFigure 1\u003c/strong\u003e). The CDM database provides patient-level service order records from over 500 hospitals, encompassing 7 million annual inpatient stays and 60 million annual outpatient visits. Key data elements include patient demographics, diagnoses, procedures, medications, devices, and both inpatient and outpatient encounters. The Dx database contributes approximately 1 billion professional fee claims annually from over 800,000 office-based physicians and specialists, representing 60\u0026ndash;70% of physician activity in the United States. The Dx database captures detailed diagnostic, procedural, and service-level information, enabling the identification of respiratory events and healthcare utilization through linked diagnosis, procedure, and billing data. The LRx database includes over 1.6 billion retail or mail-order prescription claims, representing approximately 85% of all pharmacies nationwide, including, but not limited to retail, mail, and specialty pharmacies. The LRx database captures comprehensive dispensing-level information, including National Drug Codes (NDCs), fill dates, days\u0026rsquo; supply, quantities, payer types, and paid or allowed amounts, which were used to quantify outpatient medication utilization and respiratory-related pharmacy costs during follow-up.\u003c/p\u003e\n\u003cp\u003ePatient-level linkage across databases was accomplished through IQVIA\u0026apos;s proprietary deterministic encryption algorithm, which utilized actual patient-level information (first name, last name, date of birth, gender, and five-digit ZIP code) to create unique patient identifiers [13]. This approach ensured the continuity of patient records while maintaining compliance with the Health Insurance Portability and Accountability Act (HIPAA) through source-level de-identification.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1.\u003c/strong\u003e \u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eLinkage to LRx and Dx was assessed during the study period.\u003cbr\u003e\u003csup\u003eb\u003c/sup\u003eInfants with age \u0026gt;0 at index (CDM/Dx/LRx) or those with records before index date or evidence of data quality issues or evidence or nRDS treatment or death during birth hospitalization were also excluded.\u003cbr\u003e\u003csup\u003ec\u003c/sup\u003eCensoring events: death, loss of follow-up, end of study period.\u003c/p\u003e\n\u003cp\u003eAbbreviations: CDM, hospital charge data master; Dx, professional fee claims; HCRU, healthcare resource utilization; LRx, longitudinal prescription claims; nRDS, neonatal respiratory distress syndrome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy population and patient selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cohort included preterm infants diagnosed with nRDS during their birth hospitalization, recorded in CDM between October 1, 2015, and March 31, 2022. The index date was defined as the day after discharge from the birth hospitalization. This analysis used existing HIPAA-compliant de-identified data and was therefore exempt from human subjects\u0026apos; protection requirements under 45 Code of Federal Regulations (CFR) 46.101(b).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInclusion criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eInfants were included if they met the following criteria: inpatient admission for preterm birth (GA \u0026lt;37 weeks) based on diagnosis codes in CDM during the selection window (between October 1, 2015, and March 31, 2022; \u003cstrong\u003eFigure 1\u003c/strong\u003e); nRDS diagnosis (International Classification of Diseases, tenth revision, Clinical Modification (ICD-10-CM available in \u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e) during the birth hospitalization; linkage to both Dx and LRx databases with at least one record during the study period; evidence of nRDS treatment (surfactant or continuous positive airway pressure [CPAP] only) during birth hospitalization; at least one Dx record and one LRx record after birth hospitalization discharge; at least one month of pharmacy stability after discharge; and at least three months of follow-up post-birth hospitalization discharge in both Dx and LRx databases.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eExclusion criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eInfants with any records in Dx, LRx, or CDM database before the birth hospitalization admission date and age \u0026gt;0 years in the year of birth hospitalization admission were excluded to ensure a valid neonatal cohort where the birth hospitalization was the first documented encounter to capture incident cases. To ensure data integrity and validity, those with missing critical demographics (e.g., sex) were excluded. Given this study focused on outcomes specific to nRDS after birth hospitalization, infants with evidence of death during the birth hospitalization and those with evidence of severe congenital malformations (e.g., diaphragmatic hernia, major congenital heart disease [ICD-10-CM available in \u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e]) during the first year of life were excluded. Finally, infants with records of surfactant treatment after hospital discharge (and treated with CPAP and no surfactant during birth hospitalization) were excluded to maintain the integrity of the neonatal cohort since surfactant is typically administered within first hours of life during the birth hospitalization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy periods and follow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study period was October 1, 2015, to March 31, 2024; the selection window was October 1, 2015, to March 31, 2022. The baseline period extended from the admission date of birth hospitalization to the discharge date. The follow-up period began on the index date (birth hospitalization discharge date) and continued for a minimum of three months, censored at the earliest of: evidence of death, loss of activity in Dx/LRx, loss of pharmacy stability or end of the study period (March 31, 2024).\u003c/p\u003e\n\u003cp\u003eDeath was identified based on a discharge status of \u0026quot;expired\u0026quot; in CDM or through application of a claims-based death proxy algorithm [14]. Infants were assumed to have died if they had evidence during the month preceding the latest observed Dx claim date of: critical care transport current procedural terminology (CPT) procedure; an inpatient, emergency room, or hospice claim with acute myocardial infarction diagnosis, major thoracostomy with cardiac massage, direct repair of aneurysm or excision, cardiac event including resuscitation, defibrillation, cerebral death, cardiac arrest or failure diagnosis, sudden death diagnosis, injection given to stimulate the heart, emergency room visit with high-urgent severity, emergency transport, or critical care.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical outcomes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary clinical outcomes included the frequency, number of events, and incidence rate of respiratory diseases. Chronic respiratory conditions (asthma, chronic bronchitis, pulmonary hypertension, obstructive sleep apnea) were limited to one event per patient during the follow-up period, while acute respiratory conditions (upper respiratory tract infection [URTI], lower respiratory tract infection [LRTI], bronchiolitis, pneumonia, cough, wheeze) included multiple events per patient. Each patient contributed at most one event for a chronic respiratory condition. For acute respiratory conditions, patients can contribute multiple events and are at risk for the event again after a 14-day washout period.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHealthcare resource utilization and cost outcomes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedical healthcare resource utilization (HCRU) and costs were considered respiratory disease-related if they had an ICD-10-CM diagnosis code for the respiratory disease of interest in CDM or Dx in any position, or respiratory disease-related drugs (oxygen therapy, long-acting beta-agonists, long-acting muscarinic antagonists, short-acting beta-agonists, inhaled corticosteroids, antibiotics, diuretics, anticoagulants) based on Healthcare Common Procedure Coding System (HCPCS) codes or billing descriptions. The respiratory diseases of interest included nRDS, bronchopulmonary dysplasia, chronic lung disease, asthma, chronic bronchitis, URTI, LRTI, bronchiolitis, pneumonia, cough, wheeze, pulmonary hypertension, and obstructive sleep apnea.