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).

Enteral supplementation with arachidonic and docosahexaenoic acid and pulmonary outcome in extremely preterm infants.

Enteral supplementation with arachidonic acid (AA) and docosahexaenoic acid (DHA) in extremely preterm infants has shown beneficial effects on retinopathy of prematurity and pulmonary outcome whereas exclusive DHA supplementation has been associated with increased pulmonary morbidity. This secondary analysis evaluates pulmonary outcome in 204 extremely preterm infants, randomized to receive AA (100 mg/kg/day) and DHA (50 mg/kg/day) enterally from birth until term age or standard care. Pulmonary morbidity was primarily assessed based on severity of bronchopulmonary dysplasia (BPD). Serum levels of AA and DHA during the first 28 days were analysed in relation to BPD. Supplementation with AA:DHA was not associated with increased BPD severity, adjusted OR 1.48 (95 % CI 0.85-2.61), nor with increased need for respiratory support at post menstrual age 36 weeks or duration of oxygen supplementation. Every 1 % increase in AA was associated with a reduction of BPD severity, adjusted OR 0.73 (95 % CI 0.58-0.92). In conclusion, in this study, with limited statistical power, enteral supplementation with AA:DHA was not associated with an increased risk of pulmonary morbidity, but higher levels of AA were associated with less severe BPD. Whether AA or the combination of AA and DHA have beneficial roles in the immature lung needs further research.

Superoxide dismutase for bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Free oxygen radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. Superoxide dismutase (SOD) is a naturally occurring enzyme which provides a defense against such oxidant injury. Providing supplementary SOD has been tested in clinical trials to prevent BPD in preterm infants. OBJECTIVES: To determine the efficacy and safety of SOD in the prevention and treatment of BPD on mortality and other complications of prematurity in infants at risk for, or having BPD. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, and three trials registers on 22 September 2022 together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: Randomized, quasi-randomized and cluster-randomized controlled trials (RCTs) where the participants were preterm infants who had developed, or were at risk of developing BPD, and who were randomly allocated to receive either SOD (in any form, by any route, any dose, anytime) or placebo, or no treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality, mortality prior to discharge, and BPD or death at 36 weeks' postmenstrual age. We reported risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs) for the dichotomous outcomes. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included three RCTs (380 infants) on SOD administration in preterm infants at risk for BPD, and no studies in preterm infants with evolving BPD / early respiratory insufficiency. The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days (RR 1.09, 95% CI 0.94 to 1.26; RD 0.06, 95% CI -0.05 to 0.16, 1 study, 302 infants; I2 for RR and RD not applicable), BPD defined as oxygen at 36 weeks' postmenstrual age (RR 0.96, 95% CI 0.72 to 1.29; RD -0.01, 95% CI -0.11 to 0.09, 2 studies, 335 infants; I2 for RR and RD = 0%), neonatal mortality (RR 0.98, 95% CI 0.57 to 1.68; RD -0.00, 95% CI -0.08 to 0.07, 2 studies, 335 infants; I2 for RR and RD = 0%), and mortality prior to discharge (RR 1.20, 95% CI 0.53 to 2.71; RD 0.04, 95% CI -0.14 to 0.23, 2 studies, 78 infants; I2 for RR and RD = 0%). No studies reported BPD or death at 36 weeks' postmenstrual age. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage (RR 0.95, 95% CI 0.78 to 1.15; RD -0.03, 95% CI -0.15 to 0.08, 2 studies, 335 infants; I2for RR = 0%, I2 for RD = 8%), and severe retinopathy of prematurity (ROP) (RR 0.97, 95% CI 0.57 to 1.65; RD -0.01, 95% CI -0.10 to 0.09, 1 study, 244 infants; I2 for RR and RD not applicable). No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. Certainty of evidence was very low for all outcomes. We identified no ongoing trials. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality and mortality prior to discharge compared to placebo. No studies reported BPD or death at 36 weeks' postmenstrual age and need for supplemental oxygen. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage and severe retinopathy of prematurity. No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. The effects of SOD in preterm infants has not been reported in any trial in the last few decades, considering that the most recent trial on SOD in preterm infants was conducted in 1997/1998, and no new studies are ongoing. In the light of the limited available evidence, new data from preclinical and observational studies are needed to justify the conduction of new RCTs. Observational studies might report how SOD is administered, including indication, dose and association with relevant outcomes such as mortality, BPD and long-term neurodevelopment.

Nutrition-based implications and therapeutics in the development and recovery of bronchopulmonary dysplasia.

