Receptor-interacting protein kinase-3 (RIPK3): a new biomarker for necrotising enterocolitis in preterm infants.

OBJECTIVE: This study aimed to evaluate the role of receptor-interacting protein kinase-3 (RIPK3) in the diagnosis, estimation of disease severity, and prognosis of premature infants with necrotising enterocolitis (NEC). METHODS: RIPK3, lactic acid (LA), and C-reactive protein (CRP) levels were measured in the peripheral blood of 108 premature infants between 2019 and 2023, including 24 with stage II NEC, 18 with stage III NEC and 66 controls. Diagnostic values of the indicators for NEC were evaluated via receiver operating characteristic (ROC) curve analysis. RESULTS: Plasma RIPK3 and LA levels upon NEC suspicion in neonates with stage III NEC were 32.37 ± 16.20 ng/mL. The ROC curve for the combination of RIPK3, LA, CRP for NEC diagnosis were 0.925. The time to full enteral feeding (FEFt) after recovery from NEC was different between two expression groups of plasma RIPK3 (RIPK3 < 20.06 ng/mL and RIPK3 ≥ 20.06 ng/mL). CONCLUSION: Plasma RIPK3 can be used as a promising marker for the diagnosis and estimation of disease severity of premature infants with NEC and for the guidance on proper feeding strategies after recovery from NEC.

Delineating morbidity patterns in preterm infants at near-term age using a data-driven approach.

BACKGROUND: Long-term survival after premature birth is significantly determined by development of morbidities, primarily affecting the cardio-respiratory or central nervous system. Existing studies are limited to pairwise morbidity associations, thereby lacking a holistic understanding of morbidity co-occurrence and respective risk profiles. METHODS: Our study, for the first time, aimed at delineating and characterizing morbidity profiles at near-term age and investigated the most prevalent morbidities in preterm infants: bronchopulmonary dysplasia (BPD), pulmonary hypertension (PH), mild cardiac defects, perinatal brain pathology and retinopathy of prematurity (ROP). For analysis, we employed two independent, prospective cohorts, comprising a total of 530 very preterm infants: AIRR ("Attention to Infants at Respiratory Risks") and NEuroSIS ("Neonatal European Study of Inhaled Steroids"). Using a data-driven strategy, we successfully characterized morbidity profiles of preterm infants in a stepwise approach and (1) quantified pairwise morbidity correlations, (2) assessed the discriminatory power of BPD (complemented by imaging-based structural and functional lung phenotyping) in relation to these morbidities, (3) investigated collective co-occurrence patterns, and (4) identified infant subgroups who share similar morbidity profiles using machine learning techniques. RESULTS: First, we showed that, in line with pathophysiologic understanding, BPD and ROP have the highest pairwise correlation, followed by BPD and PH as well as BPD and mild cardiac defects. Second, we revealed that BPD exhibits only limited capacity in discriminating morbidity occurrence, despite its prevalence and clinical indication as a driver of comorbidities. Further, we demonstrated that structural and functional lung phenotyping did not exhibit higher association with morbidity severity than BPD. Lastly, we identified patient clusters that share similar morbidity patterns using machine learning in AIRR (n=6 clusters) and NEuroSIS (n=8 clusters). CONCLUSIONS: By capturing correlations as well as more complex morbidity relations, we provided a comprehensive characterization of morbidity profiles at discharge, linked to shared disease pathophysiology. Future studies could benefit from identifying risk profiles to thereby develop personalized monitoring strategies. TRIAL REGISTRATION: AIRR: DRKS.de, DRKS00004600, 28/01/2013. NEuroSIS: ClinicalTrials.gov, NCT01035190, 18/12/2009.

[Discharge of infants with complex care needs from the neonatal intensive care unit : Ensuring continued inpatient care via the Bunter Kreis aftercare model]. / Entlassung von Kindern mit komplexen Versorgungsbedarfen von der neonatologischen Intensivstation : Sicherung der stationären Anschlussversorgung durch das Nachsorgemodell des Bunten Kreises e. V.

After discharge of premature infants with complex care needs from the neonatal intensive care unit, a care gap arises due to the transition from inpatient to outpatient care. Consequences can be rehospitalization, revolving door effects, and high costs. Therefore, following hospitalization or inpatient rehabilitation, the patient is intended to transition to sociomedical aftercare. The legal basis for this is formed by § 43 paragraph 2 of the Fifth Book of the German Social Code (SGB V). Over 80 aftercare institutions in Germany work according to the model of the Bunter Kreis. The comprehensive concept describes possibilities for networking which exceed the services provided by sociomedical aftercare. Simultaneously, depending on their stage of development, young adults can receive aftercare according to this model up to their 27th year of life. The interdisciplinary team at the Bunter Kreis comprises nurses, social workers, social education workers, psychologists, and specialist physicians. The largest group of supported persons, with 6000-8000 children per year, is comprised of premature and at-risk babies as well as multiple births, followed by 3000-5000 children with neurologic and syndromic diseases. Other common diseases are metabolic diseases, epilepsy, and diabetes, as well as children after trauma and with rare diseases. Overall, the various diseases sum up to around 20 clinical pictures. The current article presents the Bunter Kreis aftercare process based on case examples.