\u003c/p\u003e\n\u003cp\u003ePharmacy HCRU and costs were considered respiratory disease-related if the NDC on the claim corresponded to a respiratory disease-related drug. Outpatient medical HCRU measures included physician office visits, emergency room visits, laboratory and pathology visits, radiology visits, HCPCS codes administrations, and other outpatient visits. Inpatient hospitalization measures included the number of inpatient visits, average length of stay, total inpatient days, NICU/pediatric intensive care unit (PICU) admissions and length of stay, and discharge disposition.\u003c/p\u003e\n\u003cp\u003eBoth Dx and CDM reported charges, while LRx reported allowed or paid amounts. A cost-to-charge ratio was applied for charges in Dx and CDM. All costs were converted to 2023 United States dollars using the medical component of the Consumer Price Index and standardized as per patient per month (PPPM).\u003c/p\u003e\n\u003cp\u003eAll-cause and respiratory disease-related inpatient admissions were assessed during specific time periods: 30 days, 90 days, and 180 days following birth hospitalization discharge.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCovariates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient characteristics assessed during the birth hospitalization included demographic variables (sex, birth year, geographic region, payer type) and clinical characteristics (GA, birth weight, intrauterine growth restriction or small for GA). Birth hospitalization characteristics included: hospital length of stay, ICU visits and length of stay, NICU/PICU length of stay, premature birth complications identified based on ICD-10-CM diagnosis codes (\u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e) from the CDM database (bronchopulmonary dysplasia, intraventricular hemorrhage, retinopathy of prematurity, air leak syndrome, pulmonary hemorrhage, sepsis, necrotizing enterocolitis), electrocardiogram use identified based on procedure codes and billing descriptions from the CDM database, and treatments observed for nRDS identified based on NDC codes, procedure codes and billing descriptions from the CDM database (CPAP, surfactant therapy, mechanical ventilation [MV]).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll study measures were summarized descriptively. Continuous variables were summarized by mean, standard deviation (SD), minimum, median, first quartile, third quartile, and maximum. Categorical variables were summarized by frequency and percentage. For chronic respiratory conditions, the incidence rate was calculated by dividing the total events with a respiratory diagnosis of interest by the total person-years at risk for such events. For acute respiratory conditions, patients could contribute multiple events with a 14-day washout period between events. All study measures were reported for the overall nRDS cohort and GA categories (extremely [\u0026lt;28 weeks] and very preterm [28 to \u0026lt;32 weeks], moderate preterm [32 to \u0026lt;34 weeks], late preterm [34 to \u0026lt;37 weeks]).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy cohort identification and patient selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 200,533 infants with an inpatient admission containing at least one diagnosis code for preterm birth were identified between October 1, 2015, and March 31, 2022. Of these, 86,695 infants (43.2%) had a diagnosis code for nRDS during the birth hospitalization, and 17,229 had evidence of treatment for nRDS (surfactant or CPAP) during the birth hospitalization. After applying all study selection criteria, including follow-up activity requirements, the overall nRDS cohort comprised of 7,532 preterm infants. A schematic of the patient identification process is presented in \u003cstrong\u003eFigure 2\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eAdditionally, by GA distribution, the nRDS cohort included 43.6% late preterm infants (34 to \u0026lt;37 weeks), 23.7% moderately preterm infants (32 to \u0026lt;34 weeks), and 32.3% were very or extremely preterm (\u0026lt;32 weeks); 0.4% infants had an unspecified GA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2.\u003c/strong\u003e \u003cstrong\u003ePatient identification and flow diagram showing stepwise selection of preterm infants with nRDS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: CMD, hospital charge data master; CPAP, continuous positive airway pressure; Dx, professional fee claims; ICD-10-CM, International Classification of Diseases, tenth revision, Clinical Modification; LRx, longitudinal prescription claims; nRDS, neonatal respiratory distress syndrome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDemographic and clinical characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe nRDS cohort was 54.0% males and 46.0% females, with the majority of infants located in the South (64.6%) followed by West (15.5%), Northeast (12.6%) and the Midwest (7.2%). Commercial insurance was the most common primary payer (41.3%), followed by Medicaid (15.6%). Sex distribution varied slightly across GA subgroups with very/extreme preterm subgroup comprised 52.1% female, 47.9% male; moderate preterm subgroup comprised 44.8% female, 55.2% male; late preterm subgroup comprised 42.1% female, 57.9% male (\u003cstrong\u003eTable 1\u003c/strong\u003e). Geographical and payer distribution remained consistent across GA subgroups.\u003c/p\u003e\n\u003cp\u003eAdditionally, among infants with documented birth weight (68.8% of the overall nRDS cohort), 33.9% weighed 2,000g \u0026ndash; 2,499g, 17.1% weighed 1,750g \u0026ndash; 1,999g, 15.6% weighed 1,500g \u0026ndash; 1,749g, 13.9% weighed 1,250g \u0026ndash; 1,499g, 10.4% weighed 1,000g \u0026ndash; 1,249g, and 9.0% weighed \u0026lt;1,000g. Intrauterine growth restriction or small for GA status was documented in 5.1% infants. The mean inpatient length of stay during the birth hospitalization was 26.7 days (SD 22.8), which decreased progressively as GA increased, ranging from 49.0 days in very/extreme preterm infants to 11.9 days in late preterm infants. Overall, birth complications occurred in 24.5% of the cohort, with retinopathy of prematurity (11.3%) and sepsis (9.4%) being the most prevalent. Complication rates were substantially higher in infants with lower GA. Among very/extreme preterm, moderate preterm, and late preterm infants, the observed rates were as follows: retinopathy of prematurity - 33.1%, 2.1%, and 0.6%; sepsis - 13.7%, 8.0%, and 7.0%; intraventricular hemorrhage - 13.3%, 2.5%, and 0.6%; air leak syndrome - 2.3%, 1.6%, and 3.5%; necrotizing enterocolitis - 2.7%, 0.6%, and 0.1%, respectively. BPD was documented in 5.1% of very/extreme preterm infants and 0.1% of the moderate and late preterm infants.\u003c/p\u003e\n\u003cp\u003eRespiratory support modalities during birth hospitalization in the overall cohort included CPAP (91.5%), MV (34.2%), and surfactant therapy (29.5%). The use of CPAP remained consistently high (\u0026gt;89%) across all GA subgroups. MV and surfactant use was more frequent in lower GA subgroups and less frequent in higher GA subgroups. Electrocardiogram use was documented in 2.5% of infants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Baseline demographic, gestational, and birth hospitalization characteristics of preterm infants with nRDS\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"604\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall nRDS cohort\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=7532\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 291px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubgroups by GA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eVery or extreme preterm (N=2435)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eModerate preterm\u003c/p\u003e\n \u003cp\u003e(N=1784)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eLate preterm\u003c/p\u003e\n \u003cp\u003e(N=3285)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 203px;\"\u003e\n \u003cp\u003eSex, female, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003e3466 (46.