Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial.

BACKGROUND: Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation. METHODS: This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24. FINDINGS: Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups. INTERPRETATION: Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations. FUNDING: Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).

Effect of Maternal Docosahexaenoic Acid Supplementation on Bronchopulmonary Dysplasia-Free Survival in Breastfed Preterm Infants: A Randomized Clinical Trial.

Importance: Maternal docosahexaenoic acid (DHA) supplementation may prevent bronchopulmonary dysplasia, but evidence remains inconclusive. Objective: To determine whether maternal DHA supplementation during the neonatal period improves bronchopulmonary dysplasia-free survival in breastfed infants born before 29 weeks of gestation. Design, Setting, and Participants: Superiority, placebo-controlled randomized clinical trial at 16 Canadian neonatal intensive care units (June 2015-April 2018 with last infant follow-up in July 2018). Lactating women who delivered before 29 weeks of gestation were enrolled within 72 hours of delivery. The trial intended to enroll 800 mothers, but was stopped earlier. Interventions: There were 232 mothers (273 infants) assigned to oral capsules providing 1.2 g/d of DHA from randomization to 36 weeks' postmenstrual age and 229 mothers (255 infants) assigned to placebo capsules. Main Outcomes and Measures: The primary outcome was bronchopulmonary dysplasia-free survival in infants at 36 weeks' postmenstrual age. There were 22 secondary outcomes, including mortality and bronchopulmonary dysplasia. Results: Enrollment was stopped early due to concern for harm based on interim data from this trial and from another trial that was published during the course of this study. Among 461 mothers and their 528 infants (mean gestational age, 26.6 weeks [SD, 1.6 weeks]; 253 [47.9%] females), 375 mothers (81.3%) and 523 infants (99.1%) completed the trial. Overall, 147 of 268 infants (54.9%) in the DHA group vs 157 of 255 infants (61.6%) in the placebo group survived without bronchopulmonary dysplasia (absolute difference, -5.0% [95% CI, -11.6% to 2.6%]; relative risk, 0.91 [95% CI, 0.80 to 1.04], P = .18). Mortality occurred in 6.0% of infants in the DHA group vs 10.2% of infants in the placebo group (absolute difference, -3.9% [95% CI, -6.8% to 1.4%]; relative risk, 0.61 [95% CI, 0.33 to 1.13], P = .12). Bronchopulmonary dysplasia occurred in 41.7% of surviving infants in the DHA group vs 31.4% in the placebo group (absolute difference, 11.5% [95% CI, 2.3% to 23.2%]; relative risk, 1.36 [95% CI, 1.07 to 1.73], P = .01). Of 22 prespecified secondary outcomes, 19 were not significantly different. Conclusions and Relevance: Among breastfed preterm infants born before 29 weeks of gestation, maternal docosahexaenoic acid supplementation during the neonatal period did not significantly improve bronchopulmonary dysplasia-free survival at 36 weeks' postmenstrual age compared with placebo. Study interpretation is limited by early trial termination. Trial Registration: ClinicalTrials.gov Identifier: NCT02371460.

Impact of family integrated care on infants' clinical outcomes in two children's hospitals in China: a pre-post intervention study.

BACKGROUND: Most Neonatal Intensive Care Units (NICUs) in China have restricted visiting policies for parents. This also implicates that parents are not involved in the care of their infant. Family Integrated Care (FIC), empowering parents in direct care delivery and decisions, is becoming the standard in NICUs in many countries and can improve quality-of-life and health outcomes of preterm infants. The aim of this study was to evaluate the impact of a FIC intervention on the clinical outcomes of preterm infants with Bronchopulmonary Dysplasia (BPD). METHODS: A pre-post intervention study was conducted at NICUs in two Chinese children's hospitals. Infants with BPD were included: pre-intervention group (n = 134) from December 2015 to September 2016, post-intervention (FIC) group (n = 115) and their parents from October 2016 to June 2017. NICU nurses were trained between July and September 2016 to deliver the FIC intervention, including parent education and support. Parents had to be present and care for their infant minimal three hours a day. The infants' outcome measures were length-of-stay, breastfeeding, weight gain, respiratory and oxygen support, and parent hospital expenses. RESULTS: Compared with control group (n = 134), the FIC group (n = 115) had significantly increased breastfeeding rates (83% versus 71%, p = 0.030), breastfeeding time (31 days versus 19 days, p < 0.001), enteral nutrition time (50 days versus 34 days, p < 0.001), weight gain (29 g/day versus 23 g/day, p = 0.002), and significantly lower respiratory support time (16 days versus 25 days, p < 0.001). Oxygen Exposure Time decreased but not significant (39 days versus 41 days p = 0.393). Parents hospital expenses in local Chinese RMB currency was not significant (84 K versus 88 K, p = 0.391). CONCLUSION: The results of our study suggests that FIC is feasible in two Chinese NICUs and might improve clinical outcomes of preterm infants with BPD. Further research is needed to include all infants admitted to NICUs and should include parent reported outcome measures. Our study may help other NICUs with limited parental access to implement FIC to enhance parental empowerment and involvement in the care of their infant.

