Donor human milk for preventing necrotising enterocolitis in very preterm or very low-birthweight infants.

BACKGROUND: When sufficient maternal milk is not available, donor human milk or formula are the alternative forms of enteral nutrition for very preterm or very low-birthweight (VLBW) infants. Donor human milk may retain the non-nutritive benefits of maternal milk and has been proposed as a strategy to reduce the risk of necrotising enterocolitis (NEC) and associated mortality and morbidity in very preterm or VLBW infants. OBJECTIVES: To assess the effectiveness of donor human milk compared with formula for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants when sufficient maternal milk is not available. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Maternity and Infant Care (MIC) database, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), from the earliest records to February 2024. We searched clinical trials registries and examined the reference lists of included studies. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing feeding with donor human milk versus formula in very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants. DATA COLLECTION AND ANALYSIS: Two review authors evaluated the risk of bias in the trials, extracted data, and synthesised effect estimates using risk ratio, risk difference, and mean difference, with associated 95% confidence intervals. The primary outcomes were NEC, late-onset invasive infection, and all-cause mortality before hospital discharge. The secondary outcomes were growth parameters and neurodevelopment. We used the GRADE approach to assess the certainty of the evidence for our primary outcomes. MAIN RESULTS: Twelve trials with a total of 2296 infants fulfilled the inclusion criteria. Most trials were small (average sample size was 191 infants). All trials were performed in neonatal units in Europe or North America. Five trials were conducted more than 40 years ago; the remaining seven trials were conducted in the year 2000 or later. Some trials had methodological weaknesses, including concerns regarding masking of investigators and selective reporting. Meta-analysis showed that donor human milk reduces the risk of NEC (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.37 to 0.76; I² = 4%; risk difference (RD) -0.03, 95% CI -0.05 to -0.01; 11 trials, 2261 infants; high certainty evidence). Donor human milk probably has little or no effect on late-onset invasive infection (RR 1.12, 0.95 to 1.31; I² = 27%; RD 0.03, 95% CI -0.01 to -0.07; 7 trials, 1611 infants; moderate certainty evidence) or all-cause mortality (RR 1.00, 95% CI 0.76 to 1.31; I² = 0%; RD -0.00, 95% CI -0.02 to 0.02; 9 trials, 2116 infants; moderate certainty evidence). AUTHORS' CONCLUSIONS: The evidence shows that donor human milk reduces the risk of NEC by about half in very preterm or VLBW infants. There is probably little or no effect on late-onset invasive infection or all-cause mortality before hospital discharge.

Early High-Dose Erythropoietin and Cognitive Functions of School-Aged Children Born Very Preterm.

Importance: Children born very preterm are at risk for long-term neurodevelopmental sequelae. Prophylactic high-dose recombinant human erythropoietin (rhEpo) shortly after birth has not been shown to improve cognitive, motor, and behavioral development at 2 and 5 years. Objective: To investigate whether early high-dose rhEpo is associated with better executive functions and processing speed-late-maturing cognitive functions-in school-aged children born very preterm. Design, Setting, and Participants: This single-center cohort study was a prospective, observational follow-up study of a multicenter neonatal clinical trial; 365 children born very preterm (mean gestational age, 29.3 weeks [range, 26.0-31.9 weeks]) who had been enrolled in the Swiss EPO Neuroprotection Trial at birth between 2005 and 2012, and who were included in the primary outcome analyses at 2 years, were eligible to be recruited for the EpoKids study between 2017 and 2021 when they were at school age. Term-born children were additionally recruited and included in a control group. Data were analyzed between May and September 2022. Exposure: Administration of rhEpo (3000 IU/kg) or placebo (saline, 0.9%) intravenously 3 times within the first 2 days of life as part of the Swiss EPO Neuroprotection Trial. Main Outcome and Measures: A comprehensive neuropsychological test battery assessed executive functions and processing speed, and parents reported on their child's executive functions in everyday life to test the hypothesis that early high-dose rhEpo administration is associated with better cognitive outcomes at school age. Results: In the EpoKids study, 214 children born very preterm (58.6% of 365 children in eligible cohort) were assessed at a mean age of 10.4 years (range, 6.9-13.4 years); 117 (54.7%) were boys. There was no evidence that the 117 children who had received rhEpo differed from the 97 children who had received placebo in any of the 15 executive function and processing speed tests, nor in parent-rated executive functions (estimates ranged from -0.138 to 0.084, all 95% CIs included 0). Irrespective of rhEpo or placebo allocation, children born very preterm scored lower on 11 of 15 executive function and processing speed tests than term-born peers (estimates ranged from 0.112 to 0.255, 95% CIs did not include 0). Conclusion and Relevance: This study found no evidence for a positive association between prophylactic early high-dose rhEpo administration and long-term neurodevelopmental outcomes after very preterm birth. These results suggest that a comprehensive approach, including pharmacological and nonpharmacological prevention and intervention strategies, is needed to support these children's neurodevelopmental outcome.