Nutritional support during the first week for infants with bronchopulmonary dysplasia and respiratory distress: a multicenter cohort study in China.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major complication affecting the survival rate and long-term outcomes of preterm infants. A large, prospective, multicenter cohort study was conducted to evaluate early nutritional support during the first week of life for preterm infants with a gestational age < 32 weeks and to verify nutritional risk factors related to BPD development. METHODS: A prospective multicenter cohort study of very preterm infants was conducted in 40 tertiary neonatal intensive care units across mainland China between January 1, 2020, and December 31, 2021. Preterm infants who were born at a gestational age < 32 weeks, < 72 h after birth and had a respiratory score > 4 were enrolled. Antenatal and postnatal information focusing on nutritional parameters was collected through medical systems. Statistical analyses were also performed to identify BPD risk factors. RESULTS: The primary outcomes were BPD and severity at 36 weeks postmenstrual age. A total of 1410 preterm infants were enrolled in this study. After applying the exclusion criteria, the remaining 1286 infants were included in this analysis; 614 (47.7%) infants were in the BPD group, and 672 (52.3%) were in the non-BPD group. In multivariate logistic regression model, the following six factors were identified of BPD: birth weight (OR 0.99, 95% CI 0.99-0.99; p = 0.039), day of full enteral nutrition (OR 1.03, 95% CI 1.02-1.04; p < 0.001), parenteral protein > 3.5 g/kg/d during the first week (OR 1.65, 95% CI 1.25-2.17; p < 0.001), feeding type (formula: OR 3.48, 95% CI 2.21-5.49; p < 0.001, mixed feed: OR 1.92, 95% CI 1.36-2.70; p < 0.001; breast milk as reference), hsPDA (OR 1.98, 95% CI 1.44-2.73; p < 0.001), and EUGR ats 36 weeks (OR 1.40, 95% CI 1.02-1.91; p = 0.035). CONCLUSIONS: A longer duration to achieve full enteral nutrition in very preterm infants was associated with increased BPD development. Breastfeeding was demonstrated to have a protective effect against BPD. Early and rapidly progressive enteral nutrition and breastfeeding should be promoted in very preterm infants. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR2000030125 on 24/02/2020) and in www.ncrcch.org (No. ISRCTN84167642 on 25/02/2020).

Effects of bradycardia, hypoxemia and early intubation on bronchopulmonary dysplasia in very preterm infants: An observational study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common pulmonary complication in preterm infants. OBJECTIVES: The study aimed to explore the effects of bradycardia, hypoxemia, and early intubation on BPD in very preterm infants. METHODS: This is a prospective observational cohort study. Preterm infants with a mean gestational age of 28.67 weeks were recruited from two level III neonatal intensive care units (NICUs) in Taiwan. Continuous electrocardiography was used to monitor heart rates and oxygen saturation (SpO2). Infants were monitored for heart rates of <100 beats per minute and SpO2 levels of <90 % lasting for 30 s. Generalized estimating equations were used to analyze the effects of bradycardia, hypoxemia, and early intubation on BPD in very preterm infants. Model fit was visually assessed using receiver operating characteristic curve analysis. RESULTS: Bradycardia, hypoxemia, and early intubation significantly increased the odds of BPD among the preterm infants (N = 39) during NICU stay; the odds ratios for bradycardia, hypoxemia, and early intubation for BPD versus non-BPD were 1.058, 1.013, and 29.631, respectively (all p < 0.05). A model combining bradycardia, hypoxemia, and early intubation accurately predicted BPD development (area under the curve = 0.919). CONCLUSIONS: Bradycardia, hypoxemia, and early intubation significantly increased the odds of BPD among very preterm infants during NICU stay. The model combining bradycardia, hypoxemia, and early intubation accurately predicted BPD development.

Post-ligation cardiac syndrome after surgical versus transcatheter closure of patent ductus arteriosus in low body weight premature infants: a multicenter retrospective cohort study.

