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ObjectiveRemote ischaemic conditioning (RIC) improves the outcome of experimental necrotising enterocolitis (NEC) by preserving intestinal microcirculation. The feasibility and safety of RIC in preterm infants with NEC are unknown. The study aimed to assess the feasibility and safety of RIC in preterm infants with suspected or confirmed NEC.DesignPhase I non-randomised pilot study conducted in three steps: step A to determine the safe duration of limb ischaemia (up to 4 min); step B to assess the safety of 4 repeated cycles of ischaemia-reperfusion at the maximum tolerated duration of ischaemia determined in step A; step C to assess the safety of applying 4 cycles of ischaemia-reperfusion on two consecutive days.SettingLevel III neonatal intensive care unit, The Hospital for Sick Children (Toronto, Canada).PatientsFifteen preterm infants born between 22 and 33 weeks gestational age.InterventionFour cycles of ischaemia (varying duration) applied to the limb via a manual sphygmomanometer, followed by reperfusion (4 min) and rest (5 min), repeated on two consecutive days.OutcomesThe primary outcomes were (1) feasibility defined as RIC being performed as planned in the protocol, and (2) safety defined as perfusion returning to baseline within 4 min after cuff deflation.ResultsFour cycles/day of limb ischaemia (4 min) followed by reperfusion (4 min) and a 5 min gap, repeated on two consecutive days was feasible and safe in all neonates with suspected or confirmed NEC.ConclusionsThis study is pivotal for designing a future randomised controlled trial to assess the efficacy of RIC in preterm infants with NEC.Trial registration number NCT03860701.

Background Neonatal hyperbilirubinemia (NHb) results from increased total serum bilirubin and is a common reason for admission and readmission amongst newborn infants born in North America. The use of intravenous immunoglobulin (IVIG) therapy for treating NHb has been widely debated, and the current incidence of NHb and its therapies remain unknown. Methods Using national and provincial databases, a population-based retrospective cohort study of infants born in Ontario from April 2014 to March 2018 was conducted. Results Of the 533,084 infants born in Ontario at ≥35 weeks gestation, 29,756 (5.6%) presented with NHb. Among these infants, 80.1–88.2% received phototherapy, 1.1–2.0% received IVIG therapy and 0.1–0.2% received exchange transfusion (ET) over the study period. Although phototherapy was administered (83.0%) for NHb, its use decreased from 2014 to 2018 (88.2–80.1%) ( P  < 0.01). Similarly, the incidence of IVIG therapy increased from 71 to 156 infants (1.1–2.0%) ( P  < 0.01) and a small change in the incidence of ET (0.2–0.1%) was noted. Conclusion IVIG therapy is increasingly being used in Ontario despite limited studies evaluating its use. The results of this study could inform treatment and management protocols for NHb. Impacts Clinically significant neonatal hyperbilirubinemia still occurs in Ontario, with an increasing number of infants receiving Intravenous Immunoglobulin G (IVIG) therapy. IVIG continues to be used at increasing rates despite inconclusive evidence to recommend its use. This study highlights the necessity of a future prospective study to better determine the effectiveness of IVIG use in treating neonatal hyperbilirubinemia, especially given the recent shortage in IVIG supply in Ontario. The results of this study could inform treatment and management protocols for neonatal hyperbilirubinemia.

ObjectiveTo evaluate annual trends in the administration and duration of respiratory support among preterm infants.DesignRetrospective cohort study.SettingTertiary neonatal intensive care units in the Canadian Neonatal Network.Patients8881 extremely preterm infants born from 2010 to 2017 treated with endotracheal and/or non-invasive positive pressure support (PPS).Main outcome measuresCompeting risks methods were used to investigate the outcomes of mortality and time to first successful extubation, definitive extubation, weaning off PPS, and weaning PPS and/or low-flow oxygen, according to gestational age (GA). Cox proportional hazards and regression models were fitted to evaluate the trend in duration of respiratory support, survival and surfactant treatment over the study period.ResultsThe percentages of infants who died or were weaned from respiratory support were presented graphically over time by GA. Advancing GA was associated with ordinally earlier weaning from respiratory support. Year over year, infants born at 23 weeks were initially and definitively weaned from endotracheal and all PPS earlier (HR 1.06, 95% CI 1.01 to 1.11, for all outcomes), while survival simultaneously increased (OR 1.11, 95% CI 1.03 to 1.18). Infants born at 26 and 27 weeks remained on non-invasive PPS longer (HR 0.97, 95% CI 0.95 to 0.98 and HR 0.97, 95% CI 0.95 to 0.99, respectively). Early surfactant treatment declined among infants born at 24–27 weeks GA.ConclusionsInfants at the borderline of viability have experienced improved survival and earlier weaning from all forms of PPS, while those born at 26 and 27 weeks are spending more time on PPS in recent years. GA-based estimates of the duration of respiratory support and survival may assist in counselling, benchmarking, quality improvement and resource planning.