Neonatal cardiorespiratory failure caused by splenic hemorrhages: a case report on a fatal and a rescued case.

Two cases of neonatal splenic hemorrhage with acute cardiorespiratory failure are described in this report. The first case involves a full-term neonate who was found unresponsive without any witnesses and could not be successfully resuscitated. A postmortem diagnosis revealed a splenic hemorrhage. Second case is an extremely premature neonate who experienced a witnessed cardiovascular collapse on the 14th day of life. Rapid cardiovascular support was administered, resulting in a positive outcome. While splenic hemorrhage is commonly associated with traumatic events, these cases highlight the need of considering spontaneous splenic hemorrhages as a potential cause of acute neonatal compromise, even in the absence of birth-related trauma (e.g., asphyxia, prolonged labor, clavicle fractures, brachial plexus injuries). This report emphasizes the importance of including splenic hemorrhage timely in the differential diagnosis of neonatal cardiorespiratory instability, especially in the absence of more common diagnoses, and discusses the challenges associated with its recognition and treatment.

Cord blood transfusions in extremely low gestational age neonates to reduce severe retinopathy of prematurity: results of a prespecified interim analysis of the randomized BORN trial.

BACKGROUND: Preterm infants are at high risk for retinopathy of prematurity (ROP), with potential life-long visual impairment. Low fetal hemoglobin (HbF) levels predict ROP. It is unknown if preventing the HbF decrease also reduces ROP. METHODS: BORN is an ongoing multicenter double-blinded randomized controlled trial investigating whether transfusing HbF-enriched cord blood-red blood cells (CB-RBCs) instead of adult donor-RBC units (A-RBCs) reduces the incidence of severe ROP (NCT05100212). Neonates born between 24 and 27 + 6 weeks of gestation are enrolled and randomized 1:1 to receive adult donor-RBCs (A-RBCs, arm A) or allogeneic CB-RBCs (arm B) from birth to the postmenstrual age (PMA) of 31 + 6 weeks. Primary outcome is the rate of severe ROP at 40 weeks of PMA or discharge, with a sample size of 146 patients. A prespecified interim analysis was scheduled after the first 58 patients were enrolled, with the main purpose to evaluate the safety of CB-RBC transfusions. RESULTS: Results in the intention-to-treat and per-protocol analysis are reported. Twenty-eight patients were in arm A and 30 in arm B. Overall, 104 A-RBC units and 49 CB-RBC units were transfused, with a high rate of protocol deviations. A total of 336 adverse events were recorded, with similar incidence and severity in the two arms. By per-protocol analysis, patients receiving A-RBCs or both RBC types experienced more adverse events than non-transfused patients or those transfused exclusively with CB-RBCs, and suffered from more severe forms of bradycardia, pulmonary hypertension, and hemodynamically significant patent ductus arteriosus. Serum potassium, lactate, and pH were similar after CB-RBCs or A-RBCs. Fourteen patients died and 44 were evaluated for ROP. Ten of them developed severe ROP, with no differences between arms. At per-protocol analysis each A-RBC transfusion carried a relative risk for severe ROP of 1.66 (95% CI 1.06-2.20) in comparison with CB-RBCs. The area under the curve of HbF suggested that HbF decrement before 30 weeks PMA is critical for severe ROP development. Subsequent CB-RBC transfusions do not lessen the ROP risk. CONCLUSIONS: The interim analysis shows that CB-RBC transfusion strategy in preterm neonates is safe and, if early adopted, might protect them from severe ROP. TRIAL REGISTRATION: Prospectively registered at ClinicalTrials.gov on October 29, 2021. Identifier number NCT05100212.

