Background: Necrotizing enterocolitis (NEC) is the leading cause of death among preterm infants born at < 30 weeks’ gestation. The incidence of NEC is reduced when infants are fed human milk. However, in many neonatal intensive care units (NICUs), it is standard practice to freeze and/or pasteurize human milk, which deactivates bioactive components that may offer additional protective benefits. Indeed, our pilot study showed that one feed of fresh mother’s own milk per day was safe, feasible, and can reduce morbidity in preterm infants. To further evaluate the benefits of fresh human milk in the NICU, a randomized controlled trial is needed.Methods: Our prospective multicenter, double-blinded, randomized, controlled trial will include infants born at < 30 weeks’ gestation and admitted to one of 29 tertiary NICUs in China. Infants in the intervention (fresh human milk) group (n = 1549) will receive at least two feeds of fresh human milk (i.e., within 4 h of expression) per day from the time of enrollment until 32 weeks’ corrected age or discharge to home. Infants in the control group (n = 1549) will receive previously frozen human milk following the current standard protocols. Following informed consent, enrolled infants will be randomly allocated to the control or fresh human milk groups. The primary outcome is the composite outcome mortality or NEC ≥ stage 2 at 32 weeks’ corrected age, and the secondary outcomes are mortality, NEC ≥ stage 2, NEC needing surgery, late-onset sepsis, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), weight gain, change in weight, increase in length, increase in head circumference, time to full enteral feeds, and finally, the number and type of critical incident reports, including feeding errors.Discussion: Our double-blinded, randomized, controlled trial aims to examine whether fresh human milk can improve infant outcomes. The results of this study will impact both Chinese and international medical practice and feeding policy for preterm infants. In addition, data from our study will inform changes in health policy in NICUs across China, such that mothers are encouraged to enter the NICU and express fresh milk for their infants.Trial registration: Chinese Clinical Trial Registry; #ChiCTR1900020577; registered January 1, 2019;http://www.chictr.org.cn/showprojen.aspx?proj=34276

Objective: Nutritional deficiency soon after birth is a risk factor of chronic lung disease (bronchopulmonary dysplasia, BPD). Afflicted infants are further prone to inadequate growth during hospitalization (extrauterine growth restriction, EUGR). This multi-center retrospective study investigated risk factors of EUGR, specifically in very preterm infants with BPD. Method: Data of infants with BPD who were born less than 32 weeks gestation (n = 1010) were collected from 7 regions of China. All infants were non-small for gestational age at birth. Infants were characterized as EUGR or non-EUGR at 36 weeks gestation or discharge, or stratified by gestational age or birthweight. Logistic regression analysis was applied. Results: In 65.5% of the population, the BPD was mild. Infants with severe BPD (8.3%) had the highest rate of EUGR (72.6%, P < 0.001). Groups stratified by gestational age did not differ in rates of EUGR, but the birthweight of the EUGR group was significantly lower than that of the non-EUGR (P < 0.001). Birthweights of < 1000, 1000–1499, and ≥ 1500 g showed EUGR rates of 65.9%, 43.4%, and 23.8%, respectively (P < 0.001). Overall, the independent risk factors of EUGR were: moderate-to-severe BPD, gestational hypertension, cesarean section, cumulative fasting time, time required to achieve 110 kcal/kg/d, and hemodynamically significant patent ductus arteriosus (hsPDA). Conclusion: In very preterm infants with BPD, the lower the birthweight or the more severe the BPD, the greater the risk of EUGR. In those with hsPDA, or moderate-to-severe BPD, it is especially important to prevent EUGR through perinatal management, enteral nutrition, and nutritional strategies.

Objective: To analyse early risk factors for mortality in preterm infants treated with inhaled nitric oxide (iNO) in China. Design: A retrospective observational case-control study. Setting: 8 tertiary hospitals in 5 regions of China. Patients: 726 preterm infants treated with iNO for hypoxic respiratory failure or persistent pulmonary hypertension of newborns. Interventions: None. Measurements: The primary outcome was survival status at discharge. Main results: (1) The mortality rate was 27.1% (197/726), and which significantly reduced with increasing gestational age (GA) and birth weight. (2) Compared with the survival group, the death group had significantly greater use of assisted reproductive technology, higher multiple pregnancy rates and lower caesarean section rates. Infants in the death group had a significantly higher incidence of small for GA (SGA), Apgar score ≤3 at 1 min after birth, pneumorrhagia, sepsis and shock. In the death group, the utilisation rate of a pulmonary surfactant (PS) was significantly lower, whereas the oxygenation index (OI) before iNO treatment was significantly higher. The maximum dose of iNO in the death group was significantly higher than that in the survival group. (3) The Cox proportional hazard model showed that SGA (HR 1.800, 95% CI (1.113 to 2.911)), sepsis (HR 1.488, 95% CI (1.093 to 2.027)), shock (HR 1.473, 95% CI (1.033 to 2.100)), OI before iNO treatment (HR 1.016, 95% CI (1.006 to 1.026)) and the maximum dose of iNO treatment (HR 1.070, 95% CI (1.035 to 1.105)) were risk factors for death in preterm infants treated with iNO. Furthermore, GA (HR 0.876, 95% CI (0.831 to 0.924)), PS (HR 0.433, 95% CI (0.296 to 0.633)) and a higher initial dose of iNO (HR 0.926, 95% CI (0.891 to 0.962)) were identified as protective factors. (4) Stratified analysis and sensitivity analysis determined the stability of the core results in preterm infants with GA between 28 and 36 ⁺⁶ weeks. Conclusion: Premature infants treated with iNO had a high mortality rate. SGA, sepsis, shock and higher OI before iNO treatment increased the mortality risk in infants with GA between 28 and 36 ⁺⁶ weeks. A higher GA the use of PS, and a higher initial iNO dose could improve the survival outcome of these babies. Trial registration number: The study was registered in the Chinese Clinical Trials Registry ( http://www.chictr.org.cn ; registration number: ChiCTR2200066935).

