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.

Efficacy of minimally invasive surfactant therapy in moderate and late preterm infants: A multicentre randomized control trial.

BACKGROUND: Minimally invasive surfactant therapy (MIST) is a new strategy to avoid mechanical ventilation (MV) in respiratory distress syndrome. The primary aim of this study was to test MIST as a means of avoiding MV exposure and pneumothorax occurrence in moderate and late preterm infants (32 to 36 weeks' gestational age). METHODS: This was a randomized controlled trial including three Canadian centres. Patients were randomized to standard management or to the intervention if they required nasal continuous positive airway pressure of 6 cm H2O and 35% FiO2 in the first 24 hours of life. Patients from the intervention group received MIST immediately after inclusion. The primary outcome was either need for MV or development of a pneumothorax requiring a chest tube. To ensure that clinicians were not biased toward delaying intubation in the intervention group, clinical failure criteria were also used as a primary outcome. The primary outcome was analyzed using bivariate and multivariate logistic regressions. RESULTS: Among 45 randomized patients, 24 were assigned to MIST and 21 to standard management. Eight infants (33%) from the intervention group met the primary outcome criteria versus 19 (90%) in the control group (absolute risk reduction 0.57, 95% confidence interval 0.54 to 0.60). One patient in each group reached the primary outcome because of pneumothorax occurrence. The other patients were exposed to MV. None of the patients reached the clinical failure criteria. CONCLUSION: MIST for respiratory distress syndrome management in moderate and late preterm infants was associated with a significant reduction of MV exposure and pneumothorax occurrence.

Maternal high-dose docosahexaenoic acid supplementation and neurodevelopment at 5 Years of preterm children.

BACKGROUND & AIMS: Docosahexaenoic acid (DHA) is the most abundant omega-3 fatty acid in the brain and is accumulated by the fetal brain during the last trimester of pregnancy. Our objective was to determine whether high-dose DHA supplementation during the neonatal period, vs. placebo, improves behavioral functioning at 5 years in children born very preterm. METHODS: This is a follow-up at 5 years corrected age of a subset of children who participated in a multicenter randomized controlled trial. The participants received a high-dose DHA supplementation, or a placebo, through maternal breastmilk until 36 weeks' postmenstrual age. Primary outcome was child behavioral functioning, assessed by the Total Difficulties Score from the Strengths and Difficulties Questionnaire (SDQ). Secondary outcomes included behavioral scores from the SDQ, executive functions assessment and global developmental performance. Neurodevelopmental outcomes were assessed through interviews with parents. Mean differences between DHA and placebo groups were estimated using mixed linear models. Subgroup analyses were conducted for sex and gestational age (GA) at birth. RESULTS: Among 177 eligible children, 132 (74.6 %) completed neurodevelopmental assessment at 5 years (DHA, N = 64, placebo, N = 68). Total Difficulties Score did not differ between the DHA and placebo groups (mean differences, -0.9 [95 % confidence interval, -2.7 to 0.8], P = 0.30), nor any of the secondary outcomes. There was no significant interaction between treatment groups and sex, nor GA, for the primary outcome. However, significant interactions between treatment groups and sex or GA were found for some secondary outcomes. CONCLUSIONS: In very preterm infants, high-dose DHA supplementation did not improve behavioral functioning at 5 years. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02371460, https://clinicaltrials.gov/study/NCT02371460.

Comparison of risk factors for human metapneumovirus and respiratory syncytial virus disease severity in young children.

