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Background: Echocardiogram is the reference standard for the diagnosis of haemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. A simple blood assay for brain natriuretic peptide (BNP) or amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be useful in the diagnosis and management of hsPDA, but a summary of the diagnostic accuracy has not been reviewed recently. Objectives: Primary objective: To determine the diagnostic accuracy of the cardiac biomarkers BNP and NT-proBNP for diagnosis of haemodynamically significant patent ductus arteriosus (hsPDA) in preterm neonates. Our secondary objectives were: to compare the accuracy of BNP and NT-proBNP; and to explore possible sources of heterogeneity among studies evaluating BNP and NT-proBNP, including type of commercial assay, chronological age of the infant at testing, gestational age at birth, whether used to initiate medical or surgical treatment, test threshold, and criteria of the reference standard (type of echocardiographic parameter used for diagnosis, clinical symptoms or physical signs if data were available). Search methods: We searched the following databases in September 2021: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science. We also searched clinical trial registries and conference abstracts. We checked references of included studies and conducted cited reference searches of included studies. We did not apply any language or date restrictions to the electronic searches or use methodological filters, so as to maximise sensitivity. Selection criteria: We included prospective or retrospective, cohort or cross-sectional studies, which evaluated BNP or NT-proBNP (index tests) in preterm infants (participants) with suspected hsPDA (target condition) in comparison with echocardiogram (reference standard). Data collection and analysis: Two authors independently screened title/abstracts and full-texts, resolving any inclusion disagreements through discussion or with a third reviewer. We extracted data from included studies to create 2 × 2 tables. Two independent assessors performed quality assessment using the Quality Assessment of Diagnostic-Accuracy Studies-2 (QUADAS 2) tool. We excluded studies that did not report data in sufficient detail to construct 2 × 2 tables, and where this information was not available from the primary investigators. We used bivariate and hierarchical summary receiver operating characteristic (HSROC) random-effects models for meta-analysis and generated summary receiver operating characteristic space (ROC) curves. Since both BNP and NTproBNP are continuous variables, sensitivity and specificity were reported at multiple thresholds. We dealt with the threshold effect by reporting summary ROC curves without summary points. Main results: We included 34 studies: 13 evaluated BNP and 21 evaluated NT-proBNP in the diagnosis of hsPDA. Studies varied by methodological quality, type of commercial assay, thresholds, age at testing, gestational age and whether the assay was used to initiate medical or surgical therapy. We noted some variability in the definition of hsPDA among the included studies. For BNP, the summary curve is reported in the ROC space (13 studies, 768 infants, low-certainty evidence). The estimated specificities from the ROC curve at fixed values of sensitivities at median (83%), lower and upper quartiles (79% and 92%) were 93.6% (95% confidence interval (CI) 77.8 to 98.4), 95.5% (95% CI 83.6 to 98.9) and 81.1% (95% CI 50.6 to 94.7), respectively. Subgroup comparisons revealed differences by type of assay and better diagnostic accuracy at lower threshold cut-offs (< 250 pg/ml compared to ≥ 250 pg/ml), testing at gestational age < 30 weeks and chronological age at testing at one to three days. Data were insufficient for subgroup analysis of whether the BNP testing was indicated for medical or surgical management of PDA. For NT-proBNP, the summary ROC curve is reported in the ROC space (21 studies, 1459 infants, low-certainty evidence). The estimated specificities from the ROC curve at fixed values of sensitivities at median (92%), lower and upper quartiles (85% and 94%) were 83.6% (95% CI 73.3 to 90.5), 90.6% (95% CI 83.8 to 94.7) and 79.4% (95% CI 67.5 to 87.8), respectively. Subgroup analyses by threshold (< 6000 pg/ml and ≥ 6000 pg/ml) did not reveal any differences. Subgroup analysis by mean gestational age (< 30 weeks vs 30 weeks and above) showed better accuracy with < 30 weeks, and chronological age at testing (days one to three vs over three) showed testing at days one to three had better diagnostic accuracy. Data were insufficient for subgroup analysis of whether the NTproBNP testing was indicated for medical or surgical management of PDA. We performed meta-regression for BNP and NT-proBNP using the covariates: assay type, threshold, mean gestational age and chronological age; none of the covariates significantly affected summary sensitivity and specificity. Authors' conclusions: Low-certainty evidence suggests that BNP and NT-proBNP have moderate accuracy in diagnosing hsPDA and may work best as a triage test to select infants for echocardiography. The studies evaluating the diagnostic accuracy of BNP and NT-proBNP for hsPDA varied considerably by assay characteristics (assay kit and threshold) and infant characteristics (gestational and chronological age); hence, generalisability between centres is not possible. We recommend that BNP or NT-proBNP assays be locally validated for specific populations and outcomes, to initiate therapy or follow response to therapy.

Respiratory tract microbial dysbiosis can exacerbate inflammation and conversely inflammation may cause dysbiosis. Dysbiotic microbiome metabolites may lead to bronchopulmonary dysplasia (BPD). Hyperoxia and lipopolysaccharide (LPS) interaction alters lung microbiome and metabolome, mediating BPD lung injury sequence.C57BL6/J mice were exposed to 21% (normoxia) or 70% (hyperoxia) oxygen during postnatal days (PND) 1-14. Pups were injected with LPS (6 mg/kg) or equal PBS volume, intraperitoneally on PND 3, 5, and 7. At PND14, the lungs were collected for microbiome and metabolomic analyses (n = 5/group).Microbiome alpha and beta diversity were similar between groups. Metabolic changes included hyperoxia 31 up/18 down, LPS 7 up/4 down, exposure interaction 8. Hyperoxia increased Intestinimonas abundance, whereas LPS decreased Clostridiales, Dorea, and Intestinimonas; exposure interaction affected Blautia. Differential co-expression analysis on multi-omics data identified exposure-altered modules. Hyperoxia metabolomics response was integrated with a published matching transcriptome, identifying four induced genes (ALDOA, GAA, NEU1, RENBP), which positively correlated with BPD severity in a published human newborn cohort.We report hyperoxia and LPS lung microbiome and metabolome signatures in a clinically relevant BPD model. We identified four genes correlating with BPD status in preterm infants that are promising targets for therapy and prevention.Using multi-omics, we identified and correlated key biomarkers of hyperoxia and LPS on murine lung micro-landscape and examined their potential clinical implication, which shows strong clinical relevance for future research. Using a double-hit model of clinical relevance to bronchopulmonary dysplasia, we are the first to report integrated metabolomic/microbiome landscape changes and identify novel disease biomarker candidates.