Up-date on the NeoVitaA Trial: Obstacles, challenges, perspectives, and local experiences.

The aim of the NeoVitaA Trial is to assess the role of postnatal additional high-dose oral vitamin A supplementation for 28 days in reducing Bronchopulmonary dysplasia (BPD) or death in extremely low birth weight (ELBW) infants at 36 weeks postmenstrual age (PMA). All infants (both intervention and control group) will be provided with basic vitamin A (1000 IU/kg/day) in addition to trial intervention.In this short communication, we will give an up-date on obstacles, challenges as well as perspectives and potential solutions when putting into place a multicenter, double-blind, randomized trial in this cohort of extremely susceptible infants.

[Delayed umbilical cord clamping in preterm infants born before 37 weeks of gestation: A prospective observational study]. / Clampage tardif du cordon ombilical chez les enfants prématurés nés avant 37 semaines d'aménorrhée : étude observationnelle prospective.

INTRODUCTION AND OBJECTIVES: Many international studies have demonstrated that delayed umbilical cord clamping reduces neonatal morbidity. However, in France, delayed umbilical cord clamping is still not performed in many neonatal units. The aims of this study were to evaluate the feasibility of developing a protocol of delayed umbilical cord clamping in the maternity ward of the Toulouse university hospital and to evaluate the impact of this new protocol on neonatal mortality. METHODS: We conducted a prospective observational study including 123 preterm infants born before 37 weeks of gestation between June 2012 and June 2013 and hospitalized at birth. Delayed cord clamping was performed for at least 30s after birth; otherwise, it was evaluated as early cord clamping. We excluded twin-to-twin transfusion syndrome, congenital abnormalities, alloimmunization, and perinatal asphyxia. We analyzed the reasons why delayed umbilical cord clamping was not performed and then neonatal morbidity in our population. RESULTS: Delayed umbilical cord clamping was performed on 79 infants and 44 infants had early umbilical cord clamping. The two groups had similar baseline characteristics. Preterm infants in the delayed cord-clamping group had a higher level of hemoglobin during the first 24h of life (17.9g/dL versus 16.6g/dL, P=0.005), fewer of them required transfusion (14% versus 35%, P=0.03), and fewer presented late-onset sepsis (8% versus 26%, P=0.02) or bronchopulmonary dysplasia (9% versus 26%, P=0.03). There was no statistically significant increase of hyperbilirubinemia requiring phototherapy. DISCUSSION AND CONCLUSION: Implanting a new protocol of delayed umbilical cord clamping in our maternity ward proved to be possible without difficulty. The advantages of delayed umbilical cord clamping were observed in this prospective study. Today, delayed cord clamping has become a common practice in our maternity unit.

Vitamin D and bronchopulmonary dysplasia in preterm infants.

