Gestational Age-Dependent Variations in Effects of Prophylactic Indomethacin on Brain Injury and Intestinal Injury.

OBJECTIVE: To evaluate the impact of prophylactic indomethacin on early death (<10 days after birth) or severe neurologic injury and on early death or spontaneous intestinal perforation by completed weeks of gestational age in neonates born <29 weeks of gestation. STUDY DESIGN: This was a multicenter, retrospective cohort study of neonates (n = 12 515) born at 236/7 weeks of gestational age, admitted to neonatal intensive care units participating in the Canadian Neonatal Network who received prophylactic indomethacin started within the first 12 hours after birth. Univariate and multivariate analysis compared the composite outcomes of early death or severe neurologic injury and early death or spontaneous intestinal perforation. RESULTS: Of 12 515 eligible neonates, 1435 (11.5%) were exposed to prophylactic indomethacin; recipients were of lower gestational age and birth weight and had greater severity of illness (Score of Neonatal Acute Physiology with Perinatal Extension) on admission compared with nonrecipients. After we adjusted for confounders, prophylactic indomethacin was associated with reduced odds of early death or severe neurologic injury and early death or spontaneous intestinal perforation in neonates born at 23-24 weeks of gestational age. However, prophylactic indomethacin was associated with increased odds of early mortality or spontaneous intestinal perforation for neonates born at 26-28 weeks of gestational age. CONCLUSIONS: Prophylactic indomethacin use was associated with benefit in neonates born at 23-24 weeks of gestational age, but with harm at 26-28 weeks of gestational age. Given the observation of significantly improved survival, a randomized controlled trial is needed to investigate the effect of prophylactic indomethacin in babies born at 23-25 weeks of gestational age.

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.

Laryngeal mask airway versus bag-mask ventilation or endotracheal intubation for neonatal resuscitation.

BACKGROUND: Providing effective positive pressure ventilation is considered to be the single most important component of successful neonatal resuscitation. Ventilation is frequently initiated manually with bag and face mask (BMV) followed by endotracheal intubation if respiratory depression continues. These techniques may be difficult to perform successfully resulting in prolonged resuscitation or neonatal asphyxia. The laryngeal mask airway (LMA) may achieve initial ventilation and successful resuscitation faster than a bag-mask device or endotracheal intubation. OBJECTIVES: Among newborns requiring positive pressure ventilation for cardio-pulmonary resuscitation, is LMA more effective than BMV or endotracheal intubation for successful resuscitation? When BMV is either insufficient or ineffective, is effective positive pressure ventilation and successful resuscitation achieved faster with the LMA compared to endotracheal intubation? SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 1), MEDLINE via PubMed (1966 to 15 February 2017), Embase (1980 to 15 February 2017), and CINAHL (1982 to 15 February 2017). We also searched clinical trials registers, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that compared LMA for neonatal resuscitation with either BMV or endotracheal intubation and reported on any outcomes related to neonatal resuscitation specified in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated studies for risk of bias assessments, and extracted data using Cochrane Neonatal criteria. Categorical treatment effects were described as relative risks and continuous treatment effects were described as the mean difference, with 95% confidence intervals (95% CI) of estimates. MAIN RESULTS: We included seven trials that involved a total of 794 infants. Five studies compared LMA with BMV and three studies compared LMA with endotracheal intubation. We added six new studies for this update (754 infants).LMA was associated with less need for endotracheal intubation than BMV (typical risk ratio (RR) 0.24, 95% CI 0.12 to 0.47 and typical risk difference (RD) -0.14, 95% CI -0.14 to -0.06; 5 studies, 661 infants; moderate-quality evidence) and shorter ventilation time (mean difference (MD) -18.90 seconds, 95% CI -24.35 to -13.44; 4 studies, 610 infants). Babies resuscitated with LMA were less likely to require admission to neonatal intensive care unit (NICU) (typical RR 0.60, 95% CI 0.40 to 0.90 and typical RD -0.18, 95% CI -0.31 to -0.04; 2 studies,191 infants; moderate-quality evidence). There was no difference in deaths or hypoxic ischaemic encephalopathy (HIE) events.Compared to endotracheal intubation, there were no clinically significant differences in insertion time or failure to correctly insert the device (typical RR 0.95, 95% CI 0.17 to 5.42; 3 studies, 158 infants; very low-quality evidence). There was no difference in deaths or HIE events. AUTHORS' CONCLUSIONS: LMA can achieve effective ventilation during neonatal resuscitation in a time frame consistent with current neonatal resuscitation guidelines. Compared to BMV, LMA is more effective in terms of shorter resuscitation and ventilation times, and less need for endotracheal intubation (low- to moderate-quality evidence). However, in trials comparing LMA with BMV, over 80% of infants in both trial arms responded to the allocated intervention. In studies that allowed LMA rescue of infants failing with BMV, it was possible to avoid intubation in the majority. It is important that the clinical community resorts to the use of LMA more proactively to provide effective ventilation when newborn is not responding to BMV before attempting intubation or initiating chest compressions.LMA was found to offer comparable efficacy to endotracheal intubation (very low- to low-quality evidence). It therefore offers an alternate airway device when attempts at inserting endotracheal intubation are unsuccessful during resuscitation.Most studies enrolled infants with birth weight over 1500 g or 34 or more weeks' gestation. As such, there is lack of evidence to support LMA use in more premature infants.