Sepsis remains a significant cause of neonatal mortality and morbidity, especially in low- and middle-income countries. Neonatal sepsis presents with nonspecific signs and symptoms that necessitate tests to confirm the diagnosis. Early and accurate diagnosis of infection will improve clinical outcomes and decrease the overuse of antibiotics. Current diagnostic methods rely on conventional culture methods, which is time-consuming, and may delay critical therapeutic decisions. Nonculture-based techniques including molecular methods and mass spectrometry may overcome some of the limitations seen with culture-based techniques. Biomarkers including hematological indices, cell adhesion molecules, interleukins, and acute-phase reactants have been used for the diagnosis of neonatal sepsis. In this review, we examine past and current microbiological techniques, hematological indices, and inflammatory biomarkers that may aid sepsis diagnosis. The search for an ideal biomarker that has adequate diagnostic accuracy early in sepsis is still ongoing. We discuss promising strategies for the future that are being developed and tested that may help us diagnose sepsis early and improve clinical outcomes. IMPACT: Reviews the clinical relevance of currently available diagnostic tests for sepsis. Summarizes the diagnostic accuracy of novel biomarkers for neonatal sepsis. Outlines future strategies including the use of omics technology, personalized medicine, and point of care tests.

ContextDespite the advantages of ultrasound (US), upper gastrointestinal contrast series (UGI) remains the first-line diagnostic modality in the diagnosis of midgut malrotation and volvulus in children.ObjectiveEvaluate the diagnostic accuracy of US in the diagnosis of malrotation with or without volvulus in children and adolescents aged 0–21 years, compared with the reference standard (diagnosis by surgery, UGI, CT, MRI, and clinical follow-up individually or as a composite).Data sourcesWe searched the electronic databases Ovid-MEDLINE, Embase, Scopus, CINAHL, and the Cochrane library in October 2019 and updated on 18 August 2020.Study selectionStudies evaluating the diagnostic performance of US for diagnosis of midgut malrotation with or without volvulus in children (0–21 years).Data extraction and synthesisThe data were extracted independently by two authors and a bivariate model was used for synthesis.ResultsMeta-analysis of 17 cohort or cross-sectional studies and 2257 participants estimated a summary sensitivity of 94% (95% CI 89% to 97%) and summary specificity of 100% (95% CI 97% to 100%) (moderate certainty evidence) for the use of US for the diagnosis of malrotation with or without midgut volvulus compared with the reference standard. Subgroup analysis and meta-regression revealed better diagnostic accuracy in malrotation not complicated by volvulus, in the neonatal population and enteric fluid administration before US.ConclusionsModerate certainty evidence suggests excellent diagnostic accuracy and coupled with the advantages, a strong case exists for the use of abdominal US as the first-line diagnostic test for suspected midgut malrotation with or without volvulus in children and adolescents.

BackgroundPrognostication of mortality and decision to offer extracorporeal membrane oxygenation (ECMO) treatment in infants with congenital diaphragmatic hernia (CDH) can inform clinical management.ObjectiveTo summarise the prognostic value of echocardiography in infants with CDH.MethodsElectronic databases Ovid MEDLINE, Embase, Scopus, CINAHL, the Cochrane Library and conference proceedings up to July 2022 were searched. Studies evaluating the prognostic performance of echocardiographic parameters in newborn infants were included. Risk of bias and applicability were assessed using the Quality Assessment of Prognostic Studies tool. We used a random-effect model for meta-analysis to compute mean differences (MDs) for continuous outcomes and relative risk (RR) for binary outcomes with 95% CIs. Our primary outcome was mortality; secondary outcomes were need for ECMO, duration of ventilation, length of stay, and need for oxygen and/or inhaled nitric oxide.ResultsTwenty-six studies were included that were of acceptable methodological quality. Increased diameters of the right and left pulmonary arteries at birth (mm), MD 0.95 (95% CI 0.45 and 1.46) and MD 0.79 (95% CI 0.58 to 0.99), respectively) were associated with survival. Left ventricular (LV) dysfunction, RR 2.40, (95% CI 1.98 to 2.91), right ventricular (RV) dysfunction, RR 1.83 (95% CI 1.29 to 2.60) and severe pulmonary hypertension (PH), RR 1.69, (95% CI 1.53 to 1.86) were associated with mortality. Left and RV dysfunctions, RR 3.30 (95% CI 2.19 to 4.98) and RR 2.16 (95% CI 1.85 to 2.52), respectively, significantly predicted decision to offer ECMO treatment. Limitations are lack of consensus on what parameter is optimal and standardisation of echo assessments.ConclusionsLV and RV dysfunctions, PH and pulmonary artery diameter are useful prognostic factors among patients with CDH.

In this commentary, we summarize the current evidence from randomized controlled trials on enteral lactoferrin supplementation in preterm neonates. Our recently completed systematic review includes 12 randomized controlled trials performed all over the world. Our meta-analysis suggests clinical benefit in decreasing late-onset sepsis, late-onset fungal sepsis, length of stay in the hospital and urinary tract infections. There were no adverse effects. There was no statistically significant decrease in necrotizing enterocolitis, mortality or neurodevelopmental impairment in lactoferrin supplemented preterm infants. There was significant statistical heterogeneity in the effects of lactoferrin on late-onset sepsis between larger and smaller studies, which may reflect either small study biases, differences in the effectiveness, dose or duration of supplemental lactoferrin products, or differences in underlying population risk, or any or all of these.