Transcatheter patent ductus arteriosus (PDA) closure is a safe and effective alternative to surgical ligation in low-body-weight infants. Post-ligation cardiac syndrome (PLCS) is defined as severe hemodynamic and respiratory collapse within 24 h of PDA closure, requiring initiation or an increase of an inotropic agent by > 20% of preligation dosing and an absolute increase of at least 20% in ventilation parameters compared with the preoperative value. Whilst PLCS is routinely observed after surgery, its incidence remains poorly described following transcatheter closure. This study aimed to compare the incidence of PLCS after surgical versus transcatheter closure of PDA in low-body-weight premature infants. Propensity scores were used to compare surgical (N = 78) and transcatheter (N = 76) groups of preterm infants who underwent PDA closure at a procedural weight less than 2000 g in two tertiary institutions between 2009 and 2021. The primary outcome was the incidence of PLCS. Secondary outcomes included overall mortality before discharge, risk factors for PLCS, and post-procedural complications. Procedural success was 100% in both groups. After matching, transcatheter group experienced no PLCS vs 15% in the surgical group (p = 0.012). Furthermore, overall mortality (2% vs 17%; p = 0.03) and major complications (2% vs 23%; p = 0.002) were higher in the surgical group. Surgery (100% vs 47%; p < 0.01), gestation age (25 ± 1 vs 26 ± 2 weeks, p < 0.05) and inotropic support before closure (90% vs 29%; p < 0.001) were associated with PLCS occurrence.          Conclusion: Transcatheter PDA closure may be equally effective but safer than surgical PDA closure in low-body-weight premature infants. What is Known: • Post-ligation cardiac syndrome is a serious and common complication of surgical closure of the ductus arteriosus in preterm infants. • Transcatheter closure of preterm ductus arteriosus is a safe and effective technique that is becoming more and more common worldwide. What is New: • Device closure is safer than surgical ligation for patent ductus arteriosus closure in preterm infants and may be the first-line non-pharmacological therapeutic option in this indication in experienced teams. • Our findings should encourage neonatologists and pediatric cardiologists to start and/or strengthen a durable interventional program for transcatheter PDA closure in premature infants.

Periventricular hemorrhagic infarction in preterm neonates: Etiology and time of development.

BACKGROUND: To find the obstetrical and delivery associated risk factors of antenatal and postnatal grade III intraventricular hemorrhage (IVH) or periventricular hemorrhagic infarction (PVHI) in preterm neonates. METHODS: A retrospective study of obstetric and delivery associated risk factors included neonates (<35 gestational weeks) with severe IVH/PVHI (n = 120) and a prospectively collected control group (n = 50). The children were divided into: (1) antenatal onset group (n = 27) with insult visible on cerebral ultrasonography within the first 12 hours of birth or periventricular cystic changes visible in PVHI within the first 3 days; (2) neonatal onset group (n = 70) with insult diagnosed after initial normal findings or I-II grade IVH, and (3) unknown time-onset group (n = 23) with insult visible at > 12 h of age. RESULTS: The mothers of the antenatal onset group had significantly more bacterial infections before delivery compared to the neonatal onset group: 20/27 (74.1%) versus 23/69 (33.3%), (odds ratio (OR) 5.7 [95% confidence interval 2.1-16]; p = 0.0008) or compared to the control group (11/50 (22%); OR 11 [2.8-42]; p = 0.0005). Placental histology revealed chorioamnionitis more often in the antenatal compared to the neonatal onset group (14/21 (66.7%) versus 16/42 (38.1%), respectively; OR 3.7 [1.18-11]; p = 0.025). Neonates with neonatal development of severe IVH/PVHI had significantly more complications during delivery or intensive care. CONCLUSIONS: Bacterial infection during pregnancy is an important risk factor for development of antenatal onset severe IVH or PVHI. In neonates born to mothers with severe bacterial infection during pregnancy, cerebral ultrasonography is indicated for early detection of severe IVH or PVHI.

[Establishment and efficiency test of a clinical prediction model of bronchopulmonary dysplasia associated pulmonary hypertension in very premature infants].

