Lung function in preterm infants at 3 months corrected age after neonatal LC-PUFA supplementation.

OBJECTIVE: To test the hypothesis that long-chain polyunsaturated fatty acid (LC-PUFA) supplementation improves lung function at 3 months corrected age (CA) compared with standard treatment in very preterm infants. We also aimed to investigate the association between bronchopulmonary dysplasia (BPD), longitudinal growth, and lung function at 3 months CA. METHODS: A secondary analysis from the ImNuT trial, in which 121 infants with gestational age <29 weeks were randomized to a daily supplement with arachidonic acid (ARA) and docosahexaenoic acid (DHA) (ARA:DHA group) or MCT-oil (control group) from birth up to 36 weeks postmenstrual age (PMA). Lung function was assessed at 3 months CA by tidal flow volume loops and the outcomes were the ratio of time to peak tidal expiratory flow to expiratory time (tPTEF /tE ) and tidal volume (VT ) per body weight (mL/kg). RESULTS: Thirty-nine infants in the ARA:DHA group versus 51 in the control group had a successful lung function test. There was no mean difference (MD) in tPTEF /tE ratio (MD: 0.01, 95% confidence interval [CI]: -0.04 to 0.05; p = .77) or VT (MD: 0.09 mL/kg, 95% CI: -0.79 to 0.62; p = .81) between the study groups. The multivariable regression model showed that BPD was associated with tPTEF /tE ratio ≤ 0.25 (p = .03) and that an increase in z score for length after 36 weeks PMA correlated positively with VT (mL/kg) (p = .03). CONCLUSION: Neonatal LC-PUFA supplementation did not improve lung function at 3 months CA in very preterm infants. BPD was independently associated with reduced lung function, while improved linear growth correlated with higher tidal volumes.

Family Integrated Care Shortens the Duration of Home Oxygen Therapy in Infants With Bronchopulmonary Dysplasia.

BACKGROUND: There have been few reports on whether family integrated care (FIC) can help premature infants with moderate to severe bronchopulmonary dysplasia (BPD) to shorten the duration of home oxygen therapy (HOT). PURPOSE: To investigate the effect of FIC on the duration of HOT in premature infants with moderate to severe BPD. METHODS: The subjects were retrospectively selected from premature infants with moderate to severe BPD in our center between June 2019 and December 2021. Patients were divided into the FIC group (n = 47) and the non-FIC group (n = 34). For univariate analysis, t test, Mann-Whitney U test, Pearson χ 2 test, or Fisher exact test was performed to explore the differences between the 2 groups. For multivariate analysis, simple and multiple linear regression was conducted to explore the effect of FIC on the duration of HOT. RESULTS: (1) The duration of HOT and length of stay after grouping were significantly shorter in the FIC group than in the non-FIC group ( P < .05). (2) The results of linear regression further revealed that FIC could significantly shorten the duration of HOT (simple linear regression, FIC [A] B : -12.709, 95% confidence interval (CI): -21.665 to -3.753; multiple linear regression, FIC [B] B : -11.419, 95% CI: -18.055 to -4.783). IMPLICATIONS FOR PRACTICE AND RESEARCH: FIC improved the optimal target oxygen saturation ratio before discharge and shortened the duration of HOT in premature infants with moderate and severe BPD. FIC should be promoted in China's neonatal intensive care units, though it puts forward new requirements for nursing education and training.

Is 25OH Vitamin D Excess before 36 Weeks Corrected Age an Independent Risk Factor for Bronchopulmonary Dysplasia or Death?

Low 25-Hydroxyvitamin D (25(OH)D) in preterm infants is a risk factor for bronchopulmonary dysplasia (BPD), but increased supplementation failed to demonstrate a beneficial effect on BPD. In neonatal animal models, deficiency and excessive vitamin D exposure have been associated with increased mortality and histological alterations in the lung evocative of BPD. Our hypothesis is that 25(OH)D levels ≥ 120 nmol/L are also a risk factor for BPD or death. This retrospective single-center cohort study included only infants born at <31 weeks gestational age without major malformations with at least a determination of 25(OH)D at <36 weeks corrected age and no determination <50 nmol/L. Routine 25(OH)D determination was performed at 1 month and monthly thereafter. A total of 175 infants were included. Infants with BPD or who died had a significantly lower term and weight, but a similar frequency of 25(OH)D ≥120 nmol/L (50.5% vs. 43.9%, p = 0.53). The logistic regression identified weight (OR 0.997, 95% CI [0.995-0.998]) and term (OR 0.737, 95% CI [0.551-0.975]) as significantly associated with BPD or death; the occurrence of excessive 25(OH)D was not significantly associated (OR 1.029, 95% CI [0.503-2.093]). The present study did not demonstrate any significant association between excessive 25(OH)D after one month of age and BPD or death.