Preterm infants are at higher risk of mortality and morbidity compared to those born at term. Nutrition-related morbidities include poor growth, immune deficiency, nutritional deficiencies and adverse long-term neurodevelopment. In addition to macronutrients, many nutritional supplements have been used to enhance growth, development and decrease infections. In this review, we discuss the evidence behind the use of nutrients that enhance preterm infants’ immune status, optimize the microbiome, improve growth and development and influence the risk of necrotizing enterocolitis, sepsis and other outcomes.

Technological advances in omics evaluation, bioinformatics, and artificial intelligence have made us rethink ways to improve patient outcomes. Collective quantification and characterization of biological data including genomics, epigenomics, metabolomics, and proteomics is now feasible at low cost with rapid turnover. Significant advances in the integration methods of these multiomics data sets by machine learning promise us a holistic view of disease pathogenesis and yield biomarkers for disease diagnosis and prognosis. Using machine learning tools and algorithms, it is possible to integrate multiomics data with clinical information to develop predictive models that identify risk before the condition is clinically apparent, thus facilitating early interventions to improve the health trajectories of the patients. In this review, we intend to update the readers on the recent developments related to the use of artificial intelligence in integrating multiomic and clinical data sets in the field of perinatology, focusing on neonatal intensive care and the opportunities for precision medicine. We intend to briefly discuss the potential negative societal and ethical consequences of using artificial intelligence in healthcare. We are poised for a new era in medicine where computational analysis of biological and clinical data sets will make precision medicine a reality. IMPACT: Biotechnological advances have made multiomic evaluations feasible and integration of multiomics data may provide a holistic view of disease pathophysiology. Artificial Intelligence and machine learning tools are being increasingly used in healthcare for diagnosis, prognostication, and outcome predictions. Leveraging artificial intelligence and machine learning tools for integration of multiomics and clinical data will pave the way for precision medicine in perinatology.

Necrotizing enterocolitis (NEC) is a complex inflammatory necrosis of the neonatal intestine, which is likely to require a multipronged approach for prevention and treatment. Despite identifying and defining NEC as a disease entity several decades back, no major progress has been made toward its early identification, treatment, or prevention. This article reviews the latest research strategies that are currently ongoing for early diagnosis and monitoring and prevention of the disease.

To systematically review the diagnostic accuracy of brain natriuretic peptide (BNP) and amino-terminal pro-B-type natriuretic peptide (NT-proBNP) in bronchopulmonary dysplasia (BPD) and BPD-pulmonary hypertension (PH). PubMed, Embase, the Web of Science, and the Cochrane Library were searched in March 2019. We included studies that evaluated BNP or NT-proBNP in preterm neonates as a marker for predicting BPD, BPD or death, and BPD-PH. Nine studies evaluating NT-proBNP/BNP were included. The quality of evidence was low, using GRADE criteria. The diagnostic accuracy of NT-proBNP and BNP for diagnosing BPD-PH showed high sensitivity and specificity in infants with BPD. Lower sensitivities and specificities of NT-proBNP and BNP were reported for predicting BPD, BPD or death, compared with that for BPD-PH. Low quality evidence suggests that NT-proBNP and BNP have adequate diagnostic accuracy for diagnosing and monitoring BPD-PH and may be used to triage patients to receive an echocardiogram.

Background\ud The novel coronavirus disease was declared a pandemic in March 2020, which necessitated adaptations to medical education. This systematic review synthesises published reports of medical educational developments and innovations that pivot to online learning from workplace-based clinical learning in response to the pandemic. The objectives were to synthesise what adaptations/innovation were implemented (description), their impact (justification), and ‘how’ and ‘why’ these were selected (explanation and rationale).\ud \ud Methods\ud The authors systematically searched four online databases up to December 21, 2020. Two authors independently screened titles, abstracts and full-texts, performed data extraction, and assessed the risk of bias. Our findings are reported in alignment with the STORIES (STructured apprOach to the Reporting in healthcare education of Evidence Synthesis) statement and BEME guidance.\ud \ud Results\ud Fifty-five articles were included. Most were from North America (n = 40), and nearly 70% focused on undergraduate medical education (UGME). Key developments were rapid shifts from workplace-based learning to virtual spaces, including online electives, telesimulation, telehealth, radiology, and pathology image repositories, live-streaming or pre-recorded videos of surgical procedures, stepping up of medical students to support clinical services, remote adaptations for clinical visits, multidisciplinary team meetings and ward rounds. Challenges included lack of personal interactions, lack of standardised telemedicine curricula and need for faculty time, technical resources, and devices. Assessment of risk of bias revealed poor reporting of underpinning theory, resources, setting, educational methods, and content.\ud \ud Conclusions\ud This review highlights the response of medical educators in deploying adaptations and innovations. Whilst few are new, the complexity, concomitant use of multiple methods and the specific pragmatic choices of educators offers useful insight to clinical teachers who wish to deploy such methods within their own practice. Future works that offer more specific details to allow replication and understanding of conceptual underpinnings are likely to justify an update to this review.

The neonatal cutaneous mycobiome has not been characterized in preterm infants. Invasive fungal infections in preterm neonates are associated with high mortality. The immaturity of the preterm skin predisposes neonates to invasive infection by skin colonizers. We report the clinical and host determinants that influence the skin mycobiome. Skin swabs from the antecubital fossa, forehead, and gluteal region of 15 preterm and 15 term neonates were obtained during the first 5 weeks of life. The mycobiome was sequenced using the conserved pan-fungal ITS2 region. Blood samples were used to genotype immune modulating genes. Clinical metadata was collected to determine the clinical predictors of the abundance and diversity of the skin mycobiome. The neonatal mycobiome is characterized by few taxa. Alpha diversity of the mycobiome is influenced by antibiotic exposure, the forehead body site, and the neonatal intensive care unit (NICU) environment. Beta diversity varies with mode of delivery, diet, and body site. The host determinants of the cutaneous microbiome include single-nucleotide polymorphisms in TLR4, NLRP3,CARD8, and NOD2. The neonatal cutaneous mycobiome is composed of few genera and is influenced by clinical factors and host genetics, the understanding of which will inform preventive strategies against invasive fungal infections.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To determine the efficacy and safety of enteral lipid supplementation in the prevention and treatment of parenteral nutrition‐associated liver disease in infants.

