Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Exome sequencing links the SUMO protease SENP7 with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia.

BACKGROUND: SUMOylation involves the attachment of small ubiquitin-like modifier (SUMO) proteins to specific lysine residues on thousands of substrates with target-specific effects on protein function. Sentrin-specific proteases (SENPs) are proteins involved in the maturation and deconjugation of SUMO. Specifically, SENP7 is responsible for processing polySUMO chains on targeted substrates including the heterochromatin protein 1α (HP1α). METHODS: We performed exome sequencing and segregation studies in a family with several infants presenting with an unidentified syndrome. RNA and protein expression studies were performed in fibroblasts available from one subject. RESULTS: We identified a kindred with four affected subjects presenting with a spectrum of findings including congenital arthrogryposis, no achievement of developmental milestones, early respiratory failure, neutropenia and recurrent infections. All died within four months after birth. Exome sequencing identified a homozygous stop gain variant in SENP7 c.1474C>T; p.(Gln492*) as the probable aetiology. The proband's fibroblasts demonstrated decreased mRNA expression. Protein expression studies showed significant protein dysregulation in total cell lysates and in the chromatin fraction. We found that HP1α levels as well as different histones and H3K9me3 were reduced in patient fibroblasts. These results support previous studies showing interaction between SENP7 and HP1α, and suggest loss of SENP7 leads to reduced heterochromatin condensation and subsequent aberrant gene expression. CONCLUSION: Our results suggest a critical role for SENP7 in nervous system development, haematopoiesis and immune function in humans.

Minimally invasive surfactant therapy versus intubation for surfactant delivery in preterm infant with RDS: evaluation of safety and efficacy.

BACKGROUND: Minimally invasive surfactant therapy (MIST) is a promising mode of administration that offers the potential to limit barotrauma and prevent lung injury in preterm infants with respiratory distress syndrome (RDS). OBJECTIVE: This study assessed the effects of the implementation of MIST on safety and efficacy in infants who met criteria for surfactant administration and were treated by MIST as compared with a historical control group treated with surfactant via an endotracheal tube during mechanical ventilation. METHODS: This retrospective study included infants born between 2012 and 2017 who met the following inclusion criteria: gestational age 23-36 + 6 weeks, a diagnosis of RDS requiring at least 30% oxygen with or without nasal continuous positive airway pressure (nCPAP). MIST was introduced in 2014 and a comparison was made between the study group who received MIST and the control group who met similar criteria and received surfactant via an endotracheal tube during mechanical ventilation. RESULTS: No significant differences were found between the groups in baseline and demographic data. Severity of initial disease, assessed by the CRIB II score, was similar in the two groups (control 4.6 ± 2.8, MIST 4.4 ± 2.4, p=.995). The requirement for oxygen during the first 3 d of life was significantly lower (area under the curve [AUC]: p=.001) in the MIST group as assessed by the AUC. Likewise, the mean days of oxygen requirement were significantly lower in the MIST group (Control: 10.3 d, MIST: 5.9 d, p=.04). Only six infants in the MIST group (13%) subsequently required intubation for mechanical ventilation, only one of whom adjacent to the procedure. A modest reduction in duration of ventilation was also noted. Duration of admission was 32 ± 23 d in the control group and 26 ± 21 d in the MIST group, p=.061. No significant differences were found between the groups in the incidence of major morbidities or mortality. No major adverse events related to the procedure were observed. CONCLUSIONS: Transition to MIST was associated with significantly reduced need for oxygen, mechanical ventilation and surfactant, and a borderline shortened NICU admission.

Current evidence for prenatal and postnatal corticosteroids in preterm infants.

Antenatal corticosteroids undoubtedly save many lives and improve the quality of many others. However, the currently accepted dosage schedule has been in place since 1972, and recent studies have suggested that beneficial effects may be seen with less. Most but not all studies of long-term outcome show no adverse effects. The use of antenatal corticosteroids in women with COVID-19 raises important questions regarding potential risks and benefits. However, currently, most authorities recommend continuing according to published guidelines. With regard to postnatal corticosteroids, alternatives to systemic dexamethasone, the somewhat tainted standard of care, show promise in preventing bronchopulmonary dysplasia without adverse effects. Systemic hydrocortisone and inhaled corticosteroids are of note. The mixture of surfactant and corticosteroids deserves particular attention in the coming years.