A Volume-Adjustable Artificial Womb for Extremely Preterm Infants.

More than 13 million children are born preterm annually. Prematurity-related mortality accounts for 0.9 million deaths worldwide. The majority of those affected are Extremely Preterm Infants (gestational age less than 28 weeks). Immaturity causes organ failure and specific morbidities like germinal matrix hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis. Artificial womb and placenta technologies address these issues. As a bridge-to-life technology, they provide a liquid environment to allow organ maturation under more physiological conditions. The proposed artificial womb can adapt to fetal growth. Volume adjustment is achieved by removing fluid from the interspace between an inner and outer chamber. Results of the in vitro tests showed a temperature constancy of 36.8°C ± 0.3°C without pressure loss over 7 days. The volume of the inner sac was variable between 3.6 and 7.0 L. We designed a filtration and disinfection system for this particular purpose. This system has proven strong disinfection capabilities, effective filtering of metabolic waste, and the ability to avoid phospholipid washout. The presented artificial womb has sufficient volume variability to adapt to the physiologic growth of an extremely preterm neonate over a 4-week period. We regard this as an important step in the development of this bridge-to-life technology.

Periviability for the Ob-Gyn Hospitalist.

Periviable birth refers to births occurring between 20 0/7 and 25 6/7 weeks gestational age. Management of pregnant people and neonates during this fragile time depends on the clinical status, as well as the patient's wishes. Providers should be prepared to counsel patients at the cusp of viability, being mindful of the uncertainty of outcomes for these neonates. While it is important to incorporate the data on projected morbidity and mortality into one's counseling, shared-decision making is most essential to caring for these patients and optimizing outcomes for all.

Improving accuracy of outcome prediction for infants born extremely preterm using a digital tool: Translating 'NIC-PREDICT' into clinical practice, the first steps.

BACKGROUND: Many clinicians overestimate mortality and disability rates in infants born extremely preterm. We developed a digital tool ('NIC-PREDICT') that predicts infant mortality and survival with and without major disability in infants born 23-27 weeks' gestation. AIMS: To determine if clinicians could use NIC-PREDICT accurately, and if their perceptions of infant outcomes improved after its release in 2021. MATERIALS AND METHODS: Midwives, nurses, obstetricians, neonatologists and paediatricians working in tertiary and non-tertiary hospitals in Victoria were asked to use NIC-PREDICT to estimate three mutually exclusive outcomes: (i) mortality; (ii) survival free of major disability; and (iii) survival with major disability for six different scenarios where a liveborn infant was offered survival-focused care after birth. The proportions who completed the survey (responded to all six scenarios) and the proportions able to provide 100% accurate results for all scenarios were determined. Estimates of the three outcomes were compared with true rates. RESULTS: A total of 85 clinicians responded: 70 (82%) completed the survey, with an overall accuracy of 76%. Overall, predictions of mortality were accurate (mean difference from true value 0.7% (95% confidence interval (CI) -0.7, 2.1) P = 0.33), as were predictions of survival without major disability (mean difference - 0.7 (95% CI -3.0, 1.7) P = 0.58). However, survival with major disability was overestimated by 4.9% ((95% CI 1.7, 8.0) P = 0.003). CONCLUSIONS: Most perinatal clinicians who responded used NIC-PREDICT correctly to estimate expected outcomes in infants born extremely preterm who are offered intensive care. Undue pessimism about survival with major disability remains an ongoing concern.