Aim To summarise the quantity and quality of evidence for using music therapy for preterm infants in the neonatal intensive care unit (NICU). Methods We performed an overview of evidence for the effectiveness and safety of MT for preterm infants in the NICU. We performed a random-effects meta-analysis of data from studies that fit the definition of MT. Results We identified 12 eligible systematic reviews and the methodological quality by AMSTAR-2 ranged from moderate to critically low. We identified 14 eligible randomised trials and 7 observational studies where the intervention fits the definition of MT. Meta-analysis of the RCTs showed that MT significantly decreases heart rate, mean difference (MD) (95% CI), -3.21 [-5.22, -1.19], respiratory rate, MD -2.93 [-5.65, -0.22], and maternal anxiety, MD -17.50 [-20.10, -14.90], and increases feeding volume, MD 29.59 [12.79, 46.38]. Long-term neurodevelopmental or safety outcomes were not reported. GRADE assessment of outcomes ranged from low to very low, downgraded for high risk of bias in the included studies, inconsistency and imprecision. Conclusion Low to very low certainty evidence suggests that MT in preterm infants improves short-term physiological parameters, feeding and maternal anxiety but safety and long-term outcomes were not reported.

The interaction between the gut and its eventual trillions of microbe inhabitants during microbial colonization, represents a critical time period for establishing the overall health and wellbeing of an individual. The gut microbiome represents a diverse community of microbes that are critical for many physiological roles of the host including host metabolism. These processes are controlled by a fine-tuned chemical cross talk between the host and microbiota. Although the exact mechanisms behind this cross talk remains elusive, microbiota induced epigenetic mechanisms like DNA methylation and histone modifications may be key. This review presents our perspective on the epigenome as a mediator for host-microbiota cross talk, as well as methodology to study epigenetics, the role of dysbiosis in disease, and how the gut microbiome-host axis may be used in personal medicine.

ObjectiveWe sought to perform a meta-analysis of the predictive value of antenatal ultrasonographic markers of bowel dilation, gastric dilation, polyhydramnios and abdominal circumference that predict complex gastroschisis and adverse perinatal outcomesData sourcesPubMed, Web of Science, Scopus and Embase were searched for relevant articles up to December 2020. Studies reporting prenatal ultrasonographic markers including intra-abdominal bowel dilation (IABD), extra-abdominal bowel dilation (EABD), bowel wall thickness, polyhydramnios, abdominal circumference ResultsThirty-six studies were included in this meta-analysis. We found significant associations between complex gastroschisis and IABD (OR=5.42; 95% CI 3.24 to 9.06), EABD (OR=2.27; 95% CI 1.40 to 3.66), BD-NOS (OR=6.27; 95% CI 1.97 to 19.97), GD (OR=1.88; 95% CI 1.22 to 2.92) and polyhydramnios (OR=6.93; 95% CI 3.39 to 14.18). Second trimester IABD and EABD have greater specificity for the prediction of complex gastroschisis than third trimester values with specificity of 95.6% (95% CI 58.1 to 99.7) and 94.6% (95% CI 86.7 to 97.9) for the second trimester IABD and EABD, respectively.ConclusionPrenatal ultrasonographic markers, especially the second trimester IABD and EABD, can identify fetuses that develop complex gastroschisis. Furthermore, these specific ultrasonographic markers can identify those babies at the highest risk for severe complications of this congenital anomaly and hence selected for future antenatal interventions.

In recent years, several studies have shown that premature infants who develop NEC frequently display enteric dysbiosis with increased Gram-negative bacteria for several days to weeks prior to NEC onset. The importance of these findings, for the possibility of a causal role of these bacteria in NEC pathogenesis, and for potential value of gut dysbiosis as a biomarker of NEC, is well-recognized. In this review, we present current evidence supporting the association between NEC in premature infants and enteric dysbiosis, and its evaluation using the Bradford Hill criteria for causality. To provide an objective appraisal, we developed a novel scoring system for causal inference. Despite important methodological and statistical limitations, there is support for the association from several large studies and a meta-analysis. The association draws strength from strong biological plausibility of a role of Gram-negative bacteria in NEC and from evidence for temporality, that dysbiosis may antedate NEC onset. The weakness of the association is in the low level of consistency across studies, and the lack of specificity of effect. There is a need for an improved definition of dysbiosis, either based on a critical threshold of relative abundances or at higher levels of taxonomic resolution.

Nasal continuous positive airway pressure (NCPAP) is an effective method of respiratory support for preterm infants. Nasal masks and binasal prongs are two interfaces available to deliver NCPAP, and it is unclear if one is superior to the other. We conducted a systematic review and meta-analysis, using the methodology recommended by the Cochrane Collaboration, to compare the efficacy and safety of nasal masks versus binasal prongs to deliver NCPAP in preterm infants

Necrotizing enterocolitis (NEC) is a disease of preterm infants and associated with significant mortality and morbidity. Although the pathogenesis of NEC is not clear, microbial dysbiosis, with a bloom of the phylum Proteobacteria, has been reported. Antibiotics and the use of H2 blockers, which affect the gut microbiome, are associated with increased incidence of NEC. In association with dysbiosis, inflammatory processes are upregulated with increased Toll-like receptor signaling, leading to translocation of nuclear factor kappa-β, a transcription factor that induces transcription of various pro-inflammatory cytokines and chemokines. Microbial metabolites, short chain fatty acids including acetate and butyrate, may modulate immunity, inflammation, intestinal integrity and regulate transcription by epigenetic mechanisms. Evaluation of microbiome and metabolome may provide biomarkers for early diagnosis of NEC and microbial therapeutic approaches to correct microbial dysbiosis.