Background The COVID-19 pandemic threatens global newborn health. We describe the current state of national and local protocols for managing neonates born to SARS-CoV-2-positive mothers. Methods Care providers from neonatal intensive care units on six continents exchanged and compared protocols on the management of neonates born to SARS-CoV-2-positive mothers. Data collection was between March 14 and 21, 2020. We focused on central protocol components, including triaging, hygiene precautions, management at delivery, feeding protocols, and visiting policies. Results Data from 20 countries were available. Disease burden varied between countries at the time of analysis. In most countries, asymptomatic infants were allowed to stay with the mother and breastfeed with hygiene precautions. We detected discrepancies between national guidance in particular regarding triaging, use of personal protection equipment, viral testing, and visitor policies. Local protocols deviated from national guidance. Conclusions At the start of the pandemic, lack of evidence-based guidance on the management of neonates born to SARS-CoV-2-positive mothers has led to ad hoc creation of national and local guidance. Compliance between collaborators to share and discuss protocols was excellent and may lead to more consensus on management, but future guidance should be built on high-level evidence, rather than expert consensus. Impact At the rapid onset of the COVID19 pandemic, all countries presented protocols in place for managing infants at risk of COVID19, with a certain degree of variations among regions. A detailed review of ad hoc guidelines is presented, similarities and differences are highlighted. We provide a broad overview of currently applied recommendations highlighting the need for international context-relevant coordination.

ObjectiveImpact of antenatal corticosteroid (ACS) in context of maternal body mass index (BMI) as it relates to neonatal outcomes remains unclear. We sought to evaluate effects of ACS on clinical outcomes of preterm infants based on maternal BMI.MethodsWe performed a retrospective cohort study among neonates 23–33 weeks’ GA at a tertiary neonatal intensive care unit from 2011 to 2015. Outcomes of neonates exposed to any ACS and pre-pregnancy maternal BMI ≥ 25 (N = 491) were compared with maternal BMI < 25 (N = 484). A priori planned subgroup analyses based on ACS exposure (partial ACS; complete ACS ≤ 7 days prior to delivery (PTD); and complete ACS > 7 days PTD) were conducted. Primary outcome was composite of mortality or any of moderate/severe bronchopulmonary dysplasia, severe neurologic injury, severe retinopathy of prematurity, necrotizing enterocolitis stage, or primary bloodstream infection.ResultsPreterm neonates with maternal BMI ≥ 25 (exposed to any ACS) were not at increased risk of composite outcome vs. BMI < 25 (adjusted odd ratio (aOR) 1.03, 95% confidence interval (CI) 0.84–1.48), nor any individual neonatal morbidities. Similar findings were noted in subgroup analyses by type of ACS exposure.ConclusionImpact of ACS on neonatal outcomes do not appear to be influenced by maternal BMI based on data from this cohort. However, further research is required to definitively elucidate the impact of BMI on ACS with regards to pharmacokinetics and neonatal outcomes.

ObjectiveInvestigate relevance of diastolic flow abnormalities in celiac trunk (aCT) and middle cerebral artery (aMCA) among preterms with persistent hemodynamically significant patent ductus arteriosus (phsPDA, diameter ≥ 1.5 mm, and age ≥ 7 days).Study designFive hundred fifteen echocardiograms from 156 neonates born <28 weeks gestation age (GA) were analyzed retrospectively. Infants with aCT or aMCA at any time were compared with the rest. Separate comparisons were performed for aCT and aMCA. Primary outcome was composite of death, chronic lung disease (CLD), or necrotizing enterocolitis ≥ stage 2. Logistic regression was used to adjust for confounders.ResultMean (SD) weight and GA were 820(214) g and 25.2(1.3) weeks. aMCA, but not aCT, was associated with primary outcome [adjusted odds ratio 2.17, 95% CI: 1.01–4.67] and CLD [2.20 (0.99–4.87)].ConclusionaMCA may be a valid marker for defining the clinical significance of phsPDA in preterm neonates. aCeT may be of limited value in selecting patients for treatment.

ObjectiveTo evaluate the epidemiology and population trends of early-onset sepsis in very preterm neonates admitted to neonatal intensive care units (NICU) in Australia and New Zealand.DesignRetrospective observational cohort study using a dual-nation registry database.Setting29 NICUs that have contributed to the Australian and New Zealand Neonatal Network.ParticipantsNeonates born at <32 weeks’ gestation born between 2007 and 2018 and then admitted to a NICU.Main outcome measuresMicroorganism profiles, incidence, mortality and morbidity.ResultsOver the 12-year period, 614 early-onset sepsis cases from 43 178 very preterm admissions (14.2/1000 admissions) were identified. The trends of early-onset sepsis incidence remained stable, varying between 9.8 and 19.4/1000 admissions (linear trend, p=0.56). The leading causative organisms were Escherichia coli (E. coli) (33.7%) followed by group B Streptococcus (GBS) (16.1%). The incidence of E. coli increased between 2007 (3.2/1000 admissions) and 2018 (8.3/1000 admissions; p=0.02). Neonates with E. coli had higher odds of mortality compared with those with GBS (OR=2.8, 95% CI 1.2 to 6.1). Mortality due to GBS decreased over the same period (2007: 0.6/1000 admissions, 2018: 0.0/1000 admissions; p=0.01). Early-onset sepsis tripled the odds of mortality (OR=3.0, 95% CI 2.4 to 3.7) and halved the odds of survival without morbidity (OR=0.5, 95% CI 0.4 to 0.6).ConclusionEarly-onset sepsis remains an important condition among very preterm populations. Furthermore, E. coli is a dominant microorganism of very preterm early-onset sepsis in Australia and New Zealand. Rates of E. coli have been increasing in recent years, while GBS-associated mortality has decreased.