Premature births account for over 10% of live births worldwide. Bronchopulmonary dysplasia (BPD) represents a severe sequela in neonates born very prematurely and remains the most common chronic neonatal lung disease, often leading to serious adverse consequences in adulthood. Nutrition plays a crucial role in lung development and repair. Ongoing research has primarily focused on the pathogenesis and prevention of BPD in preterm birth. However, infants with established BPD need specialist medical care that persists throughout their hospitalization and continues after discharge. This manuscript aims to highlight the impact of growth and nutrition on BPD and highlight research gaps to provide direction for future studies. Protective practices include ensuring adequate early energy delivery through parenteral nutrition and enteral feedings while carefully monitoring total fluid intake and the use of breast milk over formula. These nutritional strategies remain the same for infants with established BPD with the addition of limiting the use of diuretics and steroids; but if employed, monitoring carefully without compromising total energy delivery. Functional nutrient supplements with a potential protective role against BPD are revisited, despite the limited evidence of their efficacy, including vitamins, trace elements, zinc, lipids, and sphingolipids. Planning post-intensive care and outpatient longitudinal nutrition support is critical in caring for an infant with established BPD.

Enteral supplementation with high-dose docosahexaenoic acid on the risk of bronchopulmonary dysplasia in very preterm infants: a collaborative study protocol for an individual participant data meta-analysis.

INTRODUCTION: Severe bronchopulmonary dysplasia (BPD) is a well-known factor consistently associated with impaired cognitive outcomes. Regarding reported benefits on long-term neurodevelopmental outcomes, the potential adverse effects of high-dose docosahexaenoic acid (DHA) supplementation on this short-term neonatal morbidity need further investigations in infants born very preterm. This study will determine whether high-dose DHA enteral supplementation during the neonatal period is associated with the risk of severe BPD at 36 weeks' postmenstrual age (PMA) compared with control, in contemporary cohorts of preterm infants born at less than 29 weeks of gestation. METHODS AND ANALYSIS: As part of an Australian-Canadian collaboration, we will conduct an individual participant data (IPD) meta-analysis of randomised controlled trials targeting infants born at less than 29 weeks of gestation and evaluating the effect of high-dose DHA enteral supplementation in the neonatal period compared with a control. Primary outcome will be severe grades of BPD (yes/no) at 36 weeks' PMA harmonised according to a recent definition that predicts early childhood morbidities. Other outcomes will be survival without severe BPD, death, BPD severity grades, serious brain injury, severe retinopathy of prematurity, patent ductus arteriosus and necrotising enterocolitis requiring surgery, sepsis, combined neonatal morbidities and growth. Severe BPD will be compared between groups using a multivariate generalised estimating equations log-binomial regression model. Subgroup analyses are planned for gestational age, sex, small-for-gestational age, presence of maternal chorioamnionitis and mode of delivery. ETHICS AND DISSEMINATION: The conduct of each trial was approved by institutional research ethics boards and written informed consent was obtained from participating parents. A collaboration and data sharing agreement will be signed between participating authors and institutions. This IPD meta-analysis will document the role of DHA in nutritional management of BPD. Findings will be disseminated through conferences, media interviews and publications to peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42023431063. TRIAL REGISTRATION NUMBER: NCT05915806.

Mediation Analysis to Untangle Opposing Associations of High-Dose Docosahexaenoic Acid With IQ and Bronchopulmonary Dysplasia in Children Born Preterm.