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e1269 (52.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e799 (44.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1383 (42.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 203px;\"\u003e\n \u003cp\u003eUS region\u003csup\u003ea\u003c/sup\u003e, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eNortheast\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e950 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e276 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e224 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e449 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eMidwest\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e544 (7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e187 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e109 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e247 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eSouth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e4862 (64.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e1623 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1153 (64.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e2068 (63.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eWest\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e1171 (15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e345 (14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e297 (16.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e521 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 203px;\"\u003e\n \u003cp\u003ePayer type, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eCommercial\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e3107 (41.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e975 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e737 (41.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1385 (42.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eMedicare (including Part D coverage)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e72 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e20 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e16 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e36 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eMedicaid (including managed Medicaid)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e1176 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e445 (18.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e263 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e465 (14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eOther Medicaid/Medicare/state assistance\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e1146 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e358 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e260 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e523 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eCash payments\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e7 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e1 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e6 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e2024 (26.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e636 (26.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e502 (28.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e876 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eBirth weight, n (%)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u0026lt;1000g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e466 (9.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e457 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e6 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e2 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e1000-1249g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e541 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e508 (22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e26 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e7 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e1250-1499g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e720 (13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e593 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e109 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e16 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e1500-1749g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e810 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e427 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e314 (21.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e69 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e1750-1999g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e888 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e188 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e460 (30.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e235 (16.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e2000-2499g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e1757 (33.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e68 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e580 (38.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1101 (77.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eWith IUGR/SGA diagnosis code, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e385 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e115 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e107 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e163 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eInpatient LOS, mean days (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e26.7 (22.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e49.0 (24.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e23.5 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e11.9 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 203px;\"\u003e\n \u003cp\u003eBirth complications, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eAny of the below\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e1849 (24.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e1233 (50.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e244 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e366 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eRetinopathy of prematurity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e851 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e805 (33.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e38 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e6 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eSepsis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e709 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e334 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e142 (8.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e229 (7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eIntraventricular hemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e390 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e324 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e45 (2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eAir leak syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e200 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e57 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e28 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e115 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eBronchopulmonary dysplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e129 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e124 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e4 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eNecrotizing enterocolitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e78 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e65 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e11 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003ePulmonary hemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e22 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e17 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e2 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 203px;\"\u003e\n \u003cp\u003eTreatments, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eCPAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e6895 (91.