Objective: To develop a risk prediction model for identifying bronchopulmonary dysplasia (BPD) associated pulmonary hypertension (PH) in very premature infants. Methods: This was a retrospective cohort study. The clinical data of 626 very premature infants whose gestational age <32 weeks and who suffered from BPD were collected from October 1st, 2015 to December 31st, 2021 of the Seventh Medical Center of the People's Liberation Army General Hospital as a modeling set. The clinical data of 229 very premature infants with BPD of Hunan Children's Hospital from January 1 st, 2020 to December 31st, 2021 were collected as a validation set for external verification. The very premature infants with BPD were divided into PH group and non PH group based on the echocardiogram after 36 weeks' corrected age in the modeling set and validation set, respectively. Univariate analysis was used to compare the basic clinical characteristics between groups, and collinearity exclusion was carried out between variables. The risk factors of BPD associated PH were further screened out by multivariate Logistic regression, and the risk assessment model was established based on these variables. The receiver operating characteristic (ROC) area under curve (AUC) and Hosmer-Lemeshow goodness-of-fit test were used to evaluate the model's discrimination and calibration power, respectively. And the calibration curve was used to evaluate the accuracy of the model and draw the nomogram. The bootstrap repeated sampling method was used for internal verification. Finally, decision curve analysis (DCA) to evaluate the clinical practicability of the model was used. Results: A total of 626 very premature infants with BPD were included for modeling set, including 85 very premature infants in the PH group and 541 very premature infants in the non PH group. A total of 229 very premature infants with BPD were included for validation set, including 24 very premature infants in the PH group and 205 very premature infants in the non PH group. Univariate analysis of the modeling set found that 22 variables, such as artificial conception, fetal distress, gestational age, birth weight, small for gestational age, 1 minute Apgar score ≤7, antenatal corticosteroids, placental abruption, oligohydramnios, multiple pulmonary surfactant, neonatal respiratory distress syndrome (NRDS)>stage Ⅱ, early pulmonary hypertension, moderate-severe BPD, and hemodynamically significant patent ductus arteriosus (hsPDA) all had statistically significant influence between the PH group and the non PH group (all P<0.05). Antenatal corticosteroids, fetal distress, NRDS >stage Ⅱ, hsPDA, pneumonia and days of invasive mechanical ventilation were identified as predictive variables and finally included to establish the Logistic regression model. The AUC of this model was 0.86 (95%CI 0.82-0.90), the cut-off value was 0.17, the sensitivity was 0.77, and the specificity was 0.84. Hosmer-Lemeshow goodness-of-fit test showed that P>0.05. The AUC for external validation was 0.88, and the Hosmer-Lemeshow goodness-of-fit test suggested P>0.05. Conclusions: A high sensitivity and specificity risk prediction model of PBD associated PH in very premature infants was established. This predictive model is useful for early clinical identification of infants at high risk of BPD associated PH.

Lung function in preterm infants at 3 months corrected age after neonatal LC-PUFA supplementation.

OBJECTIVE: To test the hypothesis that long-chain polyunsaturated fatty acid (LC-PUFA) supplementation improves lung function at 3 months corrected age (CA) compared with standard treatment in very preterm infants. We also aimed to investigate the association between bronchopulmonary dysplasia (BPD), longitudinal growth, and lung function at 3 months CA. METHODS: A secondary analysis from the ImNuT trial, in which 121 infants with gestational age <29 weeks were randomized to a daily supplement with arachidonic acid (ARA) and docosahexaenoic acid (DHA) (ARA:DHA group) or MCT-oil (control group) from birth up to 36 weeks postmenstrual age (PMA). Lung function was assessed at 3 months CA by tidal flow volume loops and the outcomes were the ratio of time to peak tidal expiratory flow to expiratory time (tPTEF /tE ) and tidal volume (VT ) per body weight (mL/kg). RESULTS: Thirty-nine infants in the ARA:DHA group versus 51 in the control group had a successful lung function test. There was no mean difference (MD) in tPTEF /tE ratio (MD: 0.01, 95% confidence interval [CI]: -0.04 to 0.05; p = .77) or VT (MD: 0.09 mL/kg, 95% CI: -0.79 to 0.62; p = .81) between the study groups. The multivariable regression model showed that BPD was associated with tPTEF /tE ratio ≤ 0.25 (p = .03) and that an increase in z score for length after 36 weeks PMA correlated positively with VT (mL/kg) (p = .03). CONCLUSION: Neonatal LC-PUFA supplementation did not improve lung function at 3 months CA in very preterm infants. BPD was independently associated with reduced lung function, while improved linear growth correlated with higher tidal volumes.

Identifying effect modifiers of systemic hydrocortisone treatment initiated 7-14 days after birth in ventilated very preterm infants on long-term outcome: secondary analysis of a randomised controlled trial.

OBJECTIVE: To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years' corrected age (CA). DESIGN: Secondary analysis of a randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestational age (GA), ventilator-dependent in the second week of postnatal life. INTERVENTION: Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: The composite of death or neurodevelopmental impairment (NDI) at 2 years' CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots. RESULTS: The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); ≥27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); ≥27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups. CONCLUSION: This secondary analysis suggests that in infants <27 weeks' GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by its component death. There was insufficient evidence for other selected candidate effect modifiers.

Neurodevelopmental outcomes of preterm neonates receiving rescue inhaled nitric oxide in the first week of age: a cohort study.