Importance: High-dose omega-3 docosahexaenoic acid (DHA) supplementation of children born at less than 29 weeks' gestation has been shown to improve IQ despite increasing the risk of bronchopulmonary dysplasia (BPD). Given that BPD is associated with poorer cognitive outcomes, it is unclear whether the increased risk of BPD with DHA supplementation is associated with decreased benefit to IQ. Objective: To investigate whether the increased risk of BPD with DHA supplementation was associated with diminished IQ benefit. Design, Setting, and Participants: This cohort study used data collected from a multicenter, blinded, randomized controlled trial of DHA supplementation in children born at less than 29 weeks' gestation. Participants were recruited from 2012 to 2015 and followed up until 5 years' corrected age. Data were analyzed from November 2022 to February 2023. Interventions: Enteral DHA emulsion (60 mg/kg/d, to match the estimated in-utero requirement) or a control emulsion from the first 3 days of enteral feeds until 36 weeks' postmenstrual age or discharge home. Main Outcomes and Measures: Physiological BPD was assessed at 36 weeks' postmenstrual age. IQ was assessed at 5 years' corrected age using the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition; children from the 5 highest-recruiting Australian hospitals were assessed. The total effect of DHA supplementation on IQ was divided into direct and indirect effects using mediation analysis, with BPD as the presumed mediating variable. Results: Among 656 surviving children from hospitals involved in IQ follow-up (mean [SD] gestational age at birth, 26.8 [1.4] weeks; 346 males [52.7%]), there were 323 children with DHA supplementation and 333 children in the control group. Mean IQ was 3.45 points (95% CI, 0.38 to 6.53 points) higher in the DHA group than the control group, despite an increase in the risk of BPD (160 children [49.7%] vs 143 children [42.8%] with BPD). The indirect effect of DHA on IQ via BPD was not statistically significant (-0.17 points; 95% CI, -0.62 to 0.13 points), with most of the effect of DHA on IQ occurring independently of BPD (direct effect = 3.62 points; 95% CI, 0.55 to 6.81 points). Conclusions and Relevance: This study found that associations of DHA with BPD and IQ were largely independent. This finding suggests that if clinicians supplement children born preterm with high-dose DHA, any resulting increase in BPD risk would not be associated with meaningful reductions in the IQ benefit.

Prenatal vitamin D supplementation mitigates inflammation-related alveolar remodeling in neonatal mice.

The development of chronic lung disease in the neonate, also known as bronchopulmonary dysplasia (BPD), is the most common long-term complication in prematurely born infants. In BPD, the disease-characteristic inflammatory response culminates in nonreversible remodeling of the developing gas exchange area, provoked by the impact of postnatal treatments such as mechanical ventilation (MV) and oxygen treatment. To evaluate the potential of prenatal treatment regimens to modulate this inflammatory response and thereby impact the vulnerability of the lung toward postnatal injury, we designed a multilayered preclinical mouse model. After administration of either prenatal vitamin D-enriched (VitD+; 1,500 IU/g food) or -deprived (VitD-; <10 IU/kg) food during gestation in C57B6 mice (the onset of mating until birth), neonatal mice were exposed to hyperoxia (FiO2 = 0.4) with or without MV for 8 h at days 5-7 of life, whereas controls spontaneously breathed room air. Prenatal vitamin D supplementation resulted in a decreased number of monocytes/macrophages in the neonatal lung undergoing postnatal injury together with reduced TGF-ß pathway activation. In consequence, neonatal mice that received a VitD+ diet during gestation demonstrated less extracellular matrix (ECM) remodeling upon lung injury, reflected by the reduction of pulmonary α-smooth muscle actin-positive fibroblasts, decreased collagen and elastin deposition, and lower amounts of interstitial tissue in the lung periphery. In conclusion, our findings support strategies that attempt to prevent vitamin D insufficiency during pregnancy as they could impact lung health in the offspring by mitigating inflammatory changes in neonatal lung injury and ameliorating subsequent remodeling of the developing gas exchange area.NEW & NOTEWORTHY Vitamin D-enriched diet during gestation resulted in reduced lung inflammation and matrix remodeling in neonatal mice exposed to clinically relevant, postnatal injury. The results underscore the need to monitor the subclinical effects of vitamin D insufficiency that impact health in the offspring when other risk factors come into play.

Association Between Enteral Supplementation With High-Dose Docosahexaenoic Acid and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-analysis.