BACKGROUND: Human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are leading pediatric pathogens. However, risk factors for severe hMPV disease remain unknown. We comparatively assessed environmental, host, and viral determinants for severe hMPV and RSV infections. METHODS: We studied a prospective cohort of >1000 children aged <3 years hospitalized in or presenting to a pediatric clinic for acute respiratory infection. We collected clinical data at enrollment and 1-month follow-up and tested nasopharyngeal secretions for respiratory viruses. Disease severity was defined as hospitalization and was also assessed with a severity score (1 point/variable) calculated on the basis of fraction of inhaled O(2) ≥ 30%, hospitalization >5 days, and pediatric intensive care unit admission. RESULTS: hMPV was identified in 58 of 305 outpatient children (19.0%) and 69 of 734 hospitalized children (9.4%), second only to RSV (48.2% and 63.6%, respectively). In multivariate regression analysis of hMPV cases, age <6 months and household crowding were associated with hospitalization. Among hospitalized patients, risk factors for severe hMPV disease were female sex, prematurity, and genotype B infection. Age <6 months, comorbidities, and household crowding were risk factors for RSV hospitalization; breast-feeding and viral coinfection were protective. Age <6 months and prematurity were associated with severe RSV cases among hospitalized children. CONCLUSIONS: hMPV and RSV severity risk factors may differ slightly. These findings will inform hMPV prevention strategies.

Effects of maternal docosahexaenoic acid supplementation on brain development and neurodevelopmental outcomes of breastfed preterm neonates: protocol for a follow-up at preschool age of a randomised clinical trial (MOBYDIckPS).

INTRODUCTION: Docosahexaenoic acid (DHA), an omega-3 fatty acid, is important for brain development with possible implications in neurodevelopmental outcomes. In the two-arm, randomised, double-blind, placebo-controlled Maternal Omega-3 Supplementation to Reduce Bronchopulmonary Dysplasia in Very Preterm Infants trial, very preterm infants (<29 weeks' gestation) were supplemented in high doses of DHA or placebo until they reached 36 weeks' postmenstrual age. We propose a long-term neurodevelopmental follow-up of these children. This protocol details the follow-up at 5 years of age, which aims to (1) confirm our long-term recruitment capacity and (2) determine the spectrum of neurodevelopmental outcomes at preschool age following neonatal DHA supplementation. METHODS AND ANALYSIS: This long-term follow-up involves children (n=194) born to mothers (n=170) randomised to DHA (n=85) or placebo (n=85) from the five sites in Quebec when they will be 5 years' corrected age. The primary outcome measure is related to the long-term recruitment capacity, which we determined as successful if 75% (±10%, 95% CI) of the eligible children consent to the 5-year follow-up study. Interviews with mothers will be conducted to assess various aspects of neurodevelopment at preschool age (executive functions, behavioural problems, global development and health-related quality of life), evaluated with standardised neurodevelopmental questionnaires. In addition, a semistructured interview conducted in a subset of the mothers will be used to determine their acceptability and identify barriers and enablers to their eventual participation to the next phase of the trial. This follow-up study will require approximately 22 months to be completed. ETHICS AND DISSEMINATION: This study was approved by the CHU de Québec-Université Laval Research Ethics Board (MP-20-2022-5926). Mothers will provide informed consent before participating in this study. Findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT02371460.

Maternal High-Dose DHA Supplementation and Neurodevelopment at 18-22 Months of Preterm Children.

OBJECTIVES: To determine whether maternal supplementation with high-dose docosahexaenoic acid (DHA) in breastfed, very preterm neonates improves neurodevelopmental outcomes at 18 to 22 months' corrected age (CA). METHODS: Planned follow-up of a randomized, double-blind, placebo-controlled, multicenter trial to compare neurodevelopmental outcomes in breastfed, preterm neonates born before 29 weeks' gestational age (GA). Lactating mothers were randomized to receive either DHA-rich algae oil or a placebo within 72 hours of delivery until 36 weeks' postmenstrual age. Neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development third edition (Bayley-III) at 18 to 22 months' CA. Planned subgroup analyses were conducted for GA (<27 vs ≥27 weeks' gestation) and sex. RESULTS: Among the 528 children enrolled, 457 (86.6%) had outcomes available at 18 to 22 months' CA (DHA, N = 234, placebo, N = 223). The mean differences in Bayley-III between children in the DHA and placebo groups were -0.07 (95% confidence interval [CI] -3.23 to 3.10, P = .97) for cognitive score, 2.36 (95% CI -1.14 to 5.87, P = .19) for language score, and 1.10 (95% CI -2.01 to 4.20, P = .49) for motor score. The association between treatment and the Bayley-III language score was modified by GA at birth (interaction P = .07). Neonates born <27 weeks' gestation exposed to DHA performed better on the Bayley-III language score, compared with the placebo group (mean difference 5.06, 95% CI 0.08-10.03, P = .05). There was no interaction between treatment group and sex. CONCLUSIONS: Maternal DHA supplementation did not improve neurodevelopmental outcomes at 18 to 22 months' CA in breastfed, preterm neonates, but subgroup analyses suggested a potential benefit for language in preterm neonates born before 27 weeks' GA.