Umbilical arterial catheter duration as risk factor for Bell's Stage III necrotizing enterocolitis in preterm neonates.

Objectives: To explore risk factors for Stage-III necrotizing enterocolitis (NEC-III) in preterm neonates. Methods: This was a retrospective case-control study of neonates born <33 weeks gestational age (GA) who were admitted to a tertiary neonatal intensive care unit, between 2015 and 2018. NEC-III cases were compared with Stage-II NEC (NEC-II) and non-NEC controls. Two to four non-NEC controls were matched by GA ± 1 week and date of birth ± 3 months, to one NEC-III case. Univariate and multivariate analyses were used to examine risk factors for NEC-III. Results: Of 1360 neonates born <33 weeks, 71 (5.2%) had NEC-II and above, with 46% being NEC-III. Mean age of onset of NEC-III was 13.7 days versus 23.9 days for NEC-II (p = 0.01). Neonates with NEC-III were of lower GA (NEC-III 25.4 weeks, NEC-II 27.3 weeks, and non-NEC 26 weeks; p = 0.0008) and had higher Score for Neonatal Acute Physiology Perinatal Extension-II scores (NEC-III 47.5, NEC-II 28.4 and non-NEC 37, p = 0.003). Multivariate analysis showed duration of umbilical arterial catheter (UAC) >5 days was significantly associated with the development of NEC-III with adjusted odds ratio (AOR) 3.8; 95% confidence interval (CI) (1.05-13.66) for NEC-III versus non-NEC and AOR 5.57; 95% CI (1.65-18.73), p = 0.006 for NEC-III versus NEC-II. Rupture of membranes (ROM) >1 week was associated with NEC-III (AOR 6.93; 95% CI [1.56-30.69] vs. non-NEC and AOR 11.74; 95% CI [1.14-120.34] vs. NEC-II). Conclusion: The increased association of NEC-III with duration of UAC and ROM could be further examined in prospective studies, and an upper limit for UAC duration could be considered in NEC prevention bundles.

D-Penicillamine for preventing retinopathy of prematurity in preterm infants.

BACKGROUND: The rate of retinopathy of prematurity (ROP) in moderately premature infants has decreased dramatically with improved care in the neonatal intensive care unit. A low rate of this disorder was unexpectedly observed among infants treated with intravenous D-penicillamine to prevent hyperbilirubinaemia. This observation led to the investigation of its use, both enterally as well as intravenously, to prevent ROP. OBJECTIVES: To determine the effect of prophylactic administration of D-penicillamine on the incidence of acute ROP or severe ROP and other morbidities in preterm infants. SEARCH METHODS: We used the Cochrane Neonatal Review Group search strategy. Two review authors independently searched multiple electronic databases, previous reviews including cross references, abstracts, conference/symposia proceedings, and expert informants. We updated the search on November 27, 2012. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials if they administered D-penicillamine and compared it with no treatment or placebo to premature infants and reported on the outcome of ROP. DATA COLLECTION AND ANALYSIS: We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of the included trials. One review author examined trials for validity. A second review author checked validity and they reached consensus on the final data before entry into this review. We used the standards of the Neonatal Cochrane Review Group to analyse data. MAIN RESULTS: Three randomised trials met the inclusion criteria. The meta-analysis showed no significant differences in the risk of any stage ROP (typical risk ratio (RR) 0.32, 95% confidence interval (CI) 0.03 to 3.70), severe ROP (typical RR 0.38, 95% CI 0.03 to 4.26) or death (typical RR 0.95, 95% CI 0.68 to 1.32) in all treated infants. When the subgroup of infants under 1500 g birth weight was examined, the results were similar. No side effects were reported, and follow-up at one year revealed no significant differences in spasticity or developmental delay. AUTHORS' CONCLUSIONS: Administration of prophylactic D-penicillamine in preterm infants does not prevent acute or severe ROP, death or neurodevelopmental delay. D-penicillamine cannot be recommended for the prevention of ROP based on the available evidence.