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e2181 (89.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1639 (91.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e3051 (92.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eSurfactant therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e2219 (29.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e1066 (43.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e475 (26.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e668 (20.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eMV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e2574 (34.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e1274 (52.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e523 (29.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e769 (23.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 203px;\"\u003e\n \u003cp\u003eWith ECG use, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003e189 (2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e100 (4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e30 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e59 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"bottom\" style=\"width: 604px;\"\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003eThere were five infants in the overall nRDS cohort with an unknown US region.\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003csup\u003eb\u003c/sup\u003eIncludes other managed Medicaid, Medicare supplement, Medigap, and state assistance.\u003cbr\u003e\u0026nbsp;\u003csup\u003ec\u003c/sup\u003eThe denominator is the number of infants with diagnosis codes indicating birth weight. There were 2,350 infants (31.2%) in the overall nRDS cohort with no diagnosis codes specifying the birth weight range.\u003c/p\u003e\n \u003cp\u003eAbbreviations: BPD, bronchopulmonary dysplasia; CPAP, continuous positive airway pressure; ECG, electrocardiogram; GA, gestational age; IUGR, intrauterine growth restriction; LOS, length of stay; MV, mechanical ventilation; nRDS, neonatal respiratory distress syndrome; SD, standard deviation; SGA, small for gestational age.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eLong-term respiratory outcomes in the overall cohort and by gestational age\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring follow-up (median duration of 1 year, range up to 9 years), nearly half of infants in the overall cohort experienced URTI (49.6%), while more than one-fourth had cough (32.4%), LRTI (31.5%) or bronchiolitis (28.6%) [\u003cstrong\u003eFigure 3\u003c/strong\u003e]. Among chronic respiratory outcomes, asthma occurred in 11.3% of infants, whereas chronic bronchitis (0.4%), obstructive sleep apnea (OSA; 1.0%), and pulmonary hypertension (0.1%) were infrequent. When stratified by GA, respiratory morbidity persisted across all subgroups. URTI was reported in 45.8% of very/extreme preterm, 50.4% of moderate preterm and 52.0% of late preterm infants. Patterns were similar for cough (30.8\u0026ndash;33.5%), LRTI (30.3\u0026ndash;32.3%) and bronchiolitis (27.1\u0026ndash;29.4%). There was no consistent trend in disease incidence rates by GA; although chronic bronchitis, URTI, LRTI, bronchiolitis, and cough were more frequent in moderate or late preterm infants, whereas asthma, pulmonary hypertension, obstructive sleep apnea, pneumonia, and wheeze had the highest incidence in very/extreme preterm infants. Notably, zero infants in the late preterm subgroup developed pulmonary hypertension during follow-up. Rates of URTI (45.8%\u0026ndash;52.0%), LRTI (30.3%\u0026ndash;32.3%), and cough (30.8%\u0026ndash;33.5%) were consistently high across all GA subgroups, exceeding 500 events per 1,000 person-years (\u003cstrong\u003eTable 2\u003c/strong\u003e). In contrast, chronic conditions such as asthma (9.8%\u0026ndash;13.5%), obstructive sleep apnea (0.5%\u0026ndash;1.6%), and chronic bronchitis (0.2%\u0026ndash;0.6%) occurred infrequently (\u0026lt;15 events per 1,000 person-years).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3. Proportion of patients with acute and chronic respiratory events during follow-up (\u0026ge;3-months), by GA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: GA, gestational age; LRTI, lower respiratory tract infection; nRDS, neonatal respiratory distress syndrome; OSA, obstructive sleep apnea; URTI, upper respiratory tract infection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Incidence rates of respiratory events anytime during the follow-up (\u0026ge;3-months)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"642\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMeasures\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall nRDS cohort\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=7532\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubgroups by GA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eVery or extreme preterm (N=2435)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eModerate preterm\u003c/p\u003e\n \u003cp\u003e(N=1784)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eLate preterm\u003c/p\u003e\n \u003cp\u003e(N=3285)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eAsthma, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e851 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e328 (13.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e199 (11.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e323 (9.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eIncidence rate per 1000 person-years, (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e97.3 (91.9\u0026ndash;103.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e114.9 (104.7\u0026ndash;125.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e100.6 (89.1\u0026ndash;113.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e83.1 (75.7\u0026ndash;91.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eChronic bronchitis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e31 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e5 (0.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e11 (0.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e15 (0.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eIncidence rate per 1000 person-years, (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e3.1 (2.3\u0026ndash;4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.5 (0.6\u0026ndash;3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4.9 (2.7\u0026ndash;8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.5 (2.1\u0026ndash;5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003ePulmonary hypertension, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e6 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4 (0.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (0.1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0 (0.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eIncidence rate per 1000 person-years, (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e0.6 (0.3\u0026ndash;1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.2 (0.4\u0026ndash;2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0.9 (0.2\u0026ndash;2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0.0 (NA\u0026ndash;NA)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eObstructive sleep apnea, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e73 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e38 (1.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e18 (1.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e17 (0.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eIncidence rate per 1000 person-years, (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e7.4 (6.0\u0026ndash;9.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e11.6 (8.7\u0026ndash;15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e8.0 (5.2\u0026ndash;11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.9 (2.5\u0026ndash;5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eUpper respiratory tract infection, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e3736 (49.