Epigenetic associations with neonatal age in infants born very preterm, particularly among genes involved in neurodevelopment.

The time from conception through the first year of life is the most dynamic period in human development. This time period is particularly important for infants born very preterm (< 30 weeks gestation; VPT), as they experience a significant disruption in the normal developmental trajectories and are at heightened risk of experiencing developmental impairments and delays. Variations in the epigenetic landscape during this period may reflect this disruption and shed light on the interrelationships between aging, maturation, and the epigenome. We evaluated how gestational age (GA) and age since conception in neonates [post-menstrual age (PMA)], were related to DNA methylation in buccal cells collected at NICU discharge from VPT infants (n = 538). After adjusting for confounders and applying Bonferroni correction, we identified 2,366 individual CpGs associated with GA and 14,979 individual CpGs associated with PMA, as well as multiple differentially methylated regions. Pathway enrichment analysis identified pathways involved in axonogenesis and regulation of neuron projection development, among many other growth and developmental pathways (FDR q < 0.001). Our findings align with prior work, and also identify numerous novel associations, suggesting that genes important in growth and development, particularly neurodevelopment, are subject to substantial epigenetic changes during early development among children born VPT.

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OBJECTIVES: To investigate the clinical characteristics of Ureaplasma urealyticum (UU) infection and colonization in extremely preterm infants and its impact on the incidence of bronchopulmonary dysplasia (BPD). METHODS: A retrospective analysis was conducted on 258 extremely preterm infants who were admitted to the Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, from September 2018 to September 2022. According to the results of UU nucleic acid testing and the evaluation criteria for UU infection and colonization, the subjects were divided into three groups: UU-negative group (155 infants), UU infection group (70 infants), and UU colonization group (33 infants). The three groups were compared in terms of general information and primary and secondary clinical outcomes. RESULTS: Compared with the UU-negative group, the UU infection group had significant increases in the incidence rate of BPD, total oxygen supply time, and the length of hospital stay (P<0.05), while there were no significant differences in the incidence rates of BPD and moderate/severe BPD between the UU colonization group and the UU-negative group (P>0.05). CONCLUSIONS: The impact of UU on the incidence of BPD in extremely preterm infants is associated with the pathogenic state of UU (i.e., infection or colonization), and there are significant increases in the incidence rate of BPD, total oxygen supply time, and the length of hospital stay in extremely preterm infants with UU infection. UU colonization is not associated with the incidence of BPD and moderate/severe BPD in extremely preterm infants.

Impact of early caffeine administration on respiratory outcomes in very preterm infants initially receiving invasive mechanical ventilation.

OBJECTIVE: The guidelines recommend early caffeine administration for preterm infants requiring non-invasive mechanical ventilation since earlier treatment is associated with better outcomes. The objective was to evaluate the impact of early caffeine therapy (within 24 hours after birth) on respiratory outcomes in very preterm infants who were initially receiving invasive mechanical ventilation. METHODS: This was an observation cohort study from 1 January 2018 to 31 December 2022 based on a database that was prospectively collected and maintained. Infants who initially received invasive mechanical ventilation were divided into two groups based on the timing of caffeine initiation: within the first 24 hours after birth (early) and within 48 hours of birth or later (late). Generalised linear mixed models with a random effect model for the centre were used to assess the impact of different caffeine initiation times on neonatal outcomes. RESULTS: Among the cohort of 9880 infants born at <32 weeks gestation, 2381 were eligible for this study (early initiation: 1758 (73.8%) and late initiation: 623 (26.2%)). For infants born at more than 28 weeks of gestation, the adjusted generalised linear mixed model showed that the duration of invasive mechanical ventilation was 1.34 (95% CI -2.40 to -0.27) days shorter and the incidence of moderate-to-severe bronchopulmonary dysplasia (BPD) was lower (adjusted OR 0.63; 95% CI 0.41 to 0.96) in the early caffeine group compared with the late caffeine group. CONCLUSION: In very preterm infants who initially receive invasive mechanical ventilation, early administration of caffeine within 24 hours after birth can shorten the duration of invasive mechanical ventilation, reduce the incidence of moderate-to-severe BPD and improve respiratory outcomes. The very early initiation of caffeine treatment does not appear to be associated with any adverse outcomes. TRIAL REGISTRATION NUMBER: ChiCTR1900025234.