Impact of the Withdrawal of Palivizumab Immunoprophylaxis on the Incidence of Respiratory Syncytial Virus (RSV) Hospitalizations Among Infants Born at 33 to 35 Weeks' Gestational Age in the Province of Quebec, Canada: The RSV-Quebec Study.

BACKGROUND: Infants born at 33-35 completed weeks' gestational age (wGA) aged <6 months at the start of or born during respiratory syncytial virus (RSV) season and classified as moderate/high risk of severe RSV disease were included in a palivizumab RSV prophylaxis program in the province of Quebec, Canada, until 2014-2015. We assessed the impact of withdrawal of this indication on lower respiratory tract infection (LRTI)/RSV hospitalizations (H) in this population. METHODS: We conducted a 4-year, retrospective, cohort study in 25 Quebec hospitals (2 seasons with and 2 without palivizumab prophylaxis for moderate- to high-risk infants). Our primary outcome was LRTI/RSV-H incidence. We compared LRTI/RSV-H incidence before (2013-2015; seasons 1 + 2 [S1/2]) and after (2015-2017; S3/4) the change in indication. RESULTS: We identified 6457 33-35 wGA births. LRTI/RSV-H occurred in 105/3353 infants (3.13%) in S1/2 and 130/3104 (4.19%) in S3/4. Among LRTI/RSV-H, 86.4% were laboratory-confirmed RSV-H. Adjusting for sex, wGA, and birth month, S3/4 was significantly associated with increased LRTI/RSV-H incidence (adjusted odds ratio [aOR], 1.36; 95% confidence interval [CI], 1.04-1.76) but not with laboratory-confirmed RSV-H (aOR, 1.19; 95% CI, 0.90-1.58). Mean duration of LRTI/RSV-H was 5.6 days; 22.6% required intensive care unit admission. Comparing S3/4 with S1/2, infant percentage with LRTI/RSV-H classified as moderate/high risk increased from 27.8% to 41.9% (P = .11). CONCLUSIONS: In a province-wide study, we observed a significant increase in LRTI/RSV-H incidence among infants born at 33-35 wGA in the 2 years after withdrawal of RSV prophylaxis.

Cost-analysis of Withdrawing Immunoprophylaxis for Respiratory Syncytial Virus in Infants Born at 33-35 Weeks Gestational Age in Quebec: A Multicenter Retrospective Study.

BACKGROUND: In 2015, the Quebec Ministry of Health limited palivizumab prophylaxis for respiratory syncytial virus (RSV) in premature infants to those born at <33 weeks gestational age (wGA), unless other indications were present. We compared RSV-related costs for 2 seasons before the change (2013-2014, 2014-2015) and 2 seasons after (2015-2016, 2016-2017) in premature infants 33-35 wGA. METHODS: Using payer and societal perspectives, costs associated with hospitalizations for RSV and lower respiratory tract infection (LRTI) in infants born at 33-35 wGA were estimated. Inputs were from a 2013-2017 retrospective cohort study in 25 Quebec hospitals of RSV/LRTI hospitalizations among infants <6 months old at the start of, or born during, the RSV season. Resource utilization data (hospital stay, procedures, visits, transportation, out-of-pocket expenses and work productivity) were collected from charts and parent interviews allowing estimation of direct and indirect costs. Costs, including palivizumab administration, were derived from provincial sources and adjusted to 2018 Canadian dollars. Costs were modeled for preterm infants hospitalized for RSV/LRTI pre- and postrevision of guidelines and with matched term infants hospitalized for RSV/LRTI during 2015-2017 (comparator). RESULTS: Average total direct and indirect costs for 33-35 wGA infants were higher postrevision of guidelines ($29,208/patient, 2015-2017; n = 130) compared with prerevision ($16,976/patient, 2013-2015; n = 105). Total costs were higher in preterm infants compared with term infants (n = 234) postrevision of guidelines ($29,208/patient vs. $10,291/patient). CONCLUSIONS: Immunoprophylaxis for RSV in infants born at 33-35 wGA held a cost advantage for hospitalizations due to RSV/LRTI.