OBJECTIVE: Vitamin D deficiency is associated with asthma and reactive airway disease in childhood but its potential contribution to bronchopulmonary dysplasia (BPD) in preterm infants is unknown. Preterm infants have lower levels of 25-hydroxyvitamin D (25(OH)D) at birth and are at risk for nutritional deficiencies after birth. The objective of the study was to evaluate the association of 25(OH)D concentrations at birth and at 36 weeks' corrected gestational age with BPD in preterm infants born before 29 completed weeks of gestation. STUDY DESIGN: We collected umbilical cord blood samples from 44 preterm infants (gestational age <29 weeks) delivered at Brigham and Women's Hospital in Boston. In addition, with parental consent we collected venous samples at 36 weeks' corrected age from 20 preterm infants born before 29 weeks' gestation (including 6 infants with previously collected cord blood). Samples were frozen at -80 °C until subsequent measurement of 25(OH)D levels by chemiluminescence. We used multivariable logistic models to adjust for gestational age and considered other confounding variables, including maternal race, age, mode of delivery and infant sex. RESULTS: Among 44 infants, 41 (93.2%) survived and 3 (6.8%) died before 36 weeks' corrected age. Median 25(OH)D levels at birth were 30.4 ng ml(-1) in preterm infants who subsequently died or developed BPD and 33.8 ng ml(-1) in infants who survived without BPD (P=0.6). Median 25(OH)D levels at corrected age of 36 weeks were 59.0 ng ml(-1) among survivors without BPD and 64.2 ng ml(-1) among survivors with BPD (P=0.9). Neither cord blood nor 36 weeks' corrected 25(OH)D levels were associated with odds of death or BPD (adjusted odds ratio (OR) 1.00, 95% confidence interval (CI): 0.73 to 1.37; and OR 0.93, 95% CI: 0.61 to 1.43, respectively). CONCLUSIONS: Among this population of extremely preterm infants neither cord blood nor the 36 weeks' corrected age 25(OH)D levels were associated with development of BPD. Notably, at the current level of supplementation, all extremely preterm infants in our cohort had achieved 25(OH)D levels >30 ng ml(-1) by 36 weeks' corrected age, which is thought to represent sufficiency in adult and pediatric populations.

Vitamin A Supplementation for Prevention of Bronchopulmonary Dysplasia: Cornerstone of Care or Futile Therapy?

OBJECTIVE: To review the evidence on vitamin A supplementation (VAS) and bronchopulmonary dysplasia (BPD) in extremely-low-birth-weight infants. We also discuss the impact of a vitamin A shortage on BPD rates. DATA SOURCES: A PubMed search inclusive of dates 1946 to March 2016 was performed using the search terms bronchopulmonary dysplasia, chronic lung disease (CLD), and vitamin A STUDY SELECTION AND DATA EXTRACTION: All English-language studies were evaluated. Only those investigating VAS by intramuscular administration were included. DATA SYNTHESIS: A total of 6 studies were evaluated. Additionally, a report on the incidence of BPD during a national shortage was reviewed. Investigators found mixed results with VAS and incidence of CLD or death in a varying number of neonates. In the largest evaluation, investigators found a statistically significant decrease in the rate of death or BPD: 55% in the VAS group versus 62% in the placebo group. The number needed to treat to prevent 1 case of BPD was 15 infants. Few studies found an increased incidence of adverse events following VAS. A report over a 2-year shortage period found that whereas the rate of VAS declined dramatically, BPD rates remained stable. This large observational evaluation calls into question the place of vitamin A in BPD prevention. CONCLUSIONS: VAS has been identified as a strategy to decrease the incidence of BPD. Initial large-scale prospective evaluations have shown clear benefit of VAS in reducing the incidence of CLD or death. However, changing definitions of BPD and implementation of noninvasive ventilation strategies limit the application of early studies. During a drug shortage, VAS declined dramatically, but BPD rates remained stable. With concerns of sepsis and necrotizing enterocolitis in small-scale studies, and in light of the recent shortage evidence, further evaluations are necessary before VAS can be recommended as a cornerstone of BPD prevention.

Early postnatal additional high-dose oral vitamin A supplementation versus placebo for 28 days for preventing bronchopulmonary dysplasia or death in extremely low birth weight infants.

BACKGROUND: Prematurity and the associated risk for bronchopulmonary dysplasia (BPD) remain a significant threat to extremely low birth weight (ELBW) infants. Vitamin A has been considered a therapeutic alternative in reducing the rate of BPD and mortality. OBJECTIVES: To investigate whether early postnatal, additional high-dose oral vitamin A supplementation for 28 days is more efficient in reducing BPD or death in ELBW infants than placebo treatment. METHODS: This is a multicenter, double-blind RCT comparing postnatal high-dose oral vitamin A supplementation (5,000 IU vitamin A/kg/day vs. placebo) for 28 days in ELBW neonates requiring mechanical ventilation, noninvasive ventilatory support or supplemental oxygen at 24 h of age. The primary end point is the proportion of children who died before 36 weeks' gestational age or developed moderate or severe BPD. BPD is defined as the need for supplemental oxygen to maintain SaO2 of ≥92% at rest at 36 weeks' postmenstrual age (PMA). Clinical secondary end points include the following: BPD (including mild form), intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, total number of days of mechanical ventilation and oxygen supplementation, and safety and tolerability of high-dose vitamin A supplementation. RESULTS AND CONCLUSIONS: The results of the NeoVitaA trial will provide robust data with regard to the efficacy of high-dose oral vitamin A supplementation in reducing the incidence of BPD or death at 36 weeks' PMA in ELBW infants.