OBJECTIVE: To assess the neurodevelopmental outcomes of preterm neonates who received inhaled nitric oxide (iNO) in the first week of age for hypoxaemic respiratory failure (HRF). METHODS: In this retrospective cohort study, we included neonates born at <29 weeks gestational age (GA) between January 2010 and December 2018 who had a neurodevelopmental assessment at 18-24 months corrected age (CA) at one of the Canadian Neonatal Follow-Up Network clinics. The primary outcome was neurodevelopmental impairment (NDI). We performed propensity score-matched analysis to compare the outcomes of those who received and did not receive iNO. RESULTS: Of the 5612 eligible neonates, 460 (8.2%) received iNO in the first week of age. Maternal age, receipt of antenatal corticosteroids, GA and birth weight were lower in the iNO group compared with the no-iNO group. Neonates in the iNO group had higher illness severity scores and higher rates of preterm prolonged rupture of membranes and were small for GA. Severe brain injury, bronchopulmonary dysplasia and mortality were higher in the iNO group. Of the 4889 survivors, 3754 (77%) neonates had follow-up data at 18-24 months CA. After propensity score matching, surviving infants who received rescue iNO were not associated with higher odds of NDI (adjusted OR 1.34; 95% CI 0.85 to 2.12). CONCLUSIONS: In preterm neonates <29 weeks GA with HRF, rescue iNO use was not associated with worse neurodevelopmental outcomes among survivors who were assessed at 18-24 months CA.

Diuretic Tolerance to Repeated-Dose Furosemide in Infants Born Very Preterm with Bronchopulmonary Dysplasia.

OBJECTIVES: To assess the presence and timing of furosemide diuretic tolerance in infants with bronchopulmonary dysplasia (BPD), and to determine if tolerance is modified by thiazide co-administration. STUDY DESIGN: We performed a retrospective cohort study among infants born very preterm with BPD exposed to repeated-dose furosemide for 72 hours, measuring net fluid balance (total intake minus total output) as a surrogate of diuresis in the 3 days before and after exposure. The primary comparison was the difference in fluid balance between the first and third 24 hours of furosemide exposure. We fit a general linear model for within-subject repeated measures of fluid balance over time, with thiazide co-administration as an interaction variable. Secondary analyses included an evaluation of weight trajectories over time. RESULTS: In 83 infants, median fluid balance ranged between + 43.6 and + 52.7 ml/kg/d in the 3 days prior to furosemide exposure. Fluid balance decreased to a median of + 29.1 ml/kg/d in the first 24 hours after furosemide, but then increased to +47.5 ml/kg/d by the third 24-hour interval, consistent with tolerance (P < .001). Thiazides did not modify the change in fluid balance during furosemide exposure for any time-period. Weight decreased significantly in the first 24 hours after furosemide and increased thereafter (P < .001). CONCLUSIONS: The net fluid balance response to furosemide decreases rapidly during repeated-dose exposures in infants with BPD, consistent with diuretic tolerance. Clinicians should consider this finding in the context of an infant's therapeutic goals. Further research efforts to identify safe and effective furosemide dosage strategies are needed.

Inguinal Hernia in Premature Infants: To Operate Before or After Discharge from Hospital?

INTRODUCTION: This study aims to find out the optimal timing for herniotomy for premature infants with inguinal hernia (IH): early during hospitalisation or delayed after hospital discharge. METHOD: A retrospective cohort study was conducted on premature infants diagnosed with IH during their initial hospitalization between 2015 and 2020. Demographic data and clinical outcomes were compared between infants undergoing herniotomy before discharge ("early") and those who were discharged without herniotomy ("delayed"). Student's t-test or Mann-Whitney U test and Fisher's exact test were used for statistical analysis. RESULTS: Of 219 premature infants, 189 (86.3%) underwent early herniotomy, while 30 were discharged with unoperated IH. In the delayed group, 15 (50%) underwent planned delayed herniotomy, and the remaining 15 experienced spontaneous resolution (absence of inguinal bulge over at least 1-year follow-up). The gestational age and birth weight of both groups were similar. At surgery, the delayed group median (interquartile range) was significantly older (42.1[38-49] vs 37.7 [36-40] weeks, p < 0.001) and heavier (3.27 [2.21-4.60] vs 2.22 [2.00-2.70] kg, p < 0.001). Two infants (1%) in the early group presented with incarcerated IH requiring urgent operation. In the delayed group, no infant developed incarcerated IH while awaiting elective operation (time from diagnosis to operation 44 [21-85] days). There was no statistically significant difference in respiratory and surgical complications between the two groups, although the delayed group had lesser surgical complications (0% vs 9.5%). CONCLUSION: Deferring herniotomy after discharge for premature infants is safe with close monitoring and associated with a chance of spontaneous resolution. LEVEL OF EVIDENCE: Level III, treatment study.

Psychomotor and Cognitive Outcome in Very Preterm Infants in Vorarlberg, Austria, 2007-2019.

