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.

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.

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 .).

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.

Optimization of airway medications in the infant.

Airway medications are frequently used in the care of the sick neonate. The most prominent airway medication, surfactant for respiratory distress syndrome, will be discussed elsewhere in this issue of Neonatology. Other indications for airway medications have included the prevention and treatment of bronchopulmonary dysplasia, pulmonary hypertension, persistent atelectasis, transient tachypnea of the newborn and upper airway edema. Indications such as the prevention of bronchopulmonary dysplasia are currently the focus of a large multicenter international trial. Other indications require further study.

Flexible fiberoptic bronchoscopy--a bedside technique for neonatologists.

BACKGROUND: Flexible fiberoptic bronchoscopy (FFB) is an under-used technology in neonates, mostly performed by external consultants from either pulmonology or otolaryngology. Modern ultra-thin scopes offer the neonatologist new diagnostic and therapeutic opportunities at the bedside. OBJECTIVE: To describe the diagnostic value, therapeutic potential, and safety profile of FFB in neonates when performed by neonatologists as a bedside procedure. METHODS: This was a retrospective case series that included 19 term and preterm infants who underwent FFB in two Neonatal Intensive Care Units (NICU). RESULTS: Twenty-five procedures were performed for the following indications: suspected airway pathology (15); BAL (8), noisy breathing (4), aid to difficult endotracheal intubation (1), investigation for failure of weaning from ventilation (6), and evaluation of tracheotomy or endotracheal tube patency (5). Thirteen procedures had more than one indication. Airway pathology was observed in 15 of 25 (60%) procedures. Treatment of atelectasis was successful in 7 of 10 cases. BAL culture results influenced antibiotic therapy in 5 of 10 cases (50%). No procedure-related mortality occurred. One serious adverse event (1/25, 4%), namely bilateral pneumothorax occurred 1 h after FFB. CONCLUSIONS: FFB is a useful and safe procedure that belongs in the neonatologists' armamentarium.

The red reflex examination in neonates: an efficient tool for early diagnosis of congenital ocular diseases.

BACKGROUND: The American Academy of Pediatrics recently published recommendations for the red reflex assessment in the newborn period to detect and treat ocular disorders as early as possible, and to prevent lifelong visual impairment and even save lives. The test is technically simple to perform, non-invasive, requires minimal equipment and can detect a variety of ocular pathologies including cataracts and retinal abnormalities. No specific national guidelines exist on this issue. OBJECTIVES: To document the implementation of red reflex examination in routine neonatal care and present the findings. METHODS: Our clinical experience following inclusion of the red reflex test into the newborn physical examination in a single center was reviewed. In addition, an electronic mail questionnaire was sent to all neonatology departments in Israel regarding performance of the red reflex test. RESULTS: During 2007-2008, five infants were identified with congenital cataracts at days 2-6 of life prior to discharge from hospital. Surgery was performed in one infant at age 2 months and all infants underwent a thorough follow-up. The incidence of congenital cataract in our center was 1:2300. Less than half the neonatology departments have endorsed the AAP recommendation and perform the red reflex test routinely. CONCLUSIONS: Abnormal red reflex test after delivery enables a rapid ophthalmologic diagnosis, intervention and close followup. We recommend that red reflex screening be performed as part of the newborn physical examination; if abnormal, an urgent ophthalmologic referral should be made.

Third trimester fetal intracranial hemorrhage owing to vitamin K deficiency associated with hyperemesis gravidarum.

In rare cases, severe fetal vitamin K deficiency bleeding may occur in utero as a result of insufficient vitamin K placental transfer. We present a case of a 32-week-preterm infant born with severe intracranial hemorrhage to a pregnant woman who suffered from hyperemesis gravidarum. Neonatal hematologic status was compatible with vitamin K deficiency whereas the maternal coagulation function was normal. This case emphasizes the potential risk of fetal bleeding owing to vitamin K deficiency in pregnancies complicated with hyperemesis gravidarum. These women should be closely monitored and vitamin K prophylaxis might be considered.

Iatrogenesis in neonatal intensive care units: observational and interventional, prospective, multicenter study.