Background In utero closure of meningomyelocele using an open hysterotomy approach is associated with preterm delivery and adverse neonatal outcomes. Objective This study compared the neonatal outcomes in in utero meningomyelocele closure using a 2-port, exteriorized uterus, fetoscopic approach vs the conventional open hysterotomy approach. Study Design This retrospective cohort study included all consecutive patients who underwent in utero meningomyelocele closure using open hysterotomy (n=44) or a 2-port, exteriorized uterus, fetoscopic approach (n=46) at a single institution between 2012 and 2020. The 2-port, exteriorized uterus, fetoscopic closure was composed of the following 3 layers: a bovine collagen patch, a myofascial layer, and a skin. The frequency of respiratory distress syndrome and a composite of other adverse neonatal outcomes, including retinopathy of prematurity, periventricular leukomalacia, and perinatal death, were compared between the study groups. Regression analyses were performed to determine any association between the fetoscopic closure and adverse neonatal outcomes, adjusted for several confounders, including gestational age of Results The fetoscopic closure was associated with a lower rate of respiratory distress syndrome than the open hysterotomy closure (11.5% [5 of 45] vs 29.5% [13 of 44]; P=.037). The proportion of neonates with a composite of other adverse neonatal outcomes in the fetoscopic group was half of that observed patients in the open hysterotomy group; however, this difference did not reach statistical significance (4.3% [2 of 46] vs 9.1% [4 of 44]; P=.429). Here, regression analysis has demonstrated that fetoscopic meningomyelocele closure was associated with a lower risk of respiratory distress syndrome (adjusted odds ratio, 0.23; 95% confidence interval, 0.06–0.84; P=.026) than open hysterotomy closure. Conclusion In utero meningomyelocele closure using a 2-port, exteriorized uterus, fetoscopic approach was associated with a lower risk of respiratory distress syndrome than the conventional open hysterotomy meningomyelocele closure.

* Abbreviations: NEC — : necrotizing enterocolitis NMA — : network meta-analysis SUCRA — : surface under the cumulative ranking curve Necrotizing enterocolitis (NEC) and sepsis are major causes of mortality among preterm infants.1,2 Microbial dysbiosis or imbalance in the preterm gut may predispose to NEC, and optimizing the gut microbiome with probiotics is a promising strategy to prevent NEC.3 Multiple previous meta-analyses have reported that enteral supplementation with probiotics, compared to placebo, reduces the risks of NEC, sepsis, and mortality.4 Prebiotics, which support the growth or activity of beneficial bacteria, may also reduce the risks of sepsis and mortality.5 However, there is uncertainty regarding the relative efficacy of different types of probiotics, prebiotics, or synbiotics (combinations of the 2) in preventing morbidity or mortality in preterm infants. In this issue of Pediatrics , Chi et al6 present a systematic review and network meta-analysis (NMA) evaluating the effects of probiotics and synbiotics in preterm infants. The protocol for the systematic review was preregistered, and trials in which authors evaluated both probiotics and synbiotics in preterm infants were searched. The primary outcomes were all-cause mortality and NEC. An NMA was performed … Address correspondence to Ravi Mangal Patel, MD, MSc, Emory Children’s Center, 2015 Uppergate Dr NE, Atlanta, GA 30322. E-mail: rmpatel{at}emory.edu

Copyright © 2020 Informa UK Limited, trading as Taylor & Francis Group, Background: The novel coronavirus disease (COVID-19) was declared a pandemic in March 2020. This rapid systematic review synthesised published reports of medical educational developments in response to the pandemic, considering descriptions of interventions, evaluation data and lessons learned. Methods: The authors systematically searched four online databases and hand searched MedEdPublish up to 24 May 2020. Two authors independently screened titles, abstracts and full texts, performed data extraction and assessed risk of bias for included articles. Discrepancies were resolved by a third author. A descriptive synthesis and outcomes were reported. Results: Forty-nine articles were included. The majority were from North America, Asia and Europe. Sixteen studies described Kirkpatrick’s outcomes, with one study describing levels 1–3. A few papers were of exceptional quality, though the risk of bias framework generally revealed capricious reporting of underpinning theory, resources, setting, educational methods, and content. Key developments were pivoting educational delivery from classroom-based learning to virtual spaces, replacing clinical placement based learning with alternate approaches, and supporting direct patient contact with mitigated risk. Training for treating patients with COVID-19, service reconfiguration, assessment, well-being, faculty development, and admissions were all addressed, with the latter categories receiving the least attention. Conclusions: This review highlights several areas of educational response in the immediate aftermath of the COVID-19 pandemic and identifies a few articles of exceptional quality that can serve as models for future developments and educational reporting. There was often a lack of practical detail to support the educational community in enactment of novel interventions, as well as limited evaluation data. However, the range of options deployed offers much guidance for the medical education community moving forward and there was an indication that outcome data and greater detail will be reported in the future.

Background: Late-onset infection is the most common serious complication associated with hospital care for newborn infants. Because confirming the diagnosis by microbiological culture typically takes 24 to 48 hours, the serum level of the inflammatory marker C-reactive protein (CRP) measured as part of the initial investigation is used as an adjunctive rapid test to guide management in infants with suspected late-onset infection. Objectives: To determine the diagnostic accuracy of serum CRP measurement in detecting late-onset infection in newborn infants. Search methods: We searched electronic databases (MEDLINE, Embase, and Science Citation Index to September 2017), conference proceedings, previous reviews, and the reference lists of retrieved articles. Selection criteria: We included cohort and cross-sectional studies evaluating the diagnostic accuracy of serum CRP levels for the detection of late-onset infection (occurring more than 72 hours after birth) in newborn infants. Data collection and analysis: Two review authors independently assessed eligibility for inclusion, evaluated the methodological quality of included studies, and extracted data to estimate diagnostic accuracy using hierarchical summary receiver operating characteristic (SROC) models. We assessed heterogeneity by examining variability of study estimates and overlap of the 95% confidence interval (CI) in forest plots of sensitivity and specificity. Main results: The search identified 20 studies (1615 infants). Most were small, single-centre, prospective cohort studies conducted in neonatal units in high- or middle-income countries since the late 1990s. Risk of bias in the included studies was generally low with independent assessment of index and reference tests. Most studies used a prespecified serum CRP threshold level as the definition of a ‘positive’ index test (typical cut-off level between 5 mg/L and 10 mg/L) and the culture of a pathogenic micro-organism from blood as the reference standard. At median specificity (0.74), sensitivity was 0.62 (95% CI 0.50 to 0.73). Heterogeneity was evident in the forest plots, but it was not possible to conduct subgroup or meta-regression analyses by gestational ages, types of infection, or types of infecting micro-organism. Covariates for whether studies used a predefined threshold or not, and whether studies used a standard threshold of between 5 mg/L and 10 mg/L, were not statistically significant. Authors’ conclusions: The serum CRP level at initial evaluation of an infant with suspected late-onset infection is unlikely to be considered sufficiently accurate to aid early diagnosis or select infants to undergo further investigation or treatment with antimicrobial therapy or other interventions.