Importance: High-dose docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid, may affect the risk of bronchopulmonary dysplasia (BPD). However, high-level summative evidence supporting such clinical association in very preterm infants is lacking. Objective: To examine the association between enteral supplementation with high-dose DHA during the neonatal period and the risk of BPD in preterm infants born at less than 29 weeks' gestation. Data Sources: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, medRxiv, and ClinicalTrials.gov were searched from inception to August 1, 2022, for eligible articles with no language restrictions. Study Selection: Randomized clinical trials (RCTs) were eligible for inclusion (1) if their interventions involved direct administration of a minimum DHA supplementation of 40 mg/kg/d or breast milk or formula feeding of at least 0.4% of total fatty acids, and (2) if they reported data on either BPD, death, BPD severity, or a combined outcome of BPD and death. Data Extraction and Synthesis: Two investigators completed independent review of titles and abstracts, full text screening, data extraction, and quality assessment using the Cochrane Risk of Bias 2.0. Risk ratios (RRs) with 95% CIs were pooled using random-effect meta-analyses. Main Outcomes and Measures: Primary outcome was BPD using trial-specific definitions, which was further stratified for RCTs that used a more stringent BPD definition based on systematic pulse oximetry assessment at 36 weeks' postmenstrual age. Other outcomes were BPD, death, BPD severity, or combined BPD and death. Results: Among the 2760 studies screened, 4 RCTs were included, which involved 2304 infants (1223 boys [53.1%]; mean [SD] gestational age, 26.5 [1.6] weeks). Enteral supplementation with high-dose DHA was associated with neither BPD (4 studies [n = 2186 infants]; RR, 1.07 [95% CI, 0.86-1.34]; P = .53; I2 = 72%) nor BPD or death (4 studies [n = 2299 infants]; RR, 1.04 [95% CI, 0.91-1.18]; P = .59; I2 = 61%). However, an inverse association with BPD was found in RCTs that used a more stringent BPD definition (2 studies [n = 1686 infants]; RR, 1.20 [95% CI, 1.01-1.42]; P = .04; I2 = 48%). Additionally, DHA was inversely associated with moderate-to-severe BPD (3 studies [n = 1892 infants]; RR, 1.16 [95% CI, 1.04-1.29]; P = .008; I2 = 0%). Conclusions and Relevance: Results of this study showed that enteral supplementation with high-dose DHA in the neonatal period was not associated overall with BPD, but an inverse association was found in the included RCTs that used a more stringent BPD definition. These findings suggest that high-dose DHA supplementation should not be recommended to prevent BPD in very preterm infants.

The prevention and management strategies for neonatal chronic lung disease.

INTRODUCTION: Survival from even very premature birth is improving, but long-term respiratory morbidity following neonatal chronic lung disease (bronchopulmonary dysplasia (BPD)) has not reduced. Affected infants may require supplementary oxygen at home, because they have more hospital admissions particularly due to viral infections and frequent, troublesome respiratory symptoms requiring treatment. Furthermore, adolescents and adults who had BPD have poorer lung function and exercise capacity. AREAS COVERED: Antenatal and postnatal preventative strategies and management of infants with BPD. A literature review was undertaken using PubMed and Web of Science. EXPERT OPINION: There are effective preventative strategies which include caffeine, postnatal corticosteroids, vitamin A, and volume guarantee ventilation. Side-effects, however, have appropriately caused clinicians to reduce use of systemically administered corticosteroids to infants only at risk of severe BPD. Promising preventative strategies which need further research are surfactant with budesonide, less invasive surfactant administration (LISA), neurally adjusted ventilatory assist (NAVA) and stem cells. The management of infants with established BPD is under-researched and should include identifying the optimum form of respiratory support on the neonatal unit and at home and which infants will most benefit in the long term from pulmonary vasodilators, diuretics, and bronchodilators.

Effect of arachidonic and docosahexaenoic acid supplementation on respiratory outcomes and neonatal morbidities in preterm infants.

BACKGROUND & AIMS: Studies have suggested that supplementation with docosahexaenoic acid (DHA) to preterm infants might be associated with an increased risk of bronchopulmonary dysplasia (BPD). Our aim was to investigate the effect of enteral supplementation with arachidonic acid (ARA) and DHA on short-term respiratory outcomes and neonatal morbidities in very preterm infants. METHODS: This is a secondary analysis of data from the ImNuT (Immature, Nutrition Therapy) study, a randomized double blind clinical trial. Infants with gestational age less than 29 weeks were randomized to receive a daily enteral supplement with ARA 100 mg/kg and DHA 50 mg/kg (intervention) or medium chain triglycerides (MCT) oil (control), from second day of life to 36 weeks postmenstrual age. Study outcomes included duration of respiratory support, incidence of BPD and other major morbidities associated with preterm birth. RESULTS: 120 infants with mean (SD) gestational age 26.4 (1.7) weeks were randomized and allocated to either the intervention or control group. Supplementation with ARA and DHA led to a significant reduction in number of days with respiratory support (mean (95% CI) 63.4 (56.6-71.3) vs 80.6 (72.4-88.8); p = 0.03) and a lower oxygen demand (FiO2) (mean (95% CI) 0.26 (0.25-0.28) vs 0.29 (0.27-0.30); p = 0.03) compared to control treatment. There were no clinically important differences in incidence of BPD and other major morbidities between the treatment groups. CONCLUSIONS: Supplementation with ARA and DHA to preterm infants was safe and might have a beneficial effect on respiratory outcomes. CLINICAL TRIAL REGISTRATION: The trial has been registered in www. CLINICALTRIALS: gov, ID: NCT03555019.

Safety and Efficacy of Early Vitamin D Supplementation in Critically Ill Extremely Preterm Infants: An Ancillary Study of a Randomized Trial.