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Neonatal SARS-CoV-2 Infections in Breastfeeding Mothers.

OBJECTIVES: To assess infection rates predischarge and postdischarge in breast milk-fed newborns with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive mothers who were separated postdelivery from their mothers and discharged from the hospital. Also, we aim to evaluate breastfeeding rates predischarge and postdischarge. METHODS: Nasopharyngeal swabs for SARS-CoV-2 were obtained from symptomatic and high-risk women in the delivery room. Mothers with positive SARS-CoV-2 test results were separated from the newborns. Newborns were screened within 48 hours of delivery, and anti-infectious guidelines were imparted to the mothers before discharge. Rescreening took place ≥14 days postdischarge. Data regarding SARS-CoV-2-positive household members and breastfeeding were obtained by follow-up phone calls. RESULTS: A total of 73 newborns of SARS-CoV-2-positive mothers were born in Israel during the ∼3-month period under study. Overall, 55 participated in this study. All neonates tested negative for the virus postdelivery. A total 74.5% of the neonates were fed unpasteurized expressed breast milk during the postpartum separation until discharge. Eighty-nine percent of the neonates were discharged from the hospital after their mothers were instructed in anti-infection measures. In 40% of the households, there were additional SARS-CoV-2-positive residents. A total of 85% of the newborns were breastfed postdischarge. Results for all 60% of the newborns retested for SARS-CoV-2 postdischarge were negative. CONCLUSIONS: No viral infection was identified in neonates born to and separated from their SARS-CoV-2-positive mothers at birth and subsequently fed unpasteurized breast milk. All infants breastfed at home remained SARS-CoV-2 negative. These findings may provide insights regarding the redundancy of postpartum mother-newborn separation in SARS-CoV-2-positive women and, assuming precautions are adhered to, support the safety of breast milk.

Reassessing vitamin D supplementation in preterm infants: a prospective study and review of the literature.

Objectives Recommendations for vitamin D (VitD) intake and target serum levels of 25(OH)D in preterm infants are diverse. We hypothesized that preterm infants with low birth weight (BW) have low dietary intake of VitD and therefore should be supplemented with higher amounts of VitD. Methods Infants with BW < 2 kg were supplemented with 600 units of VitD a day during the first 2-6 weeks of life, whereas infants with BW>2 kg continued with the routine supplementation of 400 units of VitD daily. Serum levels of 25(OH)D, calcium, phosphorous, alkaline phosphatase (AP) and parathyroid hormone (PTH) were assessed 24 h after birth and before discharge. The total daily intake of vitD was calculated in each infant. Results Sixty-two infants were enrolled, 49 with BW < 2 kg. After birth, only 24% had sufficient levels of 25(OH)D, whereas before discharge 45 of 54 infants (83%) available for analysis reached sufficient levels of 25(OH)D. All 54 infants demonstrated significant elevation in serum levels of calcium, phosphorous, AP and significant reduction in PTH levels. The total daily intake of VitD was lower than recommended (800-1000 IU/d) in 16 of 45 infants with BW < 2 kg (36%) and in all nine infants with BW>2 kg. Nevertheless, only 2 of 25 infants with insufficient intake of VitD demonstrated insufficient levels of serum 25(OH)D. No case of vitamin D excess was recorded. Conclusions Increased supplementation of VitD (600 IU/d) for premature newborns with BW < 2 kg is effective in increasing both total daily intake of VitD and serum levels of 25(OH)D.

Reduction of hospital-acquired infections in the neonatal intensive care unit: A long-term commitment.

We instituted quality improvement program. We compare the infection rate before (2011-2012) and after (2013-2015). Central line associated blood stream infection episodes decreased from 15.2 to 2.29 episodes per 1000 catheter days (P = .004). We found two major changes, 1. Hand hygiene increased mainly "before aseptic task", from 69.9% to 89.9% and 2. A significant decrease in the length of the catheter use from 5.4 ±â€¯4.5 before to 4.4 ±â€¯2.5 days after the intervention (P = .001).

Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment.