Human respiratory syncytial virus and other viral infections in infants receiving palivizumab.

BACKGROUND: Palivizumab is a humanized monoclonal antibody that prevents severe human respiratory syncytial virus (HRSV) infections. OBJECTIVES: We determined the etiology of respiratory viral infections in palivizumab recipients, and monitored the clinical outcome and HRSV genotype in HRSV-infected infants. STUDY DESIGN: Nasopharyngeal aspirates (NPAs) were collected from children receiving palivizumab who consulted or were hospitalized for acute respiratory tract infection (ARTI) during the 2004-2005 season. Viral cultures and multiplex RT-PCR for influenza A/B, HRSV and human metapneumovirus were performed. The fusion (F) gene of HRSV amplicons was also sequenced. RESULTS: Among 116 enrolled patients, 51 (44%) had > or = 1 episode of ARTI for a total of 93 visits. At least one virus was identified in 33 (36%) of the 93 NPA samples; HRSV accounted for 11 (33%) of confirmed viral etiologies. Compared to subjects who had other viral ARTI, HRSV-positive subjects had less fever (p=0.01) and tended to have more bronchiolitis (p=0.07). Ten subjects (11 visits) developed HRSV infection, although only one was hospitalized. HRSV was detected after a median of 5.5 palivizumab doses and a median of 14 days after the last dose. One of the 11 HRSV strains tested had a F mutation located in the palivizumab-binding site. CONCLUSION: HRSV is still a major cause of ARTI in children receiving palivizumab, although the outcome of infected children appears mild.

Association between Apnea of Prematurity and Respiratory Distress Syndrome in Late Preterm Infants: An Observational Study.

BACKGROUND: Late preterm infants (34-36 weeks' gestation) remain a population at risk for apnea of prematurity (AOP). As infants affected by respiratory distress syndrome (RDS) have immature lungs, they might also have immature control of breathing. Our hypothesis is that an association exists between RDS and AOP in late preterm infants. OBJECTIVE: The primary objective of this study was to assess the association between RDS and AOP in late preterm infants. The secondary objective was to evaluate if an association exists between apparent RDS severity and AOP. METHODS: This retrospective observational study was realized in a tertiary care center between January 2009 and December 2011. Data from late preterm infants who presented an uncomplicated perinatal evolution, excepted for RDS, were reviewed. Information related to AOP and RDS was collected using the medical record. Odds ratios were calculated using a binary logistic regression adjusted for gestational age and sex. RESULTS: Among the 982 included infants, 85 (8.7%) had an RDS diagnosis, 281 (28.6%) had AOP diagnosis, and 107 (10.9%) were treated with caffeine for AOP. There was a significant association between AOP treated with caffeine and RDS for all infants (OR = 3.3, 95% CI: 2.0-5.7). There was no association between AOP and RDS in 34 weeks infants [AOR: 1.6 (95% CI: 0.7-3.8)], but an association remains for 35 [AOR: 5.7 (95% CI: 2.5-13.4)] and 36 [OR = 7.8 (95% CI: 3.2-19.4)] weeks infants. No association was found between apparent RDS severity and AOP, regarding mean oxygen administration duration or complications associated with RDS. CONCLUSION: The association between RDS and AOP in late preterm infants reflects that patients affected by RDS are not only presenting lung immaturity but also respiratory control immaturity. Special consideration should be given before discontinuing monitoring after RDS resolution in those patients.

The Pediatric Investigators Collaborative Network on Infections in Canada study of predictors of hospitalization for respiratory syncytial virus infection for infants born at 33 through 35 completed weeks of gestation.