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1116 (45.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e900 (50.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1707 (52.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eIncidence rate per 1000 person-years, (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1581.2 (1557.8\u0026ndash;1605.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1369.0 (1331.6\u0026ndash;1407.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1651.2 (1600.8\u0026ndash;1702.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1711.8 (1674.7\u0026ndash;1749.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eLower respiratory tract infection, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e2373 (31.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e738 (30.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e569 (31.9)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1060 (32.3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eIncidence rate per 1000 person-years, (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e557.4 (543.5\u0026ndash;571.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e522.7 (499.6\u0026ndash;546.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e600.4 (570.2\u0026ndash;631.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e563.2 (542.0\u0026ndash;585.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eBronchiolitis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e2152 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e661 (27.1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e519 (29.1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e967 (29.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eIncidence rate per 1000 person-years, (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e462.9 (450.3\u0026ndash;475.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e431.1 (410.3\u0026ndash;452.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e505.1 (477.5\u0026ndash;533.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e467.3 (448.0\u0026ndash;487.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003ePneumonia, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e597 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e233 (9.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e115 (6.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e246 (7.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eIncidence rate per 1000 person-years, (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e89.7 (84.7\u0026ndash;95.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e107.5 (98.0\u0026ndash;117.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e96.1 (85.3\u0026ndash;108.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e72.8 (66.0\u0026ndash;80.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eCough, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e2443 (32.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e750 (30.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e582 (32.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1102 (33.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eIncidence rate per 1000 person-years, (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e680.3 (665.2\u0026ndash;695.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e625.2 (600.4\u0026ndash;650.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e726.5 (693.8\u0026ndash;760.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e696.7 (673.6\u0026ndash;720.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eWheeze, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1043 (13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e390 (16.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e241 (13.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e409 (12.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 180px;\"\u003e\n \u003cp\u003eIncidence rate per 1000 person-years, (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e199.2 (191.5\u0026ndash;207.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e240.4 (225.6\u0026ndash;255.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e198.6 (182.5\u0026ndash;215.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e169.2 (158.5\u0026ndash;180.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"bottom\" style=\"width: 642px;\"\u003e\n \u003cp\u003eAbbreviations: CI, confidence interval; GA, gestational age; nRDS, neonatal respiratory distress syndrome.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eHealthcare resource utilization and costs in the overall cohort and by gestational age\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResource utilization\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the follow-up period, the most common categories of respiratory-related healthcare utilization in the overall nRDS cohort were outpatient pharmacy use (62.2%), physician office visits (40.3%), and emergency room (ER) visits (30.8%). Other categories included HCPCS drug administration (25.4%), other outpatient medical services (22.3%), and laboratory/pathology visits (19.8%), while inpatient (5.5%) and radiology (4.9%) encounters were infrequent (\u003cstrong\u003eFigure 4\u003c/strong\u003e). Patterns of utilization were consistent across GA subgroups. Outpatient pharmacy use was nearly identical among very/extreme preterm (62.1%), moderate preterm (62.9%), and late preterm (61.9%) infants. Similarly, rates of physician office visits ranged from 35.8% in very/extreme preterm infants to 43.5% in late preterm infants, and ER visits occurred in approximately 30\u0026ndash;32% of infants across all subgroups.\u003c/p\u003e\n\u003cp\u003eInpatient visits were uncommon following discharge, with 2.8% of the overall cohort hospitalized within 30 days and 5.2% within 90 days. Rates of respiratory-related inpatient readmission were lower, occurring in 1.5% of infants within 30 days and 3.3% within 90 days. Early readmissions within 90 days occurred in 6.3% of very/extreme preterm infants, 4.6% of moderate preterm and 4.7% of late preterm infants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 4. Commonly-reported HCRU categories overall and across GA subgroups during follow-up (\u0026ge;3-months)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: ER, emergency room; GA, gestational age; HCPCS, Healthcare Common Procedure Coding System; HCRU, healthcare resource utilization; nRDS, neonatal respiratory distress syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHealthcare costs\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMean (SD) monthly respiratory-related costs during follow-up were $347 ($5,366) PPPM in the overall cohort, with inpatient costs accounting for 77.5% (mean [SD]: $269 [$5,312] PPPM) of total costs (\u003cstrong\u003eFigure 5\u003c/strong\u003e). Outpatient medical services accounted for 19.8% (mean [SD]: $69 [$680] PPPM), while outpatient pharmacy costs contributed 2.7% (mean [SD]: $9 [$38] PPPM), respectively. When stratified by GA, mean monthly respiratory-related costs increased markedly with lower GA. Very/extreme preterm infants incurred the highest average costs (mean [SD]: $684 [$9,239] PPPM), with inpatient care representing 85.3% (mean [SD]: $583 [$9,171] PPPM) of the total. Moderate preterm infants averaged a mean (SD) of $228 ($1,754) PPPM, with 70.0% (mean [SD]: $160 [$1,680] PPPM) attributable to inpatient care. Late preterm infants had the lowest mean costs (mean [SD]: $164 [$987] PPPM), of which 59.0% (mean [SD]: $97 [$860] PPPM) were inpatient-related.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 5. Mean PPPM respiratory-related healthcare costs by GA during follow-up (\u0026ge;3-months)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRespiratory-related medical costs were identified from claims with an ICD-10-CM diagnosis code for nRDS, BPD, or a respiratory disease of interest (asthma, chronic bronchitis, pulmonary hypertension, obstructive sleep apnea, upper and lower respiratory tract infection, bronchiolitis, pneumonia, cough, wheeze) in CDM or Dx in any position or HCPCS for respiratory disease-related drugs. Respiratory disease-related outpatient pharmacy costs were identified from claims with an NDC for respiratory disease-related drugs.