BACKGROUND: Despite substantial evidence that vitamin D deficiency is highly prevalent among infants born extremely preterm (≤28 weeks' of gestation), several consensus statements do not recommend vitamin D doses >400 IU/day for these infants. Safety remains a concern. OBJECTIVE: The study aim was to determine safety and efficacy profiles of enteral vitamin D in Black and White infants randomized to three different vitamin D doses soon after birth. DESIGN: Ancillary study of a masked randomized clinical trial. PARTICIPANTS/SETTING: Seventy-three infants born extremely preterm between 2012 and 2015 at a southern US academic neonatal unit (33' latitude) who had >90% compliance with the assigned intervention were included. INTERVENTION: Infants were randomized to receive placebo (placebo group), 200 IU/day vitamin D (200 IU group), or 800 IU/day vitamin D (800 IU group) during the first 28 days after birth. MAIN OUTCOME MEASURES: Safety outcomes included serum 25-hydroxy vitamin D (25[OH]D) and calcium concentrations. Efficacy outcomes included the predictive risk of bronchopulmonary dysplasia. STATISTICAL ANALYSIS: Per-protocol analysis using unadjusted, repeated-measures mixed models. RESULTS: Mean birth weight was 815 ± 199 g. Half were male and 56% were Black. Of 58 infants with 25(OH)D measurements at birth, 40 (69%) had vitamin D deficiency (<20 ng/mL). The mean difference in 25(OH)D in nanograms per milliliter between Postnatal Day 28 and Postnatal Day 1 was +9 in the placebo group, +23 in the 200 IU group, and +62 in the 800 IU group (P < 0.0001). The increase observed in 25(OH)D was more significant among Black infants. The predictive risk of severe bronchopulmonary dysplasia in the 200 IU and 800 IU groups was lower, but this difference did not reach statistical significance. No vitamin D or calcium toxicity was observed. CONCLUSIONS: A vitamin D dose of 800 IU/day safely corrected vitamin D deficiency by Postnatal Day 14.

High doses of enteral docosahexaenoic acid omega-3 supplementation for prevention of bronchopulmonary dysplasia in very preterm infants: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Docosahexaenoic acid (DHA) supplementation in the neonatal period has been proposed to prevent bronchopulmonary dysplasia (BPD) in very preterm infants. We aim to determine the effects of an enteral supplementation with high doses of DHA on the risk for BPD at 36 weeks' postmenstrual age (PMA) in very preterm infants born less than 29 weeks' gestation compared with a control. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) searching PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, MedRxiv, ClinicalTrials.gov (up to 1 November 2021) as well as reference lists and citations of included articles and previous reviews. RCTs targeting infants born less than 29 weeks' gestation and evaluating the effect of high doses of DHA enteral supplementation in the neonatal period compared with a control will be eligible. Primary outcome will be BPD defined as the need for oxygen and/or ventilation at 36 weeks' PMA. Two authors will independently screen for inclusion, extract data and assess data quality using the Cochrane instrument (risk-of-bias tool 2.0). We will perform meta-analysis using random effects models. Prespecified subgroup analyses are planned for the infant gestational age and sex, the marine source of DHA, mode of administration and duration of exposure. Sensitivity analysis will be performed according to the accuracy of the BPD definition (ie, physiological definition) and according to the risk of bias of the RCTs. ETHICS AND DISSEMINATION: This protocol for a systematic review and meta-analysis does not require ethics approval, as no primary data are collected. This study will assess the effectiveness of high doses of enteral DHA supplementation on BPD and provide evidence to clinicians and families for decision-making. Findings will be disseminated through conferences, media interviews and publications to peer review journals. PROSPERO REGISTRATION NUMBER: CRD42021286705.

Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years.

BACKGROUND: Docosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks' gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood. METHODS: We assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks' gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI. RESULTS: A total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available - 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P = 0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups. CONCLUSIONS: In infants born before 29 weeks' gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.).

Use of SMOF lipid emulsion in very preterm infants does not affect the incidence of bronchopulmonary dysplasia-free survival.