The causes of neonatal gut injury are multifactorial and include ischemia, tissue hypoxia due to anemia, excessive inflammation, deficiency of growth factors, and food protein sensitivity. The developing intestinal microbiome plays a role in some of these forms of intestinal injury but knowledge of its relative role in each remains poorly understood. Commensal bacteria are required for normal immune development and immune tolerance. Dysbiosis in the neonatal gut that alters the patterns of commensal and pathogenic bacteria may accentuate gut injury.

Background: The preferred timing of umbilical-cord clamping in preterm infants is unclear. Methods: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. Results: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. Conclusions: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088. opens in new tab.)

To study the impact of videolaryngoscopy (VL) on intubation success among pediatric trainees compared with direct laryngoscopy (DL). One hundred pediatric residents were enrolled in a randomized, crossover, simulation study comparing VL to DL. Following a didactic session on neonatal intubation, residents intubated a standard neonatal mannequin. Three Neonatal Resuscitation Program (NRP) scenarios were then conducted, followed by a mannequin intubation with the alternate device. Number of attempts and time to intubation were recorded for all intubations. Proportion of successful intubations on first attempt was greater with VL compared with DL (88% versus 63%; P=0.008). The DL group increased success after crossover with VL (63% versus 89%; P=0.008). Exposure to VL also reduced intubation time after device crossover (median intubation time: 31 versus 17 s; P=0.048). VL increased the success of endotracheal intubation by pediatric residents in simulation, with skills transferrable to DL.

CONTEXT: Our aim for this review is to determine if preoperative feeds in neonates with ductal-dependent congenital heart disease are harmful or beneficial. OBJECTIVES: To summarize current evidence for preoperative feeding in neonates with ductal-dependent congenital heart disease. DATA SOURCES: We used the following databases: Medline, Embase, and Cochrane Central Register of Controlled Trials. STUDY SELECTION: We included observational studies in which the following outcomes were addressed: necrotizing enterocolitis (NEC), hospital length of stay (LOS), time to achieve full postoperative enteral feeding, and feeding intolerance. DATA EXTRACTION: Two reviewers independently screened each study for eligibility and extracted data. Methodologic quality was assessed by using a standardized item bank, and certainty of evidence for each outcome was assessed by using Grading of Recommendations Assessment, Development and Evaluation criteria. RESULTS: Five retrospective cohort studies were eligible for inclusion, for which risk of bias was significant. When comparing neonates who received preoperative feeds with those who did not, there was no significant difference in NEC (pooled odds ratio = 1.09 [95% confidence interval 0.06–21.00; P = .95]; 3 studies, 6807 participants, very low certainty evidence), hospital LOS (mean of 14 days for those not fed versus 9.9 days for those fed preoperatively; P < .01; 1 study, 57 participants, very low certainty evidence), or feeding intolerance (odds ratio = 2.014 [95% confidence interval 0.079–51.703; P = .67]; 1 study, 56 participants, very low certainty evidence). No data were available for the outcome time to achieve full postoperative enteral feeding. All studies were observational and had small sample sizes. CONCLUSIONS: There is insufficient evidence to suggest that preoperative enteral feeds in patients with ductal-dependent cardiac lesions adversely influence the rate of NEC, LOS, or feeding intolerance.

Background Preterm infants who are fed breast milk in comparison to infant formula have decreased morbidity such as necrotizing enterocolitis. Multi-nutrient fortifiers used to increase the nutritional content of the breast milk are commonly derived from bovine milk. Human milk-derived multi-nutrient fortifier is now available, but it is not clear if it improves outcomes in preterm infants fed with breast milk. Objectives To determine whether the fortification of breast milk feeds with human milk-derived fortifier in preterm infants reduces mortality, morbidity, and promotes growth and development compared to bovine milk-derived fortifier. Search methods We searched the following databases for relevant trials in September 2018. Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 9), electronic journal reference databases including MEDLINE (1980 to 20 September 2018), PREMEDLINE, Embase (1974 to 20 September 2018), CINAHL (1982 to 20 September 2018), biological abstracts in the database BIOSIS and conference abstracts from 'Proceedings First' (from 1992 to 2011). We also included the following clinical trials registries for ongoing or recently completed trials: ClinicalTrials.gov (ClinicalTrials.gov), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; www.whoint/ictrp/search/en/) and the ISRCTN Registry (www.isrctn.com/), and abstracts of conferences: proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Paediatric Research) from 1990 in the 'Pediatric Research' journal and 'Abstracts online' (2000 to 2017). Selection criteria We included randomized and quasi-randomized controlled trials that compared preterm infants fed breast milk fortified with human milk-derived fortifier versus those fed with breast milk fortified with bovine milk-derived fortifier. Data collection and analysis The data were collected using the standard methods of Cochrane Neonatal. Two authors evaluated trial quality of the studies and extracted data. We reported dichotomous data using risk ratios (RRs), risk differences (RDs), number needed to treat (NNT) where applicable, and continuous data using mean differences (MDs). We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results One randomized trial with 127 infants met the eligibility criteria and had low risk of bias. Human milk-based fortifier did not decrease the risk of necrotizing enterocolitis in exclusively breast milk-fed preterm infants (RR 0.95, 95% CI 0.2 to 4.54; 1 study, 125 infants, low certainty of evidence). Human milk-derived fortifiers did not improve growth, decrease feeding intolerance, late-onset sepsis, or death. Authors' conclusions There is insufficient evidence evaluating human milk-derived fortifier with bovine milk-derived fortifier in exclusively breast milk-fed preterm infants. Low-certainty evidence from one study suggests that in exclusively breast milk-fed preterm infants human milk-derived fortifiers in comparison with bovine milk-derived fortifier may not change the risk of necrotizing enterocolitis, mortality, feeding intolerance, infection, or improve growth. Well-designed randomized controlled trials are needed to evaluate short-term and long-term outcomes.