\u003c/p\u003e\n\u003cp\u003eAbbreviations: BPD, bronchopulmonary dysplasia; CDM, hospital charge data master; Dx, professional fee claims; ER, emergency room; GA, gestational age; HCPCS, Healthcare Common Procedure Coding System; NDC, National Drug Code; nRDS, neonatal respiratory distress syndrome; PPPM, per patient per month.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOVID-19 sensitivity analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study period coincided with the Coronavirus disease-19 (COVID-19) pandemic, introducing potential confounding due to altered healthcare utilization patterns. To account for the likely reduction in outpatient respiratory encounters, we performed sensitivity analyses excluding infants whose follow-up overlapped with the pandemic. The sensitivity analysis was limited to infants with all follow-up before December 31, 2019 (preceding the COVID-19 pandemic) [n=3,660]. Respiratory-related healthcare costs were relatively lower than in the overall cohort (n=7,532). The mean (SD) costs declined from $347 ($5,366) PPPM in the overall cohort to $247 ($2,092) PPPM among those with all follow-up preceding the COVID-19 pandemic. By GA, very/extreme preterm infants had the highest mean costs in both groups, decreasing from mean (SD) $684 ($9,239) PPPM overall to $438 ($3,416) PPPM pre\u0026ndash;COVID-19. Corresponding mean (SD) costs were $228 ($1,754) versus $190 ($1,157) PPPM for moderate preterm infants and $164 ($1,754) versus $144 ($916) PPPM for late preterm infants (\u003cstrong\u003eSupplementary Figure 1\u003c/strong\u003e). These findings suggest that future adjusted analysis is warranted to account for variation in costs attributable to COVID-19 or other factors.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this study represents the first retrospective study of a large US cohort assessing long-term respiratory-related clinical and economic outcomes beyond the birth hospitalization among preterm infants treated for nRDS. Importantly, our cohort primarily includes preterm infants with nRDS, and very few infants carried a BPD diagnosis; this allows us to characterize long-term burden faced by preterm infants who do not have a documented diagnosis of BPD but who experience substantial respiratory morbidity, healthcare use, and economic burden throughout childhood. All preterm infants with nRDS, including moderate and late preterms without a formal diagnosis of BPD, were at risk of long-term respiratory morbidity and high rates of health care utilization during early childhood. The overall costs remained high, with inpatient care representing the primary driver; however, inpatient admissions were observed in only 5.5% of infants. The most common respiratory-related HCRU components were outpatient pharmacy, physician office visits, and ER visits. All preterm infants with nRDS, require long-term pulmonary follow-up extending beyond the neonatal period. Healthcare providers should maintain heightened vigilance for respiratory infections during early childhood, as hospitalization for respiratory illness during this period is associated with increased risk of persistent airway dysfunction. Efforts to optimize neonatal management, including universal antenatal corticosteroids, early surfactant therapy, and minimization of MV duration, may have lasting benefits for long-term respiratory health.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLong-term respiratory outcomes and gestational age\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePersistent respiratory morbidity was reported across all GA categories. During the follow-up period (mean 1.3 years; maximum 9 years), nearly half of all infants (49.6%) experienced URTI, with additional high rates of cough (32.4%), LRTI (31.5%), and bronchiolitis (28.6%). These observations are in line with other literature showing that preterm birth predisposes infants to more severe respiratory infections. For example, Wang et al. demonstrated that preterm birth significantly impacts the detection of bacterial pathogens in pediatric pneumonia, with preterm birth being a risk factor for severe pneumonia (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.24 \u0026ndash;1.78) and early-preterm infants showing even greater risk (OR 1.89, 95% CI 1.41 \u0026ndash;2.53) [15]. These findings support the observed pattern in which very or extreme preterm infants demonstrated higher readmission rates within 90 days (6.3%) than moderate-to-late preterm infants (4.6%\u0026ndash;4.7%).\u003c/p\u003e\n\u003cp\u003eOur findings extend prior evidence from longitudinal studies by showing that respiratory morbidity is not confined to extremely preterm infants. Moderate and late preterm infants have fewer complication rates (13.7% and 11.1%) than very/extreme preterm infants (50.6%), but they still experience respiratory morbidity throughout childhood. In the current study, the rates of URTI, LRTI, and cough were consistently high across all GA subgroups, ranging between 45.8%\u0026ndash;52.0%, 30.3%\u0026ndash;32.3%, and 30.8%\u0026ndash;33.5%, respectively. The PREMATURITAS 20 cohort provides insights into pulmonary outcomes extending into young adulthood [5] among survivors born at \u0026lt;32 weeks. Walicka-Serzysko et al. found that 28.0% of young adults born prematurely had airway obstruction (forced expiratory volume in 1 second/forced vital capacity [FEV₁/FVC] \u0026le;-1.646 z-score), with current asthma affecting 11.5% of subjects [5]. Leps et al. demonstrated that infants born at \u0026lt;32 weeks of gestation were more likely to be associated with all wheezing trajectories (early-remittent, late-onset, and persistent-relapsing wheeze), with the persistent-relapsing wheeze pattern showing the strongest association (OR 4.30, 95% CI 2.33 \u0026ndash;7.91), suggesting early and long-lasting damage to lung tissue [16].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHealthcare utilization and economic burden\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe economic burden of nRDS identified in this study reveals substantial long-term costs driven predominantly by inpatient hospitalizations. Mean respiratory-related healthcare costs during follow-up were $684 PPPM for very/extreme preterm infants and $164 PPPM for late preterm infants. Inpatient care emerged as the primary cost driver in our cohort. Despite the highest absolute costs occurring among very/extreme preterm infants, moderate and late preterm infants demonstrated notable use of healthcare resources, particularly outpatient and physician services. During follow-up, the most frequent categories of respiratory-related healthcare utilization were outpatient pharmacy use (62.2%), physician office visits (40.3%), and emergency room visits (30.8%). Of note, physician office visits were numerically higher in infants with higher GA, suggesting that these infants remain active users of outpatient care despite having milder neonatal courses. The high per-episode cost of hospitalizations explains why inpatient care remains the dominant cost driver, even though these visits are relatively infrequent (5.5% within 90 days). This finding aligns with established cost-effectiveness literature showing that interventions reducing hospitalization duration and complications yield significant cost savings [4].