BACKGROUND: Infants born at 33 through 35 completed weeks of gestation (33-35GA) are at risk for severe respiratory syncytial virus (RSV) infection, and palivizumab prophylaxis lowers hospitalizations for RSV infection by as much as 80%. The 33-35GA cohort comprises 3-5% of annual births; thus expert panels recommend limiting prophylaxis to situations in which frequency or health care impact of RSV infection is high. This study sought to identify independent risk factors for hospitalization for RSV infection. METHODS: This was a multicenter, prospective, observational cohort study of 33-35GA infants followed through their first RSV season (2001/2002 or 2002/2003). Baseline data were collected by interview with parents and review of medical records. Respiratory tract illnesses were identified by monthly phone calls, and medical records were reviewed for emergency room visits or hospitalizations. Risk factors were determined by stepwise logistic regression. RESULTS: Of 1,860 enrolled subjects, 1,832 (98.5%) were followed for at least 1 month, and 1,760 (94.6%) completed all follow-ups. Of 140 (7.6%) subjects hospitalized for respiratory tract illnesses, 66 infants had proven RSV infection. Independent predictors for hospitalization for RSV infection were: day-care attendance (odds ratio, 12.32; 95% confidence interval, 2.56, 59.34); November through January birth (odds ratio, 4.89; 95% confidence interval, 2.57, 9.29); preschool age sibling(s) (odds ratio, 2.76; 95% confidence interval, 1.51, 5.03); birth weight <10th percentile (odds ratio, 2.19; 95% confidence interval, 1.14, 4.22); male gender (odds ratio, 1.91; 95% confidence interval, 1.10, 3.31); > or = 2 smokers in the home (odds ratio, 1.87; 95% confidence interval, 1.07, 3.26); and households with >5 people, counting the subject (odds ratio, 1.79; 95% confidence interval, 1.02, 3.16). Family history of eczema (odds ratio, 0.42; 95% confidence interval, 0.18, 0.996) was protective. CONCLUSIONS: Specific host/environmental factors can be used to identify which 33-35GA infants are at greatest risk of hospitalization for RSV infection and likely to benefit from palivizumab prophylaxis.

Fluticasone inhalation in moderate cases of bronchopulmonary dysplasia.

OBJECTIVE: This randomized, controlled trial was designed to determine the efficacy of inhaled fluticasone propionate on oxygen therapy weaning in a population of preterm infants who were born at <32 weeks of gestation and experienced moderate bronchopulmonary dysplasia (BPD). METHODS: Thirty-two infants who were < or =32 weeks of gestation, had moderate BPD that required supplemental oxygen (fraction of inspired oxygen > or =0.25), and were aged between 28 and 60 days were randomized. Fluticasone propionate 125 microg twice daily for 3 weeks and once daily for a fourth week was delivered to infants who weighed between 500 and 1200 g. The dosage was doubled for infants who weighed > or =1200 g. RESULTS: Compared with placebo, treatment had no effect on either duration of supplemental O2 therapy or ventilatory support as assessed by survival analysis. At 28 days, a trend toward a lower cortisol/creatinine ratio in the treatment group was noted compared with placebo (25.1 +/- 18.9 vs 43 +/- 14.4). In the fluticasone group at 28 days, the systolic arterial pressure (78 +/- 3 vs 68 +/- 3 mm Hg) and diastolic arterial pressure (43 +/- 3.4 mm Hg vs 38 +/- 2.0 mm Hg) were higher compared with baseline fluticasone values. The chest radiograph score was lower than baseline (2.8 +/- 1.4 vs 3.7 +/- 2.2) in the fluticasone group at 28 days. This study has a statistical power of 1.0 to detect a significant difference in the duration of oxygen supplementation of >21 days between the study groups. CONCLUSION: We conclude that fluticasone propionate reduces neither supplemental O2 use nor the need for ventilatory support in this patient population. However, fluticasone does have a positive radiologic effect in lowering chest radiograph scores. In addition, our data point to a possible association among inhaled fluticasone treatment and higher arterial blood pressure. Thus, the results of this investigation do not support the use of inhaled corticosteroids in the treatment of oxygen-dependent infants who have established moderate BPD.