Cerebrotendinous xanthomatosis (CTX) is a progressive metabolic leukodystrophy. Early identification and treatment from birth onward effectively provides a functional cure, but diagnosis is often delayed. We conducted a pilot study using a two-tier test for CTX to screen archived newborn dried bloodspots (DBSs) or samples collected prospectively from a high-risk Israeli newborn population. All DBS samples were analyzed with flow injection analysis (FIA)-MS/MS, and 5% of samples were analyzed with LC-MS/MS. Consecutively collected samples were analyzed to identify CTX-causing founder genetic variants common among Druze and Moroccan Jewish populations. First-tier analysis with FIA-MS/MS provided 100% sensitivity to detect CTX-positive newborn DBSs, with a low false-positive rate (0.1-0.5%). LC-MS/MS, as a second-tier test, provided 100% sensitivity to detect CTX-positive newborn DBSs with a false-positive rate of 0% (100% specificity). In addition, 5ß-cholestane-3α,7α,12α,25-tetrol-3-O-ß-D-glucuronide was identified as the predominant bile-alcohol disease marker present in CTX-positive newborn DBSs. In newborns identifying as Druze, a 1:30 carriership frequency was determined for the c.355delC CYP27A1 gene variant, providing an estimated disease prevalence of 1:3,600 in this population. These data support the feasibility of two-tier DBS screening for CTX in newborns and set the stage for large-scale prospective pilot studies.

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia.

BACKGROUND: The long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of <85 [1 SD below the mean of 100] on the Bayley Scales of Infant Development, Second Edition, with higher scores on the scale indicating better performance), deafness, or blindness at a corrected age of 18 to 22 months. RESULTS: Adequate data on the prespecified composite long-term outcome were available for 629 infants. Of these infants, 148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P=0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P=0.04). CONCLUSIONS: Among surviving extremely preterm infants, the rate of neurodevelopmental disability at 2 years did not differ significantly between infants who received early inhaled budesonide for the prevention of bronchopulmonary dysplasia and those who received placebo, but the mortality rate was higher among those who received budesonide. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190 .).

Early, rapidly progressive enteral nutrition promotes growth of very low birth weight (VLBW) infants.

AIM: This study describes the effects of a quality improvement program to promote improved postnatal nutrition on the growth of very low birth weight (VLBW) infants. METHODS: Daily data regarding nutrition and growth were collected from the medical record of VLBW infants born during 1995-2010. The infants were grouped by year of birth in order to compare infants from before, during and after the policy change. Evaluation of growth included age in days at a return to birth weight and the proportion of infants with weight below the 10th percentile at discharge. RESULTS: The caloric and protein intake improved significantly. The age at a return to birth weight fell (p < 0.01) from 14.6 ± 5 d to 11 ± 8 d after the change. The proportion of infants with a discharge weight below the 10th percentile for corrected age fell (p < 0.01) from 72.1% to 42.1%. Data on enteral feeding showed that increased rate of enteral feeds (EF) was associated with better growth (p < 0.001). CONCLUSION: Increasing awareness led to increase in caloric and protein intake in VLBW infants. Aggressive EF was associated with more rapid weight gain. However, the provision of protein and calories during the first 2 weeks of life still falls short of the latest European Society of Pediatric Gastroenterology, Hepatology and Nutrition recommendations.

Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis.

CONTEXT: Bronchopulmonary dysplasia (BPD) in preterm infants remains a major health burden despite many therapeutic interventions. Inhaled corticosteroids (IC) may be a safe and effective therapy. OBJECTIVE: To assess the safety and efficacy of IC for prevention or treatment of BPD or death in preterm infants. DATA SOURCES: PubMed, the Cochrane Library, Embase, and CINAHL from their inception until November 2015 together with other relevant sources. STUDY SELECTION: Randomized controlled trials of ICs versus placebo for either prevention or treatment of BPD. DATA EXTRACTION: This meta-analysis used a random-effects model with assessment of quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Thirty-eight trials were identified, and 16 met inclusion criteria. ICs were associated with a significant reduction in death or BPD at 36 weeks' postmenstrual age (risk ratio [RR] = 0.86, 95% confidence interval [CI] 0.75 to 0.99, I2 = 0%, P = .03; 6 trials, n = 1285). BPD was significantly reduced (RR = 0.77, 95% CI 0.65 to 0.91, I2 = 0%, 7 trials, n = 1168), although there was no effect on death (RR = 0.97, 95% CI 0.42 to 2.2, I2 = 50%, 7 trials, n = 1270). No difference was found for death or BPD at 28 days' postnatal age. The use of systemic steroids was significantly reduced in treated infants (13 trials, n = 1537, RR = 0.87, 95% CI 0.76 to 0.98 I2 = 3%,). No significant differences were found in neonatal morbidities and other adverse events. LIMITATIONS: Long-term follow-up data are awaited from a recent large randomized controlled trial. CONCLUSIONS: Very preterm infants appear to benefit from ICs with reduced risk for BPD and no effect on death, other morbidities, or adverse events. Data on long-term respiratory, growth, and developmental outcomes are eagerly awaited.