ObjectivesHealth status (HS)/ health-related quality of life measures, completed by self or proxy, are important outcome indicators. Most HS literature on children born preterm includes adolescents and adults with limited data at preschool age. This study aimed to describe parent-reported HS in a large national cohort of extreme preterm children at preschool age and to identify clinical and sociodemographic variables associated with HS.MethodsInfants born before 29 weeks’ gestation between 2009 and 2011 were enrolled in a prospective longitudinal national cohort study through the Canadian Neonatal Network (CNN) and the Canadian Neonatal Follow-Up Network (CNFUN). HS, at 36 months’ corrected age (CA), was measured with the Health Status Classification System for Pre-School Children tool completed by parents. Information about HS predictors was extracted from the CNN and CNFUN databases.ResultsOf 811 children included, there were 79, 309 and 423 participants in 23–24, 25–26 and 27–28 weeks’ gestational age groups, respectively. At 36 months’ CA, 78% had a parent-reported health concern, mild in >50% and severe in 7%. Most affected HS attributes were speech (52.1%) and self-care (41.4%). Independent predictors of HS included substance use during pregnancy, infant male sex, Score for Neonatal Acute Physiology-II, bronchopulmonary dysplasia, severe retinopathy of prematurity, caregiver employment and single caregiver.ConclusionMost parents expressed no or mild health concerns for their children at 36 months’ CA. Factors associated with health concerns included initial severity of illness, complications of prematurity and social factors.

Methotrexate (MTX) is an immunomodulator used in pediatric inflammatory bowel disease (IBD) maintenance regimens. However, MTX use is associated with liver toxicity. We aimed to systematically review and meta-analyze the incidence of hepatotoxicity with MTX use among children with IBD.MethodsWe searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases from 1946 to April 2013 for cohort studies and collected information about the study design, IBD treatment results, and hepatotoxicity. Pooled proportions of toxicity with 95% confidence interval (CI) were estimated using a random-effects model.ResultsTwelve high-quality studies were included in this review. Fifty-seven of 457 patients treated with MTX developed varied degrees of abnormal liver biochemistry. The pooled proportion of patients with abnormal liver biochemistry was 10.2% (95% CI 5.4%–18.5%) across all studies included in the meta-analysis. Due to hepatotoxicity, dose reductions were required in 6.4% (95% CI 4.3%–9.5%), whereas 4.5% (95% CI 2.8%–7.2%) of patients required discontinuation.ConclusionsHepatotoxicity after the use of MTX among IBD patients was a relatively common event. Monitoring for hepatotoxicity is strongly recommended, as discontinuation of MTX may be necessary in a significant proportion of children.

Background Studies comparing perinatal outcomes in multiples conceived following the use of artificial reproductive technologies (ART) vs. spontaneous conception (SC) have reported conflicting results in terms of mortality and morbidity. Therefore, the objective of our study was to compare composite outcome of mortality and severe neonatal morbidities amongst preterm multiple births ≤ 32 weeks gestation infant born following ART vs. SC. Methods We conducted a single center cohort study at Mount Sinai Hospital, Toronto, Ontario, Canada. Data on all preterm multiple births (≤ 32 weeks GA) discharged between July 2005 and June 2008 were retrospectively collected from a prospective database at our centre. Details regarding mode of conception were collected retrospectively from maternal health records. Preterm multiple births were categorized into those born following ART vs. SC. Composite outcome was defined as combination of death or any of the three neonatal morbidities (grade 3/4 intraventricular hemorrhage or periventricular leukomalacia; retinopathy of prematurity > stage 2 or chronic lung disease). Univariate and multivariate regression analysis were preformed after adjustment of confounders (maternal age, parity, triplets, gestational age, sex, and small for gestational age). Results One hundred and thirty seven neonates were born following use of ART and 233 following SC. The unadjusted composite outcome rate was significantly higher in preterm multiples born following ART vs. SC [43.1% vs. 26.6%, p = 0.001; OR 1.98 (95% CI 1.13, 3.45)]; however, when adjusted for confounders the difference between groups was not statistically significant [OR 1.39, 95% CI 0.67, 2.89]. Conclusion In our population of preterm multiple births, the mode of conception had no detectable effect on the adjusted composite neonatal outcome of mortality and/or three neonatal morbidities.