AIM: The aim of this study was to analyze neurodevelopmental outcome of very and extremely preterm infants in Vorarlberg, Austria, accessed with neurodevelopmental testing, at the corrected age of 24 months. This article also compared these results with (inter)national data and analyzed the impact of perinatal parameters. METHODS: Population-based, retrospective multicenter study with data on very and extremely preterm infants born in Vorarlberg from 2007 to 2019 assessed with Bayley Scales of Infant Development (BSID-II/Bayley-III). RESULTS: Included were 264 infants with a mean age of 29.0 (± 2.1) weeks of gestational age and a mean birth weight of 1177 (± 328.26) g; 172 infants underwent a BSID-II, 92 a Bayley-III assessment. The psychomotor developmental index (PDI) and mental developmental index (MDI) showed mean scores of 99.6 (± 14.4) and 91 (± 20.4), respectively. Adverse outcomes (scores <70) were assessed in 4.2% for PDI and 15.5% for MDI. In the extremely preterm group (n = 79), results for mean PDI were 100.1 (± 16.8) and for mean MDI 88.4 (± 22.4). Accordingly, adverse outcomes were assessed in 5.1% for PDI and in 20.3% for MDI. In addition to bronchopulmonary dysplasia and intraventricular hemorrhage Grade 3-4, head circumference at birth and patent ductus arteriosus were also identified as risk factors for poor outcome. CONCLUSION: This study showed a remarkably good neurodevelopmental outcome in preterm infants with low rates of adverse outcome, similar to (inter)national reports, especially in the group of extremely preterm infants. Research is needed to explore the role of social factors and infants' environment, especially cognitive outcome and language skills.

[Outcomes and care practices of extremely preterm infants at 22-25 weeks' gestation age from the Chinese Neonatal Network].

Objective: To describe the current status and trends in the outcomes and care practices of extremely preterm infants at 22-25 weeks' gestation age from the Chinese Neonatal Network (CHNN) from 2019 to 2021. Methods: This cross-sectional study used data from the CHNN cohort of very preterm infants. All 963 extremely preterm infants with gestational age between 22-25 weeks who were admitted to neonatal intensive care units (NICU) of the CHNN from 2019 to 2021 were included. Infants admitted after 24 hours of life or transferred to non-CHNN hospitals were excluded. Perinatal care practices, survival rates, incidences of major morbidities, and NICU treatments were described according to different gestational age groups and admission years. Comparison among gestational age groups was conducted using χ2 and Kruskal-Wallis tests. Trends by year were evaluated by Cochran-Armitage and Jonckheere-Terpstra tests for trend. Results: Of the 963 extremely preterm infants enrolled, 588 extremely preterm infants (61.1%) were male. The gestational age was 25.0 (24.4, 25.6) weeks, with 29 extremely preterm infants (3.0%), 88 extremely preterm infants (9.1%), 264 extremely preterm infants (27.4%), and 582 extremely preterm infants (60.4%) at 22, 23, 24, and 25 weeks of gestation age, respectively. The birth weight was 770 (680, 840) g. From 2019 to 2021, the number of extremely preterm infants increased each year (285, 312, and 366 extremely preterm infants, respectively). Antenatal steroids and magnesium sulfate were administered to 67.7% (615/908) and 51.1% (453/886) mothers of extremely preterm infants. In the delivery room, 20.8% (200/963) and 69.5% (669/963) extremely preterm infants received noninvasive positive end-expiratory pressure support and endotracheal intubation. Delayed cord clamping and cord milking were performed in 19.0% (149/784) and 30.4% (241/794) extremely preterm infants. From 2019 to 2021, there were significant increases in the usage of antenatal steroids, antenatal magnesium sulfate, and delivery room noninvasive positive-end expiratory pressure support (all P<0.05). Overall, 349 extremely preterm infants (36.2%) did not receive complete care, 392 extremely preterm infants (40.7%) received complete care and survived to discharge, and 222 extremely preterm infants (23.1%) received complete care but died in hospital. The survival rates for extremely preterm infants at 22, 23, 24 and 25 weeks of gestation age were 10.3% (3/29), 23.9% (21/88), 33.0% (87/264) and 48.3% (281/582), respectively. From 2019 to 2021, there were no statistically significant trends in complete care, survival, and mortality rates (all P>0.05). Only 11.5% (45/392) extremely preterm infants survived without major morbidities. Moderate to severe bronchopulmonary dysplasia (67.3% (264/392)) and severe retinopathy of prematurity (61.5% (241/392)) were the most common morbidities among survivors. The incidences of severe intraventricular hemorrhage or periventricular leukomalacia, necrotizing enterocolitis, and sepsis were 15.3% (60/392), 5.9% (23/392) and 19.1% (75/392), respectively. Overall, 83.7% (328/392) survivors received invasive ventilation during hospitalization, with a duration of 22 (10, 42) days. The hospital stay for survivors was 97 (86, 116) days. Conclusions: With the increasing number of extremely preterm infants at 22-25 weeks' gestation admitted to CHNN NICU, the survival rate remained low, especially the rate of survival without major morbidities. Further quality improvement initiatives are needed to facilitate the implementation of evidence-based care practices.