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.

Effect of Maternal Docosahexaenoic Acid Supplementation on Very Preterm Infant Growth: Secondary Outcome of a Randomized Clinical Trial.

INTRODUCTION: The aim of the study was to determine the effect of a maternal docosahexaenoic acid (DHA) supplementation during lactation, compared with a placebo, on the neonatal growth profile of breastfed very preterm infants. METHODS: Preterm infants' growth profile, growth velocity from birth to 36 weeks' postmenstrual age (PMA), and growth at 36 weeks' PMA were pre-specified secondary outcomes of a randomized placebo-controlled trial conducted in 16 Canadian neonatal intensive care units (2015-2018). Lactating mothers who delivered before 29 weeks' gestation were given 1.2 g of DHA daily or a placebo within 72 h of delivery and up to 36 weeks' PMA. Analyses were performed using a linear regression model with generalized estimating equations. RESULTS: 461 mothers and their 528 infants (DHA, N = 273; placebo, N = 255) were included with mean gestational age of 26.5 weeks (standard deviation [SD] = 1.6); 275 (52.1%) were males; mean birth weight was 895 g (SD = 240). DHA interaction with sex was significant on weight profile (interaction p < 0.001), weight velocity (interaction p = 0.05), and weight at 36 weeks' PMA (interaction p = 0.02). Females in the DHA group gained more weight compared to the placebo group (mean difference [MD], 52.6 g [95% confidence interval [CI]: 24.5-80.8], p < 0.001). Weight velocity was significantly higher in females of the DHA group (MD, 3.4 g/kg/day [95% CI: 0.6-6.2], p = 0.02). At 36 weeks' PMA, the weight of males in the DHA group was significantly smaller (MD, -88.9 g [95% CI: -166.2 to -11.6], p = 0.02). CONCLUSION: DHA positively affected female infants' neonatal weight profile and velocity and negatively affected male infants' weight at 36 weeks' PMA.

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.

Outcome of Preterm Neonates with a Birth Weight <1,500 g with Severe Hypoxemic Respiratory Failure Rescued by Inhaled Nitric Oxide Therapy and High-Frequency Oscillatory Ventilation.

BACKGROUND: Despite being an experimental therapy in preterm neonates, inhaled nitric oxide (iNO) is used as a rescue therapy when high-frequency oscillatory ventilation (HFOV) and other conventional therapies fail. OBJECTIVE: We aimed to determine the outcomes of very-low-birth-weight (VLBW) neonates with hypoxemic respiratory failure (HRF) who had received iNO after maximal conventional therapies. METHODS: We retrospectively reviewed preterm neonates (<33 weeks of gestation with a birth weight <1,500 g) who had all received HFOV and then iNO from March 1, 2009 to April 1, 2014 at the Royal Alexandra Hospital. We collected demographic and clinical parameters, doses, duration and response to iNO, survival to neonatal intensive care unit (NICU) discharge, major complications, and neurodevelopmental outcome at 18-24 months of corrected age. RESULTS: During the study period, 1,168 eligible preterm neonates were admitted; 155 (13%) had HRF treated with HFOV, of whom 47 (30%) received iNO. The baseline characteristics between the 24 survivors and 23 nonsurvivors were not different. Survivors had a greater decrease in oxygenation index than nonsurvivors (61 vs. 33%) after 6 h of iNO (p = 0.003). The causes of death were refractory hypoxemia (8), multi-organ failure (7), treatment withdrawal (6), and others (2). During the NICU stay, 23 survivors (96%) developed complications. At 18-24 months, 7 (29%) had significant disabilities. CONCLUSIONS: Of the VLBW neonates with severe HRF rescued by HFOV and iNO, many survived without neurodevelopmental disability at early childhood, despite multiple short-term complications. Further research is necessary to understand the clinical course and risk factors of adverse outcomes and to improve the management care of these critically ill neonates.