Zinc supplementation reduces morbidity and mortality in very-low-birth-weight preterm neonates: a hospital-based randomized, placebo-controlled trial in an industrialized country.

BACKGROUND: Zinc plays a pivotal role in the pathogenesis of many diseases and in body growth. Preterm neonates have high zinc requirements. OBJECTIVE: The objective of the study was to investigate the efficacy of zinc supplementation in reducing morbidity and mortality in preterm neonates and to promote growth. DESIGN: This was a prospective, double-blind, randomized controlled study of very-low-birth-weight preterm neonates randomly allocated on the seventh day of life to receive (zinc group) or not receive (control group) oral zinc supplementation. Total prescribed zinc intake ranged from 9.7 to 10.7 mg/d in the zinc group and from 1.3 to 1.4 mg/d in the placebo control group. The main endpoint was the rate of neonates with ≥ 1 of the following morbidities: late-onset sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, periventricular leucomalacia, and retinopathy of prematurity. Secondary outcomes were mortality and body growth. RESULTS: We enrolled 97 neonates in the zinc group and 96 in the control group. Morbidities were significantly lower in the zinc group (26.8% compared with 41.7%; P = 0.030). The occurrence of necrotizing enterocolitis was significantly higher in the control group (6.3% compared with 0%; P = 0.014). Mortality risk was higher in the placebo control group (RR: 2.37; 95% CI: 1.08, 5.18; P = 0.006). Daily weight gain was similar in the zinc (18.2 ± 5.6 g · kg⁻¹ · d⁻¹) and control (17.0 ± 8.7 g · kg⁻¹ · d⁻¹) groups (P = 0.478). CONCLUSION: Oral zinc supplementation given at high doses reduces morbidities and mortality in preterm neonates. This trial was registered in the Australian New Zealand Clinical Trial Register as ACTRN12612000823875.

Tracheostomy placement in infants with bronchopulmonary dysplasia: safety and outcomes.

Optimizing the timing and safety for the placement of a tracheostomy in infants with bronchopulmonary dysplasia (BPD) has not been determined. The purpose of the present study was to describe the data from a single institution about the efficacy and safety of tracheostomy placement in infants with BPD needing long-term respiratory support. We established a service line for the comprehensive care of infants with BPD and we collected retrospective clinical data from this service line. We identified patients that had a trachostomy placed using the local Vermont-Oxford database, and obtained clinical data from chart reviews. We identified infants who had a tracheostomy placed for the indication of severe BPD only. Safety and respiratory efficacy was assessed by overall survival to discharge and the change in respiratory supportive care from just before placement to 1-month post-placement. Twenty-two patients (750 ± 236 g, 25.4 ± 2.1 weeks gestation) had a tracheostomy placed on day of life 177 ± 74 which coincided with a post-conceptual age of 51 ± 10 weeks. At placement these infants were on high settings to support their lung disease. The mean airway pressure (MAP) was 14.3 ± 3.3 cmH(2) O, the peak inspiratory pressure was 43.7 ± 8.0 cmH(2) O, and the FiO(2) was 0.51 ± 0.13. The mean respiratory severity score (MAP × FiO(2) ) 1 month after tracheostomy was significantly (P = 0.03) lower than prior to tracheostomy. Survival to hospital discharge was 77%. All patients with tracheostomies that survived were discharged home on mist collar supplemental oxygen. In conclusion, the high survival rate in these patients with severe BPD and the decreased respiratory support after placement of a tracheostomy suggests that high ventilatory pressures should not be a deterrent for placement of a tracheostomy. Future research should be aimed at determining optimal patient selection and timing for tracheostomy placement in infants with severe BPD.

Follow-up care for infants with chronic lung disease: a randomized comparison of community- and center-based models.