Duration of mechanical ventilation and clinical outcomes in very low birth weight infants: A single center 10-years cohort study.

BACKGROUND: Despite the important role of MV in reducing mortality in very preterm infants, its use is often associated with complications. The study was aimed to determine the duration of mechanical ventilation (MV), which significantly increased the risk of adverse outcomes in very low birth weight (VLBW) infants. METHODS: Data obtained from a prospectively created computer database were used in a retrospective cohort study. The database included information about 1980 VLBW infants <32 weeks of gestation who were cared for at the tertiary care center between January 2010 and December 2020. RESULTS: Out of 1980 VLBW infants, 1086 (55%) were ventilated sometime during the hospital stay. 678 (62.43%) of ventilated babies survived until discharge. With ROC analysis, it was identified that MV duration of 60.5 hours had 79.3% sensitivity and 64.6% specificity for the prediction of BPD with the AUC of 0.784 (95% CI 0.733-0.827; p < 0.0001). The duration of MV above 60.5 hours was a significant risk factor for bronchopulmonary dysplasia (aOR 6.005, 95% CI 3.626-9.946), death (aOR 3.610, 95% CI 2.470-5.276), bronchopulmonary dysplasia/death (aOR 4.561, 95% CI 3.328-6.252), sepsis (aOR 1.634, 95% CI 1.168-2.286), necrotizing enterocolitis (aOR 2.606, 95% CI 1.364-4.980), and periventricular leukomalacia (aOR 2.191, 95% CI 1.241-3.867). CONCLUSIONS: Duration of MV longer than 60.5 hours is an independent risk factor for adverse outcomes in VLBW infants. It is essential to increase and optimize efforts to avoid MV or extubate very preterm infants as soon as possible, before reaching the established threshold duration of invasive respiratory support.

Trends in neonatal morbidity and mortality for very low birthweight infants: a 20-year single-center experience.

OBJECTIVE: To describe trends in mortality and morbidity rates of very low birth weight infants as well as their pre-, peri- and postnatal characteristics over a period of 20 years' time. METHODS: Retrospective study in all very low birth weight infants admitted to the neonatal intensive care unit of the University Hospitals Ghent from 1 January 2000, to 31 December 2020. Mortality was the primary outcome variable with major morbidities being co-primary outcome variables. Pre-, peri- and postnatal characteristics are secondary outcome variables. We compared pre-, peri- and postnatal characteristics, as well as major morbidities between different groups with comparable rates of mortality. RESULTS: We included a total of 2037 very low birth weight infants and divided them in 3 epochs based on stepwise reductions in mortality in 2008 and 2013: 2000-2007 (n = 718), 2008-2012 (n = 506) and 2013-2020 (n = 813). Mortality decreased significantly over the years in all gestational ages, but predominantly in those with the youngest gestational age. Changes in obstetric and neonatal care were observed over time. Most significant changes were the increased use of antenatal corticosteroids, magnesium sulfate and surfactant. Intraventricular hemorrhage grade III/IV decreased significantly in all gestational ages. Significant increase in retinopathy of prematurity was observed. Bronchopulmonary dysplasia at 36 weeks and discharge home with oxygen is increasing in the total group. In those born below 26 weeks a slight increase in all major morbidities was observed especially of patent ductus arteriosus and retinopathy of prematurity. Increase of all other major morbidities seems to stabilize in epoch 3. The number of infants surviving without any major morbidity increases to almost 1/2 in all very low birth weight infants and to 1/10 in those born 24-25 weeks gestation. CONCLUSION: Analysis of the real-life experience showed that survival in very low birth weight infants significantly increased over time. Evolution of major morbidities will have to be carefully watched in the future.

Choline and Betaine Levels in Plasma Mirror Choline Intake in Very Preterm Infants.

Choline is essential for cell membrane formation and methyl transfer reactions, impacting parenchymal and neurological development. It is therefore enriched via placental transfer, and fetal plasma concentrations are high. In spite of the greater needs of very low birth weight infants (VLBWI), choline content of breast milk after preterm delivery is lower (median (p25-75): 158 mg/L (61-360 mg/L) compared to term delivery (258 mg/L (142-343 mg/L)). Even preterm formula or fortified breast milk currently provide insufficient choline to achieve physiological plasma concentrations. This secondary analysis of a randomized controlled trial comparing growth of VLBWI with different levels of enteral protein supply aimed to investigate whether increased enteral choline intake results in increased plasma choline, betaine and phosphatidylcholine concentrations. We measured total choline content of breast milk from 33 mothers of 34 VLBWI. Enteral choline intake from administered breast milk, formula and fortifier was related to the respective plasma choline, betaine and phosphatidylcholine concentrations. Plasma choline and betaine levels in VLBWI correlated directly with enteral choline intake, but administered choline was insufficient to achieve physiological (fetus-like) concentrations. Hence, optimizing maternal choline status, and the choline content of milk and fortifiers, is suggested to increase plasma concentrations of choline, ameliorate the choline deficit and improve growth and long-term development of VLBWI.