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.

Novel concepts of treating vascular inflammation underlying neonatal lung diseases.

Bronchopulmonary dysplasia (BPD) is the most common sequela of prematurity. Although multifactorial in etiology, there is increasing evidence that fetal growth restriction (FGR) and antenatal exposure of the fetus to inflammation play important roles in the postnatal pathophysiology of BPD. Recent studies have focused on disrupted angiogenesis and its influence on alveolarization. Although there are multiple mechanistic links, inflammation is known to be a key driver of this disruption, affecting pulmonary arterial circulation. Although postnatal corticosteroids are commonly used in extremely premature infants to treat inflammation, aimed at obviating the need for intubation and mechanical ventilation or to facilitate extubation, the use of dexamethasone has not reduced the incidence of BPD. Here, we summarize current knowledge on alternative anti-inflammatory treatment options, which have shown promising outcomes either preclinically or clinically. These include supplementation with vitamins C and E (antioxidants), ω-3 polyunsaturated fatty acids, pentoxifylline, anti-inflammatory cytokines of the IL (interleukin)-1 family, namely IL-1 receptor antagonist and IL-37, and the beneficial properties of breast milk. Evaluating these alternative treatments, either individually or as combination therapies in randomized controlled trials stands to immensely benefit the clinical outlook, particularly regarding BPD, for extremely premature infants.

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.

The Effect of Contingent Singing on Infants with Bronchopulmonary Dysplasia in the Neonatal Intensive Care Unit.

A significant component of care for infants with bronchopulmonary dysplasia (BPD) is providing an optimal environment for supporting neurodevelopment and growth. Interventions that support the behavioral and physiologic stability of this population may play an important role in improving overall outcomes. Contingent singing is a music intervention that allows the caregiver to tailor certain musical elements, such as rhythm and tempo, to match behavioral and physiologic cues and support the infant in achieving optimal stabilization. A randomized crossover design was used to study the effect of contingent singing on the behavioral state and physiologic measures compared to standard care practices in the neonatal intensive care unit (NICU). Data were collected on a sample of 37 infants diagnosed with BPD. There were no significant differences in the physiologic measures or behavioral states of infants in the contingent singing sessions compared to control sessions. Parents and staff reported favorable views of music therapy in the NICU, and there were no adverse responses from infants during contingent singing. Further research is needed to determine the effectiveness of this intervention on the physiologic stability of infants with BPD.

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.

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.

Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns.

BACKGROUND: The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD). METHODS: A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization. RESULTS: Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD. CONCLUSIONS: We find no support for an increased risk of BPD with iron supplementation. TRIAL REGISTRATION NUMBER: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.

Involvement of miRNA-34a regulated Krüppel-like factor 4 expression in hyperoxia-induced senescence in lung epithelial cells.

BACKGROUND: Premature infants, subjected to supplemental oxygen and mechanical ventilation, may develop bronchopulmonary dysplasia, a chronic lung disease characterized by alveolar dysplasia and impaired vascularization. We and others have shown that hyperoxia causes senescence in cultured lung epithelial cells and fibroblasts. Although miR-34a modulates senescence, it is unclear whether it contributes to hyperoxia-induced senescence. We hypothesized that hyperoxia increases miR-34a levels, leading to cellular senescence. METHODS: We exposed mouse lung epithelial (MLE-12) cells and primary human small airway epithelial cells to hyperoxia (95% O2/5% CO2) or air (21% O2/5% CO2) for 24 h. Newborn mice (< 12 h old) were exposed to hyperoxia (> 95% O2) for 3 days and allowed to recover in room air until postnatal day 7. Lung samples from premature human infants requiring mechanical ventilation and control subjects who were not mechanically ventilated were employed. RESULTS: Hyperoxia caused senescence as indicated by loss of nuclear lamin B1, increased p21 gene expression, and senescence-associated secretory phenotype factors. Expression of miR-34a-5p was increased in epithelial cells and newborn mice exposed to hyperoxia, and in premature infants requiring mechanical ventilation. Transfection with a miR-34a-5p inhibitor reduced hyperoxia-induced senescence in MLE-12 cells. Additionally, hyperoxia increased protein levels of the oncogene and tumor-suppressor Krüppel-like factor 4 (KLF4), which were inhibited by a miR-34a-5p inhibitor. Furthermore, KLF4 knockdown by siRNA transfection reduced hyperoxia-induced senescence. CONCLUSION: Hyperoxia increases miR-34a-5p, leading to senescence in lung epithelial cells. This is dictated in part by upregulation of KLF4 signaling. Therefore, inhibiting hyperoxia-induced senescence via miR-34a-5p or KLF4 suppression may provide a novel therapeutic strategy to mitigate the detrimental consequences of hyperoxia in the neonatal lung.