Early Inhaled Budesonide for the Prevention of Bronchopulmonary Dysplasia.

BACKGROUND: Systemic glucocorticoids reduce the incidence of bronchopulmonary dysplasia among extremely preterm infants, but they may compromise brain development. The effects of inhaled glucocorticoids on outcomes in these infants are unclear. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to early (within 24 hours after birth) inhaled budesonide or placebo until they no longer required oxygen and positive-pressure support or until they reached a postmenstrual age of 32 weeks 0 days. The primary outcome was death or bronchopulmonary dysplasia, confirmed by means of standardized oxygen-saturation monitoring, at a postmenstrual age of 36 weeks. RESULTS: A total of 175 of 437 infants assigned to budesonide for whom adequate data were available (40.0%), as compared with 194 of 419 infants assigned to placebo for whom adequate data were available (46.3%), died or had bronchopulmonary dysplasia (relative risk, stratified according to gestational age, 0.86; 95% confidence interval [CI], 0.75 to 1.00; P=0.05). The incidence of bronchopulmonary dysplasia was 27.8% in the budesonide group versus 38.0% in the placebo group (relative risk, stratified according to gestational age, 0.74; 95% CI, 0.60 to 0.91; P=0.004); death occurred in 16.9% and 13.6% of the patients, respectively (relative risk, stratified according to gestational age, 1.24; 95% CI, 0.91 to 1.69; P=0.17). The proportion of infants who required surgical closure of a patent ductus arteriosus was lower in the budesonide group than in the placebo group (relative risk, stratified according to gestational age, 0.55; 95% CI, 0.36 to 0.83; P=0.004), as was the proportion of infants who required reintubation (relative risk, stratified according to gestational age, 0.58; 95% CI, 0.35 to 0.96; P=0.03). Rates of other neonatal illnesses and adverse events were similar in the two groups. CONCLUSIONS: Among extremely preterm infants, the incidence of bronchopulmonary dysplasia was lower among those who received early inhaled budesonide than among those who received placebo, but the advantage may have been gained at the expense of increased mortality. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190.).

Use of inhaled corticosteroids for the prevention and/or treatment of bronchopulmonary dysplasia in preterm infants: a systematic review protocol.

BACKGROUND: Inhaled steroids have been studied for both prevention and treatment of bronchopulmonary dysplasia (BPD). Results have been inconsistent. Recently, a large randomized controlled trial (RCT) has been reported. METHODS/DESIGN: We will perform a comprehensive systematic literature search for randomized and quasi-randomized controlled trials that studied the efficacy and safety of inhaled corticosteroids administered to preterm infants (22-36 weeks) for either the prevention or treatment of BPD diagnosed by both clinical and physiological outcome criteria. We will assess potential risk of bias for each RCT meeting our selection criteria using the Cochrane risk of bias tool for RCTs. The primary outcome of interest will be mortality or BPD or both at 28 days postnatal age or 36 weeks postmenstrual age. Pooled estimates will be calculated using RevMan software with a random effects model as primary analysis. We will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. DISCUSSION: Meta-analytic estimates of eligible RCTs, potentially including a new large RCT, may significantly influence neonatal practice in the prevention and treatment of respiratory problems in preterm infants. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015019628.

Ethics of birth at the limits of viability: the risky business of prediction.

Infants born at the limits of viability present neonatologists in particular and society in general with difficult challenges. Ethical and legal considerations establish a framework for action, although this varies between countries, departments and individuals and shows dynamic changes over time. This brief review includes a vignette telling a familiar story. In this case, the parents ask searching questions and the caring, knowledgeable neonatologist uses up-to-date information to offer empathic and thoughtful guidance - a challenge for all.