Epigenetic age acceleration, neonatal morbidities, and neurobehavioral profiles in infants born very preterm.

Epigenetic age acceleration is a risk factor for chronic diseases of ageing and may reflect aspects of biological ageing. However, few studies have examined epigenetic ageing during the early neonatal period in preterm infants, who are at heightened risk of developmental problems. We examined relationships between neonatal age acceleration, neonatal morbidities, and neurobehavioral domains among very preterm (<30 weeks gestation) infants to characterize whether infants with early morbidities or different neurobehavioral characteristics had accelerated or decelerated epigenetic ageing. This study uses data from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) study, restricted to infants with data on variables assessed (n = 519). We used generalized estimating equations to test for differences in age acceleration associated with severe neonatal medical morbidities and neurobehavioral characteristics. We found that infants with neonatal morbidities, in particular, bronchopulmonary dysplasia (BPD), had accelerated epigenetic age - and some evidence that infants with hypertonicity and asymmetric reflexes had increased and decreased age acceleration, respectively. Adjustment for gestational age attenuated some associations, suggesting that the relationships observed may be driven by the duration of gestation. Our most robust finding shows that very preterm infants with neonatal morbidities (BPD in particular) exhibit age acceleration, but most neonatal neurobehavioral characteristics and morbidities are not associated with early life age acceleration. Lower gestational age at birth may be an upstream factor driving these associations.

[Treatment of patent ductus arteriosus in very preterm infants in China].

Objective: To describe the current status and trends in the treatment of patent ductus arteriosus (PDA) among very preterm infants (VPI) admitted to the neonatal intensive care units (NICU) of the Chinese Neonatal Network (CHNN) from 2019 to 2021, and to compare the differences in PDA treatment among these units. Methods: This was a cross-sectional study based on the CHNN VPI cohort, all of 22 525 VPI (gestational age<32 weeks) admitted to 79 tertiary NICU within 3 days of age from 2019 to 2021 were included. The overall PDA treatment rates were calculated, as well as the rates of infants with different gestational ages (≤26, 27-28, 29-31 weeks), and pharmacological and surgical treatments were described. PDA was defined as those diagnosed by echocardiography during hospitalization. The PDA treatment rate was defined as the number of VPI who had received medication treatment and (or) surgical ligation of PDA divided by the number of all VPI. Logistic regression was used to investigate the changes in PDA treatment rates over the 3 years and the differences between gestational age groups. A multivariate Logistic regression model was constructed to compute the standardized ratio (SR) of PDA treatment across different units, to compare the rates after adjusting for population characteristics. Results: A total of 22 525 VPI were included in the study, with a gestational age of 30.0 (28.6, 31.0) weeks and birth weight of 1 310 (1 100, 1 540) g; 56.0% (12 615) of them were male. PDA was diagnosed by echocardiography in 49.7% (11 186/22 525) of all VPI, and the overall PDA treatment rate was 16.8% (3 795/22 525). Of 3 762 VPI who received medication treatment, the main first-line medication used was ibuprofen (93.4% (3 515/3 762)) and the postnatal day of first medication treatment was 6 (4, 10) days of age; 59.3% (2 231/3 762) of the VPI had been weaned from invasive respiratory support during the first medication treatment, and 82.2% (3 092/3 762) of the infants received only one course of medication treatment. A total of 143 VPI underwent surgery, which was conducted on 32 (22, 46) days of age. Over the 3 years from 2019 to 2021, there was no significant change in the PDA treatment rate in these VPI (P=0.650). The PDA treatment rate decreased with increasing gestational age (P<0.001). The PDA treatment rates for VPI with gestational age ≤26, 27-28, and 29-31 weeks were 39.6% (688/1 737), 25.9% (1 319/5 098), and 11.4% (1 788/15 690), respectively. There were 61 units having a total number of VPI≥100 cases, and their rates of PDA treatment were 0 (0/116)-47.4% (376/793). After adjusting for population characteristics, the range of standardized ratios for PDA treatment in the 61 units was 0 (95%CI 0-0.3) to 3.4 (95%CI 3.1-3.8). Conclusions: From 2019 to 2021, compared to the peers in developed countries, VPI in CHNN NICU had a different PDA treatment rate; specifically, the VPI with small birth gestational age had a lower treatment rate, while the VPI with large birth gestational age had a higher rate. There are significant differences in PDA treatment rates among different units.