The association of the room air challenge with long-term outcomes in extremely preterm infants.

OBJECTIVE: Evaluate the association between results of the room air (RA) challenge and death, respiratory morbidity, and neurodevelopmental impairment (NDI) at 2 years' corrected age. STUDY DESIGN: Cohort study of infants born <27 weeks' gestational age who underwent a RA challenge to determine BPD diagnosis at 36 weeks postmenstrual age. RESULTS: Of 1022 infants eligible for the RA challenge, 554 underwent testing and 223 passed. Test result was not associated with death or serious respiratory morbidities [adjusted relative risk (aRR) 1.01, 95% confidence interval (CI) 0.65-1.56] or death or moderate/severe NDI (aRR 1.06, 95% CI 0.81-1.39) at 2 years. CONCLUSION: Results of the RA challenge were not associated with differences in respiratory or neurodevelopmental morbidity at 2 years, suggesting the RA challenge does not add prognostic value in contemporary extremely preterm infants. GOV ID: Generic Database: NCT00063063.

Variability of Care Practices for Extremely Early Deliveries.

OBJECTIVES: Assess temporal changes, intercenter variability, and birthing person (BP) factors relating to interventions for extremely early deliveries. METHODS: Retrospective study of BPs and newborns delivered from 22-24 completed weeks at 13 US centers from 2011-2020. Rates of neonatology consultation, antenatal corticosteroids, cesarean delivery, live birth, attempted resuscitation (AR), and survival were assessed by epoch, center, and gestational age. RESULTS: 2028 BPs delivering 2327 newborns were included. Rates increased in epoch 2-at 22 weeks: neonatology consultation (37.6 vs 64.3%, P < .001), corticosteroids (11.4 vs 29.5%, P < .001), live birth (66.2 vs 78.6%, P < .001), AR (20.1 vs 36.9%, P < .001), overall survival (3.0 vs 8.9%, P = .005); and at 23 weeks: neonatology consultation (73.0 vs 80.5%, P = .02), corticosteroids (63.7 vs 83.7%, P < .001), cesarean delivery (28.0 vs 44.7%, P < .001), live birth (88.1 vs 95.1%, P < .001), AR (67.7 vs 85.2%, P < .001), survival (28.8 vs 41.6%, P < .001). Over time, intercenter variability increased at 22 weeks for corticosteroids (interquartile range 18.0 vs 42.0, P = .014) and decreased at 23 for neonatology consultation (interquartile range 23.0 vs 5.2, P = .045). In BP-level multivariate analysis, AR was associated with increasing gestational age and birth weight, Black BP race, previous premature delivery, and delivery center. CONCLUSIONS: Intervention rates for extremely early newborns increased and intercenter variability changed over time. In BP-level analysis, factors significantly associated with AR included Black BP race, previous premature delivery, and center.

Evaluating endotracheal tube length in very and extremely preterm infants.