\u003c/p\u003e\n\u003cp\u003eOur findings are consistent with the European multinational cohort study by Kim et al., who reported incremental societal costs of \u0026euro;2,755 (p\u0026lt;0.001) for children born at \u0026le;26 weeks compared to those born at 30\u0026ndash;31 weeks. Importantly, Kim et al. found that indirect costs, such as parental work loss, accounted for more than half of total societal costs, whereas our study captured only direct medical costs, including inpatient, outpatient, emergency room, and pharmacy expenses. The absence of indirect cost data in our analysis likely underestimates the true societal economic burden of nRDS, as families of preterm infants with ongoing respiratory morbidity face substantial productivity losses and caregiving demands not reflected in healthcare claims [12]. Our results add to the existing literature by providing real-world evidence of long-term costs beyond the birth hospitalization in a large US cohort, an area where data have been limited. Broader literature shows that survivors of preterm nRDS frequently exhibit persistent respiratory symptoms, neurodevelopmental delays, and abnormal lung function into childhood, irrespective of initial respiratory management [3, 17, 18]. The persistent high costs observed in our cohort, particularly among the most premature infants, underscore the need for strategies that not only optimize initial neonatal management but also address long-term respiratory health through preventive care, early intervention for respiratory infections, and coordinated follow-up to reduce costly hospitalizations [5].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeveral limitations should be acknowledged. As with all observational analyses using administrative claims data, there is potential for misclassification of exposures and outcomes, and clinical details such as ventilation parameters and surfactant dosing were unavailable. The databases are open-source, potentially resulting in incomplete capture of healthcare encounters outside participating facilities/providers/pharmacies. The study period overlapped with the COVID-19 pandemic, which may have impacted healthcare utilization and costs. Important confounders were unavailable, including surfactant timing, maternal risk factors, RSV prophylaxis, breastfeeding duration, and social determinants of health.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAlthough adverse short and long-term respiratory outcomes in preterm children after NICU discharge are well known, there are only limited data on specific diagnoses, and quantification of HCRU and economic costs beyond the NICU course. Based on rigorous analyses of an extensive database, we report new insights into the long-term clinical and economic burdens in a large real-world cohort of infants with nRDS. Regardless of GA and even in only rare the absence of a formal diagnosis of BPD at 36 weeks postmenstrual age (PMA), preterm newborns with nRDS face ongoing risk for respiratory disease and the need for frequent use of health care resources throughout childhood. Interestingly, incidence rates for specific respiratory conditions (chronic bronchitis, URTI, LRTI, bronchiolitis, and cough) were higher among moderate- and late-preterm infants than among those with lower GA While outpatient pharmacy and ER visits were similar across GA subgroups, physician office visits were higher in moderate and late preterm infants. These findings underscore the need for structured long-term follow-up programs and preventive strategies across all GA, independent of the traditional diagnosis of BPD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBPD: Bronchopulmonary dysplasia\u003c/p\u003e\n\u003cp\u003eCCR: Cost charge ratio\u003c/p\u003e\n\u003cp\u003eCDM: Hospital charge data master\u003c/p\u003e\n\u003cp\u003eCE: Continuous enrollment\u003c/p\u003e\n\u003cp\u003eCFR: Code of Federal Regulations\u003c/p\u003e\n\u003cp\u003eCI: Confidence interval\u003c/p\u003e\n\u003cp\u003eCOVID-19: Coronavirus disease-19\u003c/p\u003e\n\u003cp\u003eCPAP: Continuous positive airway pressure\u003c/p\u003e\n\u003cp\u003eCPT: Current Procedural Terminology\u003c/p\u003e\n\u003cp\u003eDx: Professional fee claims\u003c/p\u003e\n\u003cp\u003eECG: Electrocardiogram\u003c/p\u003e\n\u003cp\u003eER: Emergency room\u003c/p\u003e\n\u003cp\u003eFEV₁/FVC: Forced expiratory volume in 1 second/forced vital capacity\u003c/p\u003e\n\u003cp\u003eHCPCS: Healthcare Common Procedure Coding System\u003c/p\u003e\n\u003cp\u003eHCRU: Healthcare resource utilization\u003c/p\u003e\n\u003cp\u003eHIPAA: Health Insurance Portability and Accountability Act\u003c/p\u003e\n\u003cp\u003eICD-10-CM: International Classification of Diseases, tenth revision, Clinical Modification\u003c/p\u003e\n\u003cp\u003eICD-9-CM: International Classification of Diseases, ninth revision, Clinical Modification\u003c/p\u003e\n\u003cp\u003eICS: Inhaled corticosteroids\u003c/p\u003e\n\u003cp\u003eICU: Intensive care unit\u003c/p\u003e\n\u003cp\u003eIUGR: Intrauterine growth restriction\u003c/p\u003e\n\u003cp\u003eLOS: Length of stay\u003c/p\u003e\n\u003cp\u003eLRTI: Lower respiratory tract infection\u003c/p\u003e\n\u003cp\u003eLRx: Longitudinal prescription claims\u003c/p\u003e\n\u003cp\u003eMV: Mechanical ventilation\u003c/p\u003e\n\u003cp\u003eNDC: National Drug Code\u003c/p\u003e\n\u003cp\u003eNICU: Neonatal intensive care unit\u003c/p\u003e\n\u003cp\u003enRDS: Neonatal respiratory distress syndrome\u003c/p\u003e\n\u003cp\u003eOR: Odds ratio\u003c/p\u003e\n\u003cp\u003eOSA: Obstructive sleep apnea\u003c/p\u003e\n\u003cp\u003ePICU: Pediatric intensive care unit\u003c/p\u003e\n\u003cp\u003ePPPM: Per patient per month\u003c/p\u003e\n\u003cp\u003eSD: Standard deviation\u003c/p\u003e\n\u003cp\u003eSGA: Small for gestational age\u003c/p\u003e\n\u003cp\u003eURTI: Upper respiratory tract infection\u003c/p\u003e\n\u003cp\u003eUS: United States\u003c/p\u003e\n\u003cp\u003eUSD: United States dollar\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVisual abstract\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: CPAP, Continuous positive airway pressure; GA, gestational age; HCRU, Healthcare resource utilization; LRTI, lower respiratory tract infection; PPPM, Per patient per month; nRDS, neonatal respiratory distress syndrome; URTI, upper respiratory tract infection.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis observational study was exempt from Institutional Review Board (IRB) informed consent stipulations. The researchers accessed a de-identified limited dataset, and only summary statistics were reported. This work is fully compliant with all relevant provisions of the US Federal Health Insurance Portability and Accountability Act of 1996 (HIPAA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This study does not contain data from any individual person.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIQVIA analysed the data on behalf of Chiesi and provided summarized insights; however, because of data confidentiality, the supporting raw data cannot be made publicly available. IQVIA has direct access to the data and clarification could be provided upon reasonable request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare the following: SA is an employee at the Department of Pediatrics at University of Colorado School of Medicine and Children\u0026rsquo;s Hospital Colorado, Aurora, CO, USA and also serves as an advisor to Chiesi. AC, NM, LF, TM are employees of Chiesi Farmaceutici S.p.A., Via Palermo, 26/A, 43122, Parma, Italy. XS and JM are employees of Chiesi USA, Inc.175 Regency Woods Place, Suite 600, Cary, NC, USA. MD, JT, SM were employees of IQVIA, Inc, Falls Church, VA, USA* whose activities on research projects are funded by various pharmaceutical/biotech/medical device companies\u003c/p\u003e\n\u003cp\u003e*At the time of the conduct of this study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was sponsored and funded by Chiesi.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors contributed substantially to the conceptualization and design of this study. Authors MD, JT, and SM, were employees of IQVIA, Inc. at the time of this study, engaged in data acquisition and analysis. All the authors contributed to the study design, interpretation of the results, critically reviewed the manuscript and approved the final manuscript and take responsibility for its content.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Abhilasha Verma, PhD, for providing medical writing assistance on this manuscript in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFraser J, Walls M, McGuire W. Respiratory complications of preterm birth. \u003cem\u003eBMJ. \u003c/em\u003e2004;329(7472):962-965.\u003c/li\u003e\n\u003cli\u003eHermansen CL, Mahajan A: Newborn respiratory distress. \u003cem\u003eAm Fam Physician. \u003c/em\u003e2015;92(11):994-1002.