The neonatal cutaneous mycobiome has not been characterized in preterm infants. Invasive fungal infections in preterm neonates are associated with high mortality. The immaturity of the preterm skin predisposes neonates to invasive infection by skin colonizers. We report the clinical and host determinants that influence the skin mycobiome.Skin swabs from the antecubital fossa, forehead, and gluteal region of 15 preterm and 15 term neonates were obtained during the first 5 weeks of life. The mycobiome was sequenced using the conserved pan-fungal ITS2 region. Blood samples were used to genotype immune modulating genes. Clinical metadata was collected to determine the clinical predictors of the abundance and diversity of the skin mycobiome.The neonatal mycobiome is characterized by few taxa. Alpha diversity of the mycobiome is influenced by antibiotic exposure, the forehead body site, and the neonatal intensive care unit (NICU) environment. Beta diversity varies with mode of delivery, diet, and body site. The host determinants of the cutaneous microbiome include single-nucleotide polymorphisms in TLR4, NLRP3,CARD8, and NOD2.The neonatal cutaneous mycobiome is composed of few genera and is influenced by clinical factors and host genetics, the understanding of which will inform preventive strategies against invasive fungal infections.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is a disease entity that describes a physiology in which there is persistence of increased pulmonary arterial pressure. PPHN is characterised by failure to adapt to a functional postnatal circulation with a fall in pulmonary vascular resistance. PPHN is responsible for impairment in oxygenation and significant neonatal mortality and morbidity. Prostanoids and their analogues may be useful therapeutic interventions due to their pulmonary vasodilatory and immunomodulatory effects. OBJECTIVES: Primary objective • To determine the efficacy and safety of prostanoids and their analogues (iloprost, treprostinil, and beraprost) in decreasing mortality and the need for extracorporeal membrane oxygenation (ECMO) among neonates with PH Secondary objective • To determine the efficacy and safety of prostanoids and their analogues (iloprost, treprostinil, and beraprost) in decreasing neonatal morbidity (necrotizing enterocolitis (NEC), chronic lung disease (CLD), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), length of hospital stay, and duration of mechanical ventilation) and improving neurodevelopmental outcomes among neonates with PH Comparisons • Prostanoids and their analogues at any dosage or duration used to treat PPHN versus ‘standard treatment without these agents’, placebo, or inhaled nitric oxide (iNO) therapy • Prostanoids and their analogues at any dosage or duration used to treat refractory PPHN as an ‘add‐on’ therapy to iNO versus iNO alone SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE via PubMed (1966 to 16 September 2018), Embase (1980 to 16 September 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 16 September 2018). We also searched clinical trials databases, conference proceedings of the Pediatric Academic Societies (1990 to 16 September 2018), and the reference lists of retrieved articles for randomized controlled trials and quasi‐randomized trials. We contacted authors who have published in this field as discerned from the reference lists of identified clinical trials and review authors' personal files. SELECTION CRITERIA: Randomized and quasi‐randomized controlled trials evaluating prostanoids or their analogues (at any dose, route of administration, or duration) used in neonates at any gestational age less than 28 days' postnatal age for confirmed or suspected PPHN. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal to conduct a systematic review and to assess the methodological quality of included studies (neonatal.cochrane.org/en/index.html). Three review authors independently assessed the titles and abstracts of studies identified by the search strategy and obtained full‐text versions for assessment if necessary. We designed forms for trial inclusion or exclusion and for data extraction. We planned to use the GRADE approach to assess the quality of evidence. MAIN RESULTS: We did not identify any eligible neonatal trials evaluating prostanoids or their analogues as sole agents in the treatment of PPHN. AUTHORS' CONCLUSIONS: Implications for practice Currently, no evidence shows the use of prostanoids or their analogues as pulmonary vasodilators and sole therapeutic agents for the treatment of PPHN in neonates (age 28 days or less). Implications for research The safety and efficacy of different preparations and doses and routes of administration of prostacyclins and their analogues in neonates must be established. Well‐designed, adequately powered, randomized, multi‐center trials are needed to address the efficacy and safety of prostanoids and their analogues in the treatment of PPHN. These trials should evaluate long‐term neurodevelopmental and pulmonary outcomes, in addition to short‐term outcomes.

Neonatal sepsis and necrotizing enterocolitis (NEC) cause significant neonatal mortality and morbidity despite appropriate antibiotic therapy. Enhancing host defense and modulating inflammation by using lactoferrin as an adjunct to antibiotics in the treatment of sepsis, NEC, or both, may improve clinical outcomes.The primary objective was to assess safety and efficacy of oral lactoferrin as an adjunct to antibiotics in the treatment of neonates with suspected or confirmed sepsis, NEC, or both.We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 9), MEDLINE via PubMed, PREMEDLINE, (1966 to 20 September 2018) Embase (1980 to 20 September 2018), and CINAHL (1982 to 20 September 2018). We also searched clinical trial databases, conference proceedings, the reference lists of retried articles and clinical trials, and the authors' personal files.We included randomized or quasi-randomized controlled trials evaluating enteral lactoferrin (at any dose or duration), used as an adjunct to antibiotic therapy, compared with antibiotic therapy alone (with or without placebo) or other adjuncts to antibiotic therapy to treat neonates at any gestational age up to 44 weeks' postmenstrual age with confirmed or suspected sepsis or necrotizing enterocolitis (Bell's Stage II or III).We used the standardized methods of Cochrane Neonatal for conducting a systematic review and for assessing the methodological quality of studies (neonatal.cochrane.org/en/index.html). The titles and the abstracts of studies identified by the search strategy were independently assessed by the two review authors and full text versions were obtained for assessment if necessary. Forms were designed to record trial inclusion/exclusion and data extraction. We used the GRADE approach to assess the quality of evidence.We did not identify any eligible trials evaluating lactoferrin for the treatment of neonatal sepsis or NEC.Implications for practice: currently there is no evidence to support or refute the use of enteral lactoferrin, as an adjunct to antibiotic therapy, for the treatment of neonatal sepsis or necrotizing enterocolitis.given the lack of efficacy of enteral lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis, evaluation of enteral lactoferrin as an adjunctive agent for treatment of sepsis or necrotizing enterocolitis does not appear to be a research priority.