OBJECTIVES: The goals were to determine the incidence of iatrogenic events in NICUs and to determine whether awareness of iatrogenic events could influence their occurrence. METHODS: We performed a prospective, observational, interventional, multicenter study including all consecutive infants hospitalized in 4 NICUs. In the first 3 months (observation period), the medical teams were unaware of the study; in the next 3 months (intervention period), they were made aware of daily ongoing monitoring of iatrogenic events by a designated "Iatrogenesis Advocate." RESULTS: The numbers of infants admitted to the NICUs were comparable during the observation and intervention periods (328 and 369 infants, respectively). There was no difference between the 2 periods with respect to the number of infants of <1500 g, hospitalization days, or mean daily occupancy of the NICUs. Although the prevalence rates of iatrogenic events were comparable in the observation and intervention periods (18.0 and 18.2 infants with iatrogenic events per 100 hospitalized infants, respectively), the incidence rate decreased significantly during the intervention period (3.2 and 2.4 iatrogenic events per 100 hospitalization days of new admissions, respectively). Of all iatrogenic events, 7.9% were classified as life-threatening and 45.1% as harmful. There was no death related to an iatrogenic event. Eighty-three percent of iatrogenic events were considered preventable, of which 26.9% resulted from medical errors in ordering or delivery of medical care. Only 1.6% of all iatrogenic events were intercepted before reaching the infants, and only 47.0% of iatrogenic events were corrected. For younger and smaller infants, the rate of iatrogenic events was higher (57% at gestational ages of 24 to 27 weeks, compared with 3% at term) and the iatrogenic events were more severe and harmful. Increased length of stay was associated independently with more iatrogenic events. CONCLUSIONS: Neonatal medical teams and parents should be aware of the burden of iatrogenesis, which occurs at a significant rate.

"Masculinizing" effect on respiratory morbidity in girls from unlike-sex preterm twins: a possible transchorionic paracrine effect.

OBJECTIVES: Preterm male infants are at a disadvantage when compared with female infants regarding the incidence of respiratory and neurologic morbidity and mortality. At term, female infants from unlike-sex twin pairs have birth weights that are closer to their male co-twins than to girls from like-sex twin pairs. We hypothesized that if the male disadvantage is mediated via factors that affect fetal lung development, there may be a potential effect on the incidence of respiratory distress syndrome and its complications in female infants from unlike-sex pairs. PATIENTS AND METHODS: In this population-based study we used data from the Israel Neonatal Network, which included data from 8858 very low birth weight (500-1500 g) infants of 24 to 34 weeks' gestation. The incidence of morbidity and mortality was compared in male and female infants from singletons and like-sex and unlike-sex twin pairs. Multivariable analyses were used, accounting for relevant confounding variables. RESULTS: Male singletons and like-sex twins were at increased risk for mortality, respiratory distress syndrome, pneumothorax, bronchopulmonary dysplasia, periventricular-intraventricular hemorrhage, and periventricular leukomalacia. However, in unlike-sex twin pairs, no difference was seen in the incidence of respiratory morbidity between male and female twins. The male disadvantage was maintained for mortality and periventricular-intraventricular hemorrhage. CONCLUSIONS: These findings suggest that the difference in morbidity and mortality between male and female premature infants represents a male disadvantage as opposed to a female advantage and that this disadvantage may be transferred from boys to girls in unlike-sex twin pairs, perhaps via an intrauterine paracrine effect.

Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice.

Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. Am J Physiol Lung Cell Mol Physiol 293: , 2007. First published August 17, 2007; - Mechanical ventilation (MV) with O(2)-rich gas offers life-saving treatment for extremely premature infants with respiratory failure but often leads to neonatal chronic lung disease (CLD), characterized by defective formation of alveoli and blood vessels in the developing lung. We discovered that MV of 2- to 4-day-old mice with 40% O(2) for 8 h, compared with unventilated control pups, reduced lung expression of genes that regulate lung septation and angiogenesis (VEGF-A and its receptor, VEGF-R2; PDGF-A; and tenascin-C). MV with air for 8 h yielded similar results for PDGF-A and tenascin-C but did not alter lung mRNA expression of VEGF or VEGF-R2. MV of 4- to 6-day-old mice with 40% O(2) for 24 h reduced lung protein abundance of VEGF-A, VEGF-R2, PDGF-A, and tenascin-C and resulted in lung structural abnormalities consistent with evolving CLD. After MV with 40% O(2) for 24 h, lung volume was similar to unventilated controls, whereas distal air space size, assessed morphometrically, was greater in lungs of ventilated pups, indicative of impaired septation. Immunostaining for vimentin, which is expressed in myofibroblasts, was reduced in distal lung after 24 h of MV with 40% O(2). These molecular, cellular, and structural changes occurred without detectable lung inflammation as evaluated by histology and assays for proinflammatory cytokines, myeloperoxidase activity, and water content in lung. Thus lengthy MV of newborn mice with O(2)-rich gas reduces lung expression of genes and proteins that are critical for normal lung growth and development. These changes yielded lung structural defects similar to those observed in evolving CLD.