BACKGROUND: We aim to assess whether the docosahexaenoic acid (DHA)-containing lipid emulsion (LE) SMOFlipid 20% (Fresenius Kabi Canada Ltd) is associated with bronchopulmonary dysplasia (BPD)-free survival at 36 weeks' postmenstrual age in very preterm infants. METHODS: This cohort study is nested in the MOBYDIck randomized clinical trial (NCT02371460), which investigated the effect of maternal DHA supplementation on BPD-free survival in breastfed very preterm infants born between 23 0/7 and 28 6/7 weeks' gestation in 16 Canadian neonatal intensive care units (2015-2018). Parenteral SMOF-LE was given to the infants according to the sites' routine care protocols. Relative risks (RRs) were estimated using a modified Poisson regression model with generalized estimating equations taking into account recruitment site, multiple birth, DHA supplementation, birth weight, sex, and gestational age. RESULTS: Among 528 infants (mean gestational age, 26.5 weeks [SD, 1.6]), 272 received SMOF-LE. Overall, 56.7% of the infants in the SMOF-LE group and 59.7% infants in the non-SMOF-LE group survived without BPD (adjusted RR, 0.94 [95% CI, 0.77-1.14]; P = 0.51). BPD rates were 39.3% in the SMOF-LE group vs 34.1% in the non-SMOF-LE group (adjusted RR, 1.10 [95% CI, 0.82-1.47]; P = 0.53). Severe BPD rates were 31.8% in the SMOF-LE group vs 28.8% in the non-SMOF-LE group (adjusted P = 0.59). Mortality was not significantly different between the SMOF-LE (6.7%) and non-SMOF-LE groups (9.5%; adjusted P = 0.40). CONCLUSION: In very preterm infants, intravenous DHA-containing SMOF-LE during the neonatal period was not associated with BPD-free survival.

Oral vitamin A supplementation in preterm infants to improve health outcomes: A systematic review and meta-analysis.

OBJECTIVE: To determine the effects of oral vitamin A supplementation on clinical outcomes in preterm infants. DESIGN: We conducted the meta-analysis by searching PubMed/Medline, Scopus, Embase, CINAHL, and the Cochrane Library databases from inception to 12 August 2021, including reference lists of retrieved articles. Only randomized controlled trials (RCTs) evaluating the effects of oral vitamin A on premature babies were included. We used a random-effects model to calculate risk ratios (RRs) and weighted mean differences (MDs) with 95% confidence intervals (CIs). We used the GRADE approach to grade evidence quality and assess how oral vitamin A supplementation affects clinical outcomes. MAIN OUTCOMES MEASURES: The primary outcomes were respiratory outcomes, including the length of respiratory support, the need for oxygen at 36 weeks postmenstrual age (PMA), and moderate-to-severe bronchopulmonary dysplasia (BPD) at 36 weeks PMA. Secondary outcomes were hospitalization time, vitamin A status, mortality, other related outcomes, and potential adverse drug-related events. RESULTS: We included four RCTs, with 800 patients total. In all trials, oral vitamin A treatment was compared to a placebo. Oral vitamin A supplementation did not significantly affect mechanical ventilation duration (MD, -1.07 days; 95% CI, -2.98 to 0.83 days), oxygen requirement at 36 weeks PMA (RR, 0.65; 95% CI, 0.33 to 1.31), or moderate-to-severe BPD at 36 weeks PMA (RR, 0.53; 95% CI, 0.07 to 4.17). However, oral vitamin A supplementation yielded a slightly shorter noninvasive ventilation duration (MD, -0.96 days; 95% CI, -1.59 to -0.33 days). CONCLUSIONS: Administering oral vitamin A to preterm newborns did not alter the mechanical ventilation duration, oxygen needed at 36 weeks PMA, moderate-to-severe BPD at 36 weeks PMA, death, or short-term benefits. However, oral vitamin A supplementation may slightly affect the duration of noninvasive respiratory support without adverse drug-related events.

Interventions to Prevent Bronchopulmonary Dysplasia in Preterm Neonates: An Umbrella Review of Systematic Reviews and Meta-analyses.