Neonatal outcomes from a quasi-experimental clinical trial of Family Integrated Care versus Family-Centered Care for preterm infants in U.S. NICUs.

BACKGROUND: Family Integrated Care (FICare) benefits preterm infants compared with Family-Centered Care (FCC), but research is lacking in United States (US) Neonatal Intensive Care Units (NICUs). The outcomes for infants of implementing FICare in the US are unknown given differences in parental leave benefits and health care delivery between the US and other countries where FICare is used. We compared preterm weight and discharge outcomes between FCC and mobile-enhanced FICare (mFICare) in the US. METHODS: In this quasi-experimental study, we enrolled preterm infant (≤ 33 weeks)/parent dyads from 3 NICUs into sequential cohorts: FCC or mFICare. Our primary outcome was 21-day change in weight z-scores. Our secondary outcomes were nosocomial infection, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and human milk feeding (HMF) at discharge. We used intention-to-treat analyses to examine the effect of the FCC and mFICare models overall and per protocol analyses to examine the effects of the mFICare intervention components. FINDINGS: 253 infant/parent dyads participated (141 FCC; 112 mFICare). There were no parent-related adverse events in either group. In intention-to-treat analyses, we found no group differences in weight, ROP, BPD or HMF. The FCC cohort had 2.6-times (95% CI: 1.0, 6.7) higher odds of nosocomial infection than the mFICare cohort. In per-protocol analyses, we found that infants whose parents did not receive parent mentoring or participate in rounds lost more weight relative to age-based norms (group-difference=-0.128, CI: -0.227, -0.030; group-difference=-0.084, CI: -0.154, -0.015, respectively). Infants whose parents did not participate in rounds or group education had 2.9-times (CI: 1.0, 9.1) and 3.8-times (CI: 1.2, 14.3) higher odds of nosocomial infection, respectively. CONCLUSION: We found indications that mFICare may have direct benefits on infant outcomes such as weight gain and nosocomial infection. Future studies using implementation science designs are needed to optimize intervention delivery and determine acute and long-term infant and family outcomes. CLINICAL TRIAL REGISTRATION: NCT03418870 01/02/2018.

SMOFlipid Impact on Growth and Neonatal Morbidities in Very Preterm Infants.

The soybean oil, medium-chain triglycerides, olive oil, and fish oil lipid (SMOFlipid) is increasingly being used worldwide without definite evidence of its benefits. We examined the effect of SMOFlipid on growth velocity and neonatal morbidities in very preterm infants. Very preterm infants who received soybean-based lipid emulsion between January 2015 and 2018 were compared with those who received SMOFlipids between 2019 and January 2022 in our neonatal tertiary center. Linear regression analysis was conducted to analyze the association between type of lipid emulsion and growth velocity. Modified log-Poisson regression with generalized linear models and a robust variance estimator (Huber−White) were applied to adjust for potential confounding factors. A total of 858 infants met our inclusion criteria. Of them, 238 (27.7%) received SMOFlipid. SMOFlipid was associated with lower growth velocity between birth and 36-week corrected gestational age compared with intralipid Δ weight z-score (adjusted mean difference (aMD) −0.67; 95% CI −0.69, −0.39). Subgroup analysis indicated that mainly male infants in the SMOFlipid−LE group had a lower Δ weight z-score compared to those in the intralipid group (p < 0.001), with no difference observed in females (p = 0.82). SMOFlipid was associated with a lower rate of bronchopulmonary dysplasia (BPD) (aRR 0.61; 95% CI 0.46, 0.8) and higher rate of late-onset sepsis compared with intralipid (aRR 1.44; 95% CI 1.22−1.69). SMOFlipid was associated with lower growth velocity and BPD but higher rate of late-onset sepsis­it is a double-edged sword.

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.).