\u003c/li\u003e\n\u003cli\u003eMagni T, Ragni C, Pelizzi N, et al. Health economic studies of surfactant replacement therapy in neonates with respiratory distress syndrome: A systematic literature review. \u003cem\u003ePharmacoecon Open. \u003c/em\u003e2023;7(3):359-371.\u003c/li\u003e\n\u003cli\u003eHannan KE, Hwang SS, Bourque SL. Readmissions among NICU graduates: Who, when and why? \u003cem\u003eSemin Perinatol. \u003c/em\u003e2020;44(4):151245.\u003c/li\u003e\n\u003cli\u003eWalicka-Serzysko K, Postek M, Borawska-Kowalczyk U, et al. Long-term pulmonary outcomes of young adults born prematurely: a Polish prospective cohort study PREMATURITAS 20. \u003cem\u003eBMC Pulm. Med. \u003c/em\u003e2024;24(1):126.\u003c/li\u003e\n\u003cli\u003eDargaville PA, Kamlin COF, Orsini F, et al. Two-year outcomes after minimally invasive surfactant therapy in preterm infants: Follow-up of the OPTIMIST-A randomized clinical trial. \u003cem\u003eJAMA. \u003c/em\u003e2023;330(11):1054-1063.\u003c/li\u003e\n\u003cli\u003eHascoet JM, Deforge H, Demoulin S, et al. Outcomes at 7 Years of age of former very preterm neonates with repeated surfactant treatment for prolonged respiratory distress in the neonatal period. \u003cem\u003eJ Clin Med. \u003c/em\u003e2023;12(19):6220.\u003c/li\u003e\n\u003cli\u003eCheah IGS. Economic assessment of neonatal intensive care. \u003cem\u003eTransl Pediatr. \u003c/em\u003e2019;8(3):246-256.\u003c/li\u003e\n\u003cli\u003eNeil N, Sullivan SD, Lessler DS. The economics of treatment for infants with respiratory distress syndrome. \u003cem\u003eMedical Decis Making. \u003c/em\u003e1998;18(1):44-51.\u003c/li\u003e\n\u003cli\u003ePandya S, Baser O, Wan GJ, et al. The burden of hypoxic respiratory failure in preterm and term/near-term infants in the United States 2011-2015. \u003cem\u003eJ Health Econ Outcomes Res. \u003c/em\u003e2019;6(3):130-141.\u003c/li\u003e\n\u003cli\u003eWang N, Lu K-Y, Jiang S-Y, et al. The current clinical landscape of neonatal respiratory failure in Jiangsu Province of China: patient demographics, NICU treatment interventions, and patient outcomes. \u003cem\u003eBMC Pediatr. \u003c/em\u003e2024;24(1):272.\u003c/li\u003e\n\u003cli\u003eKim SW, Andronis L, Sepp\u0026auml;nen AV, et al. Economic costs at age five associated with very preterm birth: multinational European cohort study. \u003cem\u003ePediatr Res. \u003c/em\u003e2022; 92(3):700-711.\u003c/li\u003e\n\u003cli\u003eHuse D RP, Vasey J. Expanding the evidence base in outcomes research: linking electronic medical records and claims data. \u003cem\u003eISPOR Connect. \u003c/em\u003e2013;19(3):5-7.\u003c/li\u003e\n\u003cli\u003ePelletier EM, Shim B, Goodman S, et al. Epidemiology and economic burden of brain metastases among patients with primary breast cancer: results from a US claims data analysis. \u003cem\u003eBreast Cancer Res Treat. \u003c/em\u003e2008;108(2):297-305.\u003c/li\u003e\n\u003cli\u003eWang XR, Du J, Zhang SS, et al. Preterm birth and detection of common respiratory pathogens among pediatric pneumonia. \u003cem\u003eiScience. \u003c/em\u003e2023; 26(9):107488.\u003c/li\u003e\n\u003cli\u003eLeps C, Carson C, Quigley MA. Gestational age at birth and wheezing trajectories at 3-11 years. \u003cem\u003eArch Dis Child. \u003c/em\u003e2018;103(12):1138-1144.\u003c/li\u003e\n\u003cli\u003eMarlow N, Hennessy EM, Bracewell MA, et al. Motor and executive function at 6 years of age after extremely preterm birth. \u003cem\u003ePediatrics. \u003c/em\u003e2007;120(4):793-804.\u003c/li\u003e\n\u003cli\u003eTelford K, Waters L, Vyas H, et al. Respiratory outcome in late childhood after neonatal continuous negative pressure ventilation. \u003cem\u003eArch Dis Child Fetal Neonatal Ed. \u003c/em\u003e2007;92(1):F19-24.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Neonatal respiratory distress syndrome (nRDS), preterm infants, respiratory morbidity, healthcare resource utilization (HCRU)","lastPublishedDoi":"10.21203/rs.3.rs-9141627/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9141627/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eNeonatal respiratory distress syndrome (nRDS) is a leading cause of morbidity among preterm infants. While short-term outcomes during birth hospitalization are well described, real-world evidence on long-term respiratory outcomes, healthcare resource utilization (HCRU), and economic burden following discharge remains limited.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective observational cohort study used linked IQVIA US Hospital Charge Data Master, Professional Fee Claims, and Longitudinal Prescription Claims databases from October 2015 to March 2024. Preterm infants (\u0026lt;\u0026thinsp;37 weeks\u0026rsquo; gestation) diagnosed with nRDS between October 1, 2015, and March 31, 2022, and treated with surfactant or continuous positive airway pressure during birth hospitalization were included. Follow-up began at discharge and continued for \u0026ge;\u0026thinsp;3 months. The outcomes included respiratory diseases during follow-up, respiratory-related HCRU, and costs standardized to 2023 USD per patient per month (PPPM). The results were reported overall and by gestational age (GA): very/extreme (\u0026lt;\u0026thinsp;32 weeks), moderate (32 to \u0026lt;\u0026thinsp;34 weeks), and late preterm (34 to \u0026lt;\u0026thinsp;37 weeks).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe cohort comprised 7,532 preterm infants with nRDS; 43.6% were late preterm, 23.7% moderate preterm, and 32.3% very/extreme preterm (median follow-up: 1 year). Respiratory morbidity persisted across all GA categories: upper respiratory tract infection (URTI; 49.6%), cough (32.4%), lower respiratory tract infection (LRTI; 31.5%), and bronchiolitis (28.6%). Acute respiratory conditions, including URTI, LRTI, bronchiolitis, and cough, were more frequent among moderate and late preterm infants, whereas asthma, pulmonary hypertension, obstructive sleep apnea, pneumonia, and wheeze occurred most often in very/extreme preterm infants. Respiratory-related HCRU was common, including outpatient pharmacy use (62.2%), physician office visits (40.3%), and emergency room visits (30.8%), with similar patterns across GA subgroups. Mean respiratory-related costs were \u003cspan\u003e$\u003c/span\u003e347 PPPM overall, driven primarily by inpatient care (77.5%). Costs increased markedly with lower GA, averaging \u003cspan\u003e$\u003c/span\u003e684 PPPM in very/extreme preterm infants versus \u003cspan\u003e$\u003c/span\u003e164 PPPM in late preterm infants.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePreterm infants with nRDS experience substantial long-term respiratory morbidity and healthcare costs following discharge, even in the absence of BPD. Persistent burden across all GAs highlights the need for structured long-term respiratory follow-up and preventive strategies that extend beyond the neonatal period.\u003c/p\u003e","manuscriptTitle":"Long-term clinical and economic outcomes post birth hospitalization in preterm infants with neonatal respiratory distress syndrome: A real-world retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-07 16:56:12","doi":"10.21203/rs.3.rs-9141627/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-09T14:21:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"275753852831798557645735234592408768000","date":"2026-05-04T00:39:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-01T20:40:15+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-23T05:21:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-23T02:18:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-23T02:18:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2026-03-16T20:08:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a429d6b4-1d43-45db-b48b-85d043048c57","owner":[],"postedDate":"April 7th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-09T14:21:15+00:00","index":51,"fulltext":""},{"type":"reviewerAgreed","content":"275753852831798557645735234592408768000","date":"2026-05-04T00:39:21+00:00","index":48,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T16:56:12+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-07 16:56:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9141627","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9141627","identity":"rs-9141627","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}