OBJECTIVE: Our study objective was to evaluate changes in ETT tube depth throughout the initial intubation course in very and extremely preterm infants in order to evaluate the risk of outgrowing an endotracheal tube (ETT). METHODS: This was a retrospective cohort study of preterm infants born at <32 weeks of gestation who were admitted to the NICU between 2012 and 2021 and required intubation for mechanical ventilation. Infants who were intubated only for surfactant administration and those with airway malformations were excluded. Descriptive statistics were used to define the range of ETT depths at the time of extubation, stratified by gestational age (<28 weeks vs 28-32 weeks of gestation). Relative ETT depth was defined as the final depth minus the initial depth. RESULTS: Out of 496 infants, 140 patients met all criteria for inclusion. Descriptive analysis of extubation depths across the populations demonstrated median relative ETT depth of 0 cm for the 28-32-week gestational age group, and -0.25 cm for the <28-week gestational age group. The 95th percentile for both gestational age groups was a relative depth of 0.5 cm and the 99th percentile was 1.0-1.5 cm. CONCLUSION: The results of our study suggest that the vast majority of patients in the NICU are unlikely to "outgrow" ETT tube length which should be taken into account when deciding where to trim the ETT in order to minimize airway resistance.

High threshold of total developmental quotient at 3 years for follow-up in extremely preterm infants.

AIM: To investigate the relationship between the developmental quotient (DQ) at age 3 years and the need for educational support at school age in extremely preterm infants. METHODS: A total of 176 infants with a gestational age of <28 weeks were analyzed. The total DQ and subscales were evaluated using the Kyoto Scale of Psychological Development (KSPD) test. Neurodevelopment at age 3 years was stratified using total DQ in a conventional (DQ < 70 as developmental delay, DQ 70- <85 as subnormal, DQ ≥85 as normal) and a modified way (subdividing normal into DQ 85- <93 as low-normal and DQ ≥93 as high-normal). The prevalence of future educational support was compared for each stratum. Additionally, subscales were compared between those with and without educational support in each total DQ stratum. RESULTS: In conventional stratification, the prevalence of educational support was 32 (63 %) for developmental delay, 14 (24 %) for subnormal, and 10 (15 %) for normal. In modified stratification, the prevalence was 8 (26 %) for low-normal and 2 (5 %) for high-normal. While there was no significant difference in the odds of educational support between the normal and subnormal, the low-normal had significantly higher odds compared to the high-normal (OR 6.00; 95 % CI, 1.16-30.95, p = 0.03). Among the low-normal stratum, the language-social subscale was significantly lower in those with educational support. CONCLUSION: Setting high thresholds for total DQ and evaluating detailed subscales at age 3 years may be useful for developmental follow-up in extremely preterm infants.

A real-world study on the treatment of extremely preterm infants: a multi-center study in southwest area of Fujian Province in China.

BACKGROUND: Due to regional and cultural differences, the current status of extremely preterm infants(EPIs) treatment across different areas of mainland China remains unclear. This study investigated the survival rate and incidence of major diseases among EPIs in the southwest area of Fujian province. METHOD: This retrospective and multicenter study collected perinatal data from EPIs with gestational ages between 22-27+ 6w and born in the southwest area of Fujian province. The study population was divided into 6 groups based on gestational age at delivery. The primary outcome was the survival status at ordered hospital discharge or correct gestational age of 40 weeks, and the secondary outcome was the incidence of major diseases. The study analyzed the actual survival status of EPIs in the area. RESULT: A total of 2004 preterm infants with gestational ages of 22-27+ 6 weeks were enrolled in this study. Among them, 1535 cases (76.6%) were born in the delivery room but did not survive, 469 cases (23.4%) were transferred to the neonatal department for treatment, 101 cases (5.0%) received partial treatment, and 368 cases (18.4%) received complete treatment. The overall all-cause mortality rate was 84.4% (1691/2004). The survival rate and survival rate without major serious disease for EPIs who received complete treatment were 85.1% (313/368) and 31.5% (116/318), respectively. The survival rates for gestational ages 22-22+ 6w, 23-23+ 6w, 24-24+ 6w, 25-25+ 6w, 26-26+ 6w, and 27-27+ 6w were 0%, 0%, 59.1% (13/22), 83% (39/47), 88.8% (87/98), and 89.7% (174/198), respectively. The survival rates without major serious disease were 0%, 0%, 9.1% (2/22), 19.1% (9/47), 27.6% (27/98), and 40.2% (78/194), respectively. CONCLUSION: The all-cause mortality of EPIs in the southwest area of Fujian Province remains high, with a significant number of infants were given up after birth in the delivery room being the main influencing factor. The survival rate of EPIs who received complete treatment at 25-27 weeks in the NICU was similar to that in developed countries. However, the survival rate without major serious disease was significantly lower compared to high-income countries.

