Probiotics, Prebiotics, Lactoferrin, and Combination Products for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis.

Importance: Modulation of intestinal microbiome by administering probiotics, prebiotics, or both may prevent morbidity and mortality in premature infants. Objective: To assess the comparative effectiveness of alternative prophylactic strategies through a network meta-analysis (NMA) of randomized clinical trials. Data Sources: MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, and Google Scholar from inception until May 10, 2023. Study Selection: Eligible trials tested probiotics, prebiotics, lactoferrin, and combination products for prevention of morbidity or mortality in preterm infants. Data Extraction and Synthesis: A frequentist random-effects model was used for the NMA, and the certainty of evidence and inferences regarding relative effectiveness were assessed using the GRADE approach. Main Outcomes and Measures: All-cause mortality, severe necrotizing enterocolitis, culture-proven sepsis, feeding intolerance, time to reach full enteral feeding, and duration of hospitalization. Results: A total of 106 trials involving 25 840 preterm infants were included. Only multiple-strain probiotics were associated with reduced all-cause mortality compared with placebo (risk ratio [RR], 0.69; 95% CI, 0.56 to 0.86; risk difference [RD], -1.7%; 95% CI, -2.4% to -0.8%). Multiple-strain probiotics alone (vs placebo: RR, 0.38; 95% CI, 0.30 to 0.50; RD, -3.7%; 95% CI, -4.1% to -2.9%) or in combination with oligosaccharides (vs placebo: RR, 0.13; 95% CI, 0.05 to 0.37; RD, -5.1%; 95% CI, -5.6% to -3.7%) were among the most effective interventions reducing severe necrotizing enterocolitis. Single-strain probiotics in combination with lactoferrin (vs placebo RR, 0.33; 95% CI, 0.14 to 0.78; RD, -10.7%; 95% CI, -13.7% to -3.5%) were the most effective intervention for reducing sepsis. Multiple-strain probiotics alone (RR, 0.61; 95% CI, 0.46 to 0.80; RD, -10.0%; 95% CI, -13.9% to -5.1%) or in combination with oligosaccharides (RR, 0.45; 95% CI, 0.29 to 0.67; RD, -14.1%; 95% CI, -18.3% to -8.5%) and single-strain probiotics (RR, 0.61; 95% CI, 0.51 to 0.72; RD, -10.0%; 95% CI, -12.6% to -7.2%) proved of best effectiveness in reduction of feeding intolerance vs placebo. Single-strain probiotics (MD, -1.94 days; 95% CI, -2.96 to -0.92) and multistrain probiotics (MD, -2.03 days; 95% CI, -3.04 to -1.02) proved the most effective in reducing the time to reach full enteral feeding compared with placebo. Only single-strain and multistrain probiotics were associated with greater effectiveness compared with placebo in reducing duration of hospitalization (MD, -3.31 days; 95% CI, -5.05 to -1.58; and MD, -2.20 days; 95% CI, -4.08 to -0.31, respectively). Conclusions and Relevance: In this systematic review and NMA, moderate- to high-certainty evidence demonstrated an association between multistrain probiotics and reduction in all-cause mortality; these interventions were also associated with the best effectiveness for other key outcomes. Combination products, including single- and multiple-strain probiotics combined with prebiotics or lactoferrin, were associated with the largest reduction in morbidity and mortality.

Impact of 2019 Novel Coronavirus (2019-nCov) Pandemic and Lockdown on Parents and Caregivers in Ontario, Canada.

The COVID-19 pandemic has impacted parents' and children's well-being. This study aimed to evaluate the impact of the COVID-19 pandemic and its preventive measures on children's well-being and their parents' anxiety level. Parents/caregivers were invited to respond to a self-administered survey. The primary outcome was to assess the rate and severity of parental anxiety during the pandemic/lockdown. Four hundred and thirty parents completed the survey. Ninety-two (21