IMPORTANCE: Bronchopulmonary dysplasia (BPD) has multifactorial etiology and long-term adverse consequences. An umbrella review enables the evaluation of multiple proposed interventions for the prevention of BPD. OBJECTIVE: To summarize and assess the certainty of evidence of interventions proposed to decrease the risk of BPD from published systematic reviews. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and Web of Science were searched from inception until November 9, 2020. STUDY SELECTION: Meta-analyses of randomized clinical trials comparing interventions in preterm neonates that included BPD as an outcome. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed in duplicate. Quality of systematic reviews was evaluated using Assessment of Multiple Systematic Reviews version 2, and certainty of evidence was assessed using Grading of Recommendation, Assessment, Development, and Evaluation. MAIN OUTCOMES AND MEASURES: (1) BPD or mortality at 36 weeks' postmenstrual age (PMA) and (2) BPD at 36 weeks' PMA. RESULTS: A total of 154 systematic reviews evaluating 251 comparisons were included, of which 110 (71.4%) were high-quality systematic reviews. High certainty of evidence from high-quality systematic reviews indicated that delivery room continuous positive airway pressure compared with intubation with or without routine surfactant (relative risk [RR], 0.80 [95% CI, 0.68-0.94]), early selective surfactant compared with delayed selective surfactant (RR, 0.83 [95% CI, 0.75-0.91]), early inhaled corticosteroids (RR, 0.86 [95% CI, 0.75-0.99]), early systemic hydrocortisone (RR, 0.90 [95% CI, 0.82-0.99]), avoiding endotracheal tube placement with delivery room continuous positive airway pressure and use of less invasive surfactant administration (RR, 0.90 [95% CI, 0.82-0.99]), and volume-targeted compared with pressure-limited ventilation (RR, 0.73 [95% CI, 0.59-0.89]) were associated with decreased risk of BPD or mortality at 36 weeks' PMA. Moderate to high certainty of evidence showed that inhaled nitric oxide, lower saturation targets (85%-89%), and vitamin A supplementation are associated with decreased risk of BPD at 36 weeks' PMA but not the competing outcome of BPD or mortality, indicating they may be associated with increased mortality. CONCLUSIONS AND RELEVANCE: A multipronged approach of delivery room continuous positive airway pressure, early selective surfactant administration with less invasive surfactant administration, early hydrocortisone prophylaxis in high-risk neonates, inhaled corticosteroids, and volume-targeted ventilation for preterm neonates requiring invasive ventilation may decrease the combined risk of BPD or mortality at 36 weeks' PMA.

Protective Effects of 18ß-Glycyrrhetinic Acid on Neonatal Rats with Hyperoxia Exposure.

Bronchopulmonary dysplasia (BPD) is a common devastating pulmonary complication in preterm infants. Supplemental oxygen is a lifesaving therapeutic measure used for premature infants with pulmonary insufficiency. However, oxygen toxicity is a significant trigger for BPD. Oxidative stress disrupts lung development, accompanied by increased pro-inflammatory cytokines and chemokines expression and immune cells infiltration in lung tissue. Licorice, a typical traditional herbal medicine, is commonly used in the medicine and food industries. 18ß-Glycyrrhetinic acid (18ß-GA), a primary active ingredient of licorice, has powerful anti-oxidative and anti-inflammatory effects. This study aimed to determine whether 18ß-GA has a protective effect on neonatal rats with hyperoxia exposure. Newborn Sprague-Dawley rats were kept in either 21% (normoxia) or 80% O2 (hyperoxia) continuously from postnatal day (PN) 1 to 14. 18ß-GA was injected intragastrically at 50 or 100 mg/kg body weight once a day from PN 1 to 14. We examined the body weight and alveolar development and measured ROS level and the markers of pulmonary inflammation. Mature-IL-1ß and NF-κB pathway proteins, and the NLRP3 inflammasome, were assessed; concurrently, caspase-1 activity was measured. Our results indicated that hyperoxia resulted in alveolar simplification and decreased bodyweight of neonatal rats. Hyperoxia increased ROS level and pulmonary inflammation and activated NF-κB and the NLRP3 inflammasome. 18ß-GA treatment inhibited the activation of NF-κB and the NLRP3 inflammasome, decreased ROS level and pulmonary inflammation, improved alveolar development, and increased the bodyweight of neonatal rats with hyperoxia exposure. Our study demonstrates that 18ß-GA has a protective effect on neonatal rats with hyperoxia exposure.

Stability of glutathione added as a supplement to parenteral nutrition.

BACKGROUND: Most very premature newborns (<32 weeks of gestation) receive parenteral nutrition (PN) that is inherently contaminated with peroxides. Oxidative stress induced by PN is associated with bronchopulmonary dysplasia, a main pathological complication in these infants who have weak antioxidant capacity to detoxify peroxides because of their glutathione deficiency. In animals, glutathione supplementation of PN prevented oxidative stress and alveolar loss (the main characteristic of bronchopulmonary dysplasia). Of its two forms-oxidized glutathione (GSSG) and reduced glutathione (GSH)-GSSG was used because of its better stability. However, a 30% loss of GSSG in PN is observed. The potentially high therapeutic benefits of GSSG supplementation on the health of very premature infants make the study of its stability highly important. METHODS: GSSG was incubated in combination with the following components of PN: dextrose, multivitamins, Primene, and Travasol, and with cysteine, cystine, and peroxides, for 24 h. Total glutathione in these solutions was measured 0-24 h after the addition of GSSG. RESULTS: The combination of cysteine and multivitamins caused the maximum loss of glutathione. The stability of GSSG was not affected by multivitamins. The cysteine was responsible for ∼20% of the loss of GSSG; in the presence of multivitamins, the loss reached >70%. Removing the cysteine prevented the degradation of glutathione. CONCLUSION: GSSG reacts with cysteine to form cysteine-glutathione mixed disulfide, another suitable glutathione substrate for preterm neonates. The study confirms that GSSG added to PN can potentially provide a precursor to de novo synthesis of glutathione in vivo.