Selective early medical treatment of the patent ductus arteriosus in extremely low gestational age infants: a pilot randomised controlled trial protocol (SMART-PDA).

INTRODUCTION: Patent ductus arteriosus (PDA) is the most common cardiovascular problem that develops in extremely preterm infants and is associated with poor clinical outcomes. Uncertainty exists on whether early pharmacotherapeutic treatment of a clinically symptomatic and echocardiography-confirmed haemodynamically significant PDA in extremely preterm infants improves outcomes. Given the wide variation in the approach to PDA treatment in this gestational age (GA) group, a randomised trial design is essential to address the question. Before embarking on a large RCT in this vulnerable population, it is important to establish the feasibility of such a trial. METHODS AND ANALYSIS: Design: a multi-centre, open-labelled, parallel-designed pilot randomised controlled trial. Participants: preterm infants born <26 weeks of gestation with a PDA diagnosed within 72 hours after birth. Intervention (selective early medical treatment (SMART) strategy): selective early pharmacological treatment of a moderate-severe PDA shunt (identified based on pre-defined clinical signs and routine screening echocardiography) within the first 72 postnatal hours with provision for repeat treatment if moderate-severe shunt persists. Comparison (early conservative management strategy): no treatment of PDA in the first postnatal week. Primary outcomes: (1) proportion of eligible infants recruited during the study period; (2) proportion of randomised infants treated outside of protocol-mandated therapy. Sites and sample size: the study is being conducted in seven neonatal intensive care units across Canada and the USA with a target of 100 randomised infants. Analysis: the primary feasibility outcomes will be expressed as proportions. A pre-planned Bayesian analysis will be conducted for secondary clinical outcomes such as mortality, severe intraventricular haemorrhage, procedural PDA closure and chronic lung disease to aid stakeholders including parent representatives decide on the appropriateness of enrolling this vulnerable population in a larger trial if the feasibility of recruitment in the pilot trial is established. ETHICS AND DISSEMINATION: The study has been approved by the IWK Research Ethics Board (#1027298) and six additional participating sites. On the completion of the study, results will be presented at national and international meetings, published in peer-reviewed journals and incorporated into existing systematic reviews. TRIAL REGISTRATION NUMBER: NCT05011149 (WHO Trial Registration Data Set in Appendix A). PROTOCOL VERSION: Ver 7.2 (dated July 19, 2023).

Neonatal Sepsis Episodes and Retinopathy of Prematurity in Very Preterm Infants.