Introduction While evidence-based medicine (EBM) is an Accreditation Council for Graduate Medical Education core competency, EBM teaching in pediatric subspecialties is rarely reported. Therefore, we designed, implemented, and evaluated this focused EBM curriculum for trainees in neonatal-perinatal medicine. Methods This EBM curriculum consists of seven weekly 1-hour sessions. Specific EBM skills taught in the sessions include formulating a structured clinical question, conducting an efficient literature search, critically appraising published literature in both intervention and diagnostic studies, and incorporating evidence into clinical decision-making. The course was evaluated by a neonatology-adapted Fresno test (NAFT) and neonatology case vignettes, which were administered to learners before and after the curriculum. This publication includes the needs assessment survey, PowerPoint slides for the seven sessions, the NAFT, and the scoring rubric for the test. Results The NAFT was internally reliable, with a Cronbach's alpha of .74. The intraclass correlation coefficient of the three raters' variability in assessment of learners was excellent at .98. Mean test scores increased significantly (54 points, p < .001) in 14 learners after the EBM curriculum, indicating an increase in EBM-related knowledge and skills. Discussion This focused EBM curriculum enhances trainees' knowledge and skills and fosters evidence-based practice. The curriculum can be easily adapted for learners in pediatrics, as well as family medicine, in order to enhance trainees' EBM skills and knowledge.

Zika Virus (ZIKV), previously the cause of only rare and sporadic human infections, is now considered a Public Health Emergency of International Concern. Over the past two years, ZIKV has become a pandemic encompassing much of the Americas. ZIKV is now proven to cause microcephaly and ophthalmic anomalies in the newborn. Hydrops fetalis, developmental delay, and other anomalies are increasingly being attributed to ZIKV infection in fetuses and neonates. Sequelae of congenital infection and rapid spread of ZIKV throughout the Americas has catapulted Zika virus concerns to the forefront of the medical community. Areas covered: This review seeks to consolidate ZIKV epidemiology, diagnostic testing methods, CDC screening recommendations, and preventive strategies including potential vaccines. Expert commentary: Many unknowns still exist regarding ZIKV infections and its long-term effects in neonates. In addition, further studies need to evaluate if genomic differences that have occurred from the African to the Asian lineage of the virus have led to increased virulence of the virus. The authors believe that all pregnant women with fetuses showing microcephaly and/or intracranial calcifications should be tested for ZIKV infection if they cannot recall their sexual partner travel history. This change from the current CDCs recommendations could increase substantially the number of pregnant women and neonates, screened for ZIKV.

Background Invasive candidiasis (IC) is an important cause of sepsis in premature infants and is associated with a high risk of death and neurodevelopmental impairment. Prevention of IC has become a major focus in very low birth weight infants, with fluconazole increasingly used as prophylaxis. Methods We identified all randomized, placebo-controlled trials evaluating fluconazole prophylaxis in premature infants conducted in the United States. We obtained patient-level data from the study investigators and performed an aggregated analysis. The occurrence of each endpoint in infants who received prophylaxis with fluconazole vs placebo was compared. Endpoints evaluated were IC or death, IC, death, Candida colonization, and fluconazole resistance among tested isolates. Safety endpoints evaluated included clinical and laboratory parameters. Results Fluconazole prophylaxis reduced the odds of IC or death, IC, and Candida colonization during the drug exposure period compared with infants given placebo: odds ratios of 0.48 (95% confidence interval [CI], .30-.78), 0.20 (95% CI, .08-.51), and 0.28 (95% CI, .18-.41), respectively. The incidence of clinical and laboratory adverse events was similar for infants who received fluconazole compared with placebo. There was no statistically significant difference in the proportion of tested isolates that were resistant to fluconazole between the fluconazole and placebo groups. Conclusions Fluconazole prophylaxis is effective and safe in reducing IC and Candida colonization in premature infants, and has no impact on resistance.

Background: Substantial health care resources are expended on standardised formal neonatal resuscitation training (SFNRT) programmes, but their effectiveness has not been proven. Objectives: To determine whether SFNRT programmes reduce neonatal mortality and morbidity, improve acquisition and retention of knowledge and skills, or change teamwork and resuscitation behaviour. Methods: We searched CENTRAL, MEDLINE, PREMEDLINE, EMBASE, CINAHL, Web of Science and the Oxford Database of Perinatal Trials, ongoing trials and conference proceedings in April 2015, and included randomised or quasi-randomised trials that reported at least one of our specified outcomes. Results: SFNRT in low- and middle-income countries decreased early neonatal mortality [risk ratio (RR) 0.85 (95% CI 0.75-0.96)]; the number needed to treat for benefit [227 (95% CI 122-1,667; 3 studies, 66,162 participants, moderate-quality evidence)], and 28-day mortality [RR 0.55 (95% CI 0.33-0.91); 1 study, 3,355 participants, low-quality evidence]. Decreasing trends were noted for late neonatal mortality [RR 0.47 (95% CI 0.20-1.11)] and perinatal mortality [RR 0.94 (95% CI 0.87-1.00)], but there were no differences in fresh stillbirths [RR 1.05 (95% CI 0.93-1.20)]. Teamwork training with simulation increased the frequency of teamwork behaviour [mean difference (MD) 2.41 (95% CI 1.72-3.11)] and decreased resuscitation duration [MD -149.54 (95% CI -214.73 to -84.34); low-quality evidence, 2 studies, 130 participants]. Conclusions: SFNRT in low- and middle-income countries reduces early neonatal mortality, but its effects on birth asphyxia and neurodevelopmental outcomes remain uncertain. Follow-up studies suggest normal neurodevelopment in resuscitation survivors.