Docosahexaenoic acid and bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common and serious complication of extremely preterm birth. Given the anti-inflammatory properties, docosahexaenoic acid (DHA) supplementation has been proposed as a strategy for the management of BPD. This study aimed to investigate the effects of DHA supplementation on BPD based on a systematic review. METHODS: A comprehensive literature search was conducted using ClinicalTrials.Gov, CINAHL, Cochrane Library, EMBASE, MEDLINE, PubMed, and the WHO ICTRP from their respective dates of inception to June 2017. The studies included were randomized controlled trials (RCTs) that enrolled preterm infants <33 weeks of gestational age. Trials were included if DHA supplementation was compared with a control. RESULTS: Four RCTs from five reports (1,966 neonates) met our inclusion criteria. The meta-analysis of these studies showed that DHA supplementation did not decrease the risk of BPD at 36 weeks of postmenstrual age among preterm infants (low certainty of evidence). DHA supplementation did not significantly reduce the risk of other neonatal morbidities including death (low certainty of evidence), BPD at 28 days of life (moderate certainty of evidence), necrotizing enterocolitis (low certainty of evidence), intraventricular hemorrhage, severe retinopathy of prematurity, or sepsis. CONCLUSION: DHA supplementation may not exert significant clinical benefits in the treatment of BPD and other neonatal morbidities.

Vitamin E and preterm infants.

In evaluating vitamin E (VE) nutritional status of preterm infants, it is essential that any data should be compared with those of healthy term infants, and never with those of adults. Moreover, it should be evaluated in terms of gestational age (GA), not birth weight (BW), because placental transfer of most nutrients from mother to fetus is dependent on GA, not BW. Judging from the limited data during the last 75 years, there was no significant correlation between GA and VE concentrations in circulation or in the red blood cells (RBCs), leukocytes, and buccal mucosal cells. In addition, the oxidizability of polyunsaturated fatty acids (PUFAs) in plasma or RBCs, as targets for protection by VE chain-breaking ability, was lower in preterm infants. However, because of the minimal information available about hepatic VE levels, which is considered a key determinant of whole body VE status, the decision on whether VE status of preterm infants is comparable with that of term infants should be postponed. Clinical trials of VE supplementation in preterm infants were repeatedly undertaken to investigate whether VE reduces severity or inhibits development of several diseases specific to preterm infants, namely retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and germinal matrix hemorrhage - intraventricular hemorrhage (GMH-IVH). Most of these trials resulted in a misfire, with a few exceptions for IVH prevention. However, almost all these studies were performed from 1980s to early 1990s, in the pre-surfactant era, and the study populations were composed of mid-preterm infants with GAs of approximately 30 weeks (wks). There is considerable difference in 'preterm infants' between the pre- and post-surfactant eras; modern neonatal medicine mainly treats preterm infants of 28 wks GA or less. Therefore, these results are difficult to apply in modern neonatal care. Before considering new trials of VE supplementation, we should fully understand modern neonatal medicine, especially the recent method of oxygen supplementation. Additionally, a deeper understanding of recent progress in pathophysiology and therapies for possible target diseases is necessary to decide whether VE administration is still worth re-challenging in modern neonatal intensive care units (NICUs). In this review, we present recent concepts and therapeutic trends in ROP, BPD, and GMH-IVH for those unfamiliar with neonatal medicine. Numerous studies have reported the possible involvement of reactive oxygen species (ROS)-induced damage in relation to supplemental oxygen use, inflammation, and immature antioxidant defense in the development of both BPD and ROP. Various antioxidants effectively prevented the exacerbation of BPD and ROP in animal models. In the future, VE should be re-attempted as a complementary factor in combination with various therapies for BPD, ROP, and GMH-IVH. Because VE is a natural and safe supplement, we are certain that it will attract attention again in preterm medicine.