Objective: To investigate the use of inhaled nitric oxide (iNO) in hospitalized preterm infants in China over 10 years and its clinical outcomes. Methods: A total of 616 premature infants who were administered iNO in the Neonatology Departments of 5 Class A tertiary hospitals in China for ten years from January 2013 to December 2022 were included retrospectively. Based on their enrollment periods, the patients were divided into two groups: Group 1 from January 2013 to December 2017 and Group 2 from January 2018 to December 2022, respectively. The perinatal characteristics, short‐term clinical outcomes, and mortality rates were compared between these two groups. Results: The utilization of iNO in preterm infants grew annually over the past10 years; the utilization of iNO in Group 2 infants increased approximately one‐fold when compared with Group 1 (1.52% vs. 0.80%, p < .001), and the increase was greater in gestational age (GA) < 34 weeks compared with 34–36 weeks preterm infants. Moreover, the iNO usage in Group 1 infants with GA < 34 weeks increased from 1.14% to 2.46% and 0.60% to 0.99% in 34–36 weeks preterm infants ( p < .001) in Group 2, respectively. Apart from a smaller GA (32.9 w vs. 33.5 w, p < .001) and birth weight (BW, 1900 g vs. 2141 g, p < .001), the initial [14 parts per million (ppm) versus 10 ppm, p < .001] and maximum (15 ppm vs. 10 ppm, p < .001) doses of Group 2 were larger; however, their recent clinical outcomes did not improve with increasing iNO utilization ( p > .05)as compared to Group 1, respectively. Although the overall iNO preterm mortality rates over the past 10 years were 25.8%, the mortality rates for preterm infants at 34–36 weeks were significantly lower than for preterm infants at GA < 34 weeks (15.4% vs. 33.8%, p < .001). Nonetheless, no improvement in mortality was observed in Group 2 preterm infants with GA < 34 weeks for the past 5 years when compared with Group 1 (32.9% vs. 35.8%, p > .05) infants, and significantly lower mortality rates were noticed in preterm infants with 34–36 weeks (11.2% vs. 22.7%, p < .001). Patients with hypoxic respiratory failure (HRF) or persistent pulmonary hypertension of the newborn (PPHN) iNO preterm infants did not show lower mortality rates with the increase of iNO use rate ( p > .05). The overall mortality rates of preterm PPHN infants with iNO were lower than that of HRF (20.2% vs. 36.5%, p < .001), while the mortality rates of Group 2 preterm PPHN infants with iNO significantly lower than that of HRF (17.7% vs 36.0%, p < .001). Conclusion: The iNO has been extensively used in Chinese preterm infants over the past 10 years, this increase was more significant in preterm infants with GA < 34 weeks. Moreover, preterm infants using iNO have lower GA and BW, larger initial and maximum doses, and more aggressive strategies in the last past 5 years. Although iNO use in preterm infants with GA of 34–36 weeks has significantly reduced mortality, mortality rates and short‐term clinical outcomes of iNO in preterm infants <34 weeks of GA has no obvious improvement. Further studies are required to investigate the efficacy and safety of iNO in preterm infants <34 weeks of GA.

Background: Bronchopulmonary Dysplasia (BPD) is a chronic lung disease affecting preterm infants, with limited prevention and treatment options. Inhaled Nitric Oxide (iNO) is sometimes used to treat Persistent Pulmonary Hypertension of the Newborn (PPHN) and Hypoxemic Respiratory Failure (HRF), and its impact on BPD development remains debated.Objective: To assess whether iNO-related factors are potential contributors to the development of BPD Grade Ⅱ-Ⅲ in very premature infants (VPI) diagnosed with PPHN or HRF at birth using Propensity Score Matching (PSM).Methods: We conducted a retrospective cohort study of infants born at 22–32 weeks gestation with PPHN or HRF, treated with iNO for over 3 h. PSM matched groups by gestational age, birth weight, and gender, etc. Multivariate logistic regression evaluated the association between iNO treatment and BPD outcomes to identify influencing factors, while Restricted Cubic Spline (RCS) and mediation analysis examined iNO dose effects and potential mediators like mechanical ventilation time and oxygenation index (OI).Results: A higher initial iNO dose was significantly associated with a reduced risk of BPD Grade Ⅱ-Ⅲ (adjusted OR = 0.68, 95% CI: 0.52–0.89, p &lt; 0.01). Additionally, administration of iNO within the first 7 days of life was identified as an important influencing factor No significant mediation effects were observed for factors such as mechanical ventilation time and OI.Conclusion: A higher initial iNO dose within the first 7 days was associated with a reduced risk of BPD Grade Ⅱ-Ⅲ in VPI with PPHN or HRF.