Importance: Retinopathy of prematurity (ROP) is a major morbidity of preterm infants causing visual impairment, including blindness, for which timely treatment is vital and prevention is key. Increasing evidence suggests that exposure to neonatal sepsis contributes to ROP development. Objective: To investigate the association between neonatal sepsis and ROP in 2 large-scale cohorts of preterm infants born at less than 29 weeks' gestation. Design, Setting, and Participants: This retrospective cohort study was conducted using data from the German Neonatal Network (GNN) and Norwegian Neonatal Network (NNN). The GNN involves 68 and the NNN includes 21 level III neonatal intensive care units. Participants were infants born at a gestation of 22 weeks and 0 days to 28 weeks and 6 days and enrolled in the GNN between January 1, 2009, and December 31, 2022, and NNN between January 1, 2009, and December 31, 2018. Data were analyzed from February through September 2023. Exposure: Single or multiple episodes of culture-proven sepsis. Main Outcomes and Measures: Any ROP and treatment-warranted ROP. Results: Among 12 794 infants in the GNN (6043 female [47.2%] and 6751 male [52.8%]; mean [SD] gestational age, 26.4 [1.5] weeks) and 1844 infants in the NNN (866 female [47.0%] and 978 male [53.0%]; mean [SD] gestational age, 25.6 [1.5] weeks), the mean (SD) birth weight was 848 (229) g and 807 (215) g, respectively. Any ROP was present in 6370 infants (49.8%) in GNN and 620 infants (33.6%) in NNN, and treatment-warranted ROP was present in 840 infants (6.6%) in GNN and 140 infants (7.6%) in NNN. In both cohorts, there were increasing rates of treatment-warranted ROP with each sepsis episode (no sepsis: 572 of 10 658 infants [5.4%] in GNN and 85 of 1492 infants (5.7%) in NNN; 1 episode: 190 of 1738 infants in GNN [10.9%] and 29 of 293 infants [9.9%] in NNN; 2 episodes: 53 of 314 infants in GNN [16.9%] and 13 of 49 infants [26.5%] in NNN; 3 episodes: 25 of 84 infants [29.8%] in GNN and 3 of 10 infants [30.0%] in NNN). After adjusting for multiple confounders in the GNN dataset, the number of sepsis episodes was associated with ROP and treatment-warranted ROP compared with 0 episodes (1 episode: adjusted odds ratio [aOR], 1.44 [95% CI, 1.27-1.63]; P < .001 and OR, 1.60 [95% CI, 1.31-1.96]; P < .001, respectively; 2 episodes: OR, 1.81 [95% CI, 1.35-2.42]; P < .001 and OR, 2.38 [95% CI, 1.68-3.37]; P < .001, respectively; 3 episodes: OR, 4.39 [95% CI, 2.19-8.78]; P < .001 and OR, 3.88 [95% CI, 2.29-6.55]; P < .001, respectively). These associations were confirmed for any ROP by propensity score matching (for example, the aOR with propensity score matching was 1.76 [95% CI, 1.54-2.02]; P < .001 for 1 episode vs 0 episodes and 1.58 [95% CI, 1.12-2.22]; P = .007 for 3 episodes vs 0 or 1 episode). In the NNN dataset, surgical NEC was associated with treatment-warranted ROP (multivariable analysis: aOR, 3.37 [95% CI, 1.78-6.37]; P < .001). Conclusions and Relevance: This study found that in the large-scale GNN cohort, recurrent culture-proven sepsis was associated with ROP and treatment-warranted ROP in infants born at less than 29 weeks.

Advances in the pharmacological management of bronchopulmonary dysplasia: an update of the literature.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is the commonest adverse outcome of extremely prematurely born infants, and its incidence is increasing. Affected infants suffer chronic respiratory morbidity and are at risk of early onset of chronic obstructive pulmonary disease. It is, therefore, important that these infants are appropriately managed, with efficacious pharmacological treatments. AREAS COVERED: Searches were made on Embase, PubMed, and the Cochrane database for ('treatment' or 'drug therapy/') and ('bronchopulmonary dysplasia' or 'chronic lung disease') and ('neonatology' or 'newborn' or 'prematurity' or 'baby') between 2019 and 2024. Corticosteroids, diuretics, caffeine, anti-asthmatics, nutritional supplements, and medications treating patent ductus arteriosus and pulmonary hypertension are discussed. EXPERT OPINION: Dexamethasone is associated with adverse neurodevelopmental outcomes and impairment of adult lung function. Inhaled corticosteroids have not resulted in significant effects on BPD. Diuretics only result in short-term improvements in lung function and have side-effects. Evidence suggests it is better to wait and see than aggressively treat PDA; inhaled nitric oxide and sildenafil can improve oxygenation, but whether they improve long-term outcomes remains to be tested. Stem cells are a promising therapy, but further research is required. Appropriately designed trials are required to identify efficacious treatments for infants with BPD.