OBJECTIVES: Premature infants with chronic lung disease benefit from comprehensive care, which typically is based in tertiary medical centers. When such centers are not easily accessible, alternative models of care are needed. The purpose of this work was to compare community-based follow-up, provided via telephone contacts, to traditional center-based follow-up of premature infants with chronic lung disease. PATIENTS AND METHODS: After discharge from neonatal intensive care, 150 premature infants with chronic lung disease were randomly assigned to either community-based (n = 75) or center-based (n = 75) follow-up. In community-based follow-up, a nurse specialist maintained telephone contact with the infant's primary caregiver and health care providers. Center-based follow-up consisted of visits to a medical center-based multidisciplinary clinic staffed by a neonatologist, a nurse specialist, and a social worker. The outcomes of interest were Bayley Scales of Infant Development mental developmental index and psychomotor developmental index, Vineland Adaptive Behavioral Composite, and growth delay (weight for length <5th percentile) at 1-year adjusted age and respiratory rehospitalizations through 1-year adjusted age. RESULTS: In each randomization group, 73 infants survived, and 69 were evaluated at 1-year adjusted age. The median mental development index (corrected for gestational age) was 90 for both groups. The median psychomotor developmental index was 82 for the center-based group and 81 for the community-based group. The median Vineland Adaptive Behavioral Composite was 100 and 102 for the center-based and community-based groups, respectively. In the center-based and community-based groups, respectively, the proportions with growth delay were 13% and 26%, and the proportions rehospitalized for respiratory illness were 33% and 29%. CONCLUSIONS: Infants randomly assigned to community-based, as compared with those randomly assigned to center-based follow-up, had similar developmental and health outcomes. The former approach might be a preferred alternative for families in rural settings or families for whom access to a tertiary care medical center is difficult.

Low plasma retinol concentrations increase the risk of developing bronchopulmonary dysplasia and long-term respiratory disability in very-low-birth-weight infants.

BACKGROUND: The effect of inadequate vitamin A during the neonatal period on lung status is still unknown. OBJECTIVE: We tested the hypothesis that low plasma retinol concentrations during the first month of life are independently associated with bronchopulmonary dysplasia (BPD) and long-term respiratory morbidity at 6 mo gestationally corrected age (ie, the age the infant would be had the pregnancy gone to term). DESIGN: Respiratory outcome information was obtained to 6 mo corrected age for a historical cohort of very-low-birth-weight neonates (<1250 g) who were admitted to intensive care over a 7-y period. Neonates with one or more plasma measurements of retinol concentrations < 0.35 micromol/L (<100 microg/L) on days 1-28 were classified as having low vitamin A. BPD was defined at day 28 by clinical and radiologic criteria and by use of supplemental oxygen at 36 wk postmenstrual age (PMA). Dependence on supplemental oxygen was used to identify long-term respiratory disability at 6 mo corrected age. Multivariate logistic regression analyses were conducted. RESULTS: Of the 350 study infants, 192 (55%) had low vitamin A status. BPD occurred in 52% of survivors at day 28 (173/331) and at 36 wk PMA (147/285). Fourteen percent (33/244) required oxygen support at 6 mo corrected age. Adjusted odds ratios of BPD with low vitamin A were 3.5 (95% CI: 1.7, 7.2) at day 28 and 1.7 (1.0, 2.7) at 36 wk PMA. At 6 mo corrected age, the adjusted odds ratio was 2.6 (1.1, 6.4) for respiratory disability with low vitamin A. CONCLUSION: Poor vitamin A status during the first month of life significantly increased the risk of developing BPD and long-term respiratory disability.

Subependymal caudothalamic groove hyperechogenicity and neonatal chronic lung disease.

Chronic lung disease is associated with several poorly defined risk factors for impaired cerebral development. Late neonatal onset of subependymal hyperechogenic areas in the caudothalamic groove has been reported in association with dexamethasone treatment and postnatal cytomegalovirus infection. We reviewed charts of 18 patients who developed subependymal hyperechogenicity beyond the first week of life, as well as charts of 79 patients belonging to a prospective surfactant study group. Thirteen of the 18 patients with subependymal hyperdensities had been treated with surfactant and were all found in the subgroup with chronic lung disease. In the surfactant-treated patients who did not develop chronic lung disease, we could not find any patient with subependymal hyperdensities. From the remaining five patients with ultrasound lesions, but who were not treated with surfactant, three had developed chronic lung disease. There was no evident association with dexamethasone treatment or cytomegalovirus infection. Our results support the idea of an association between chronic lung disease and the described echographic lesions in the caudothalamic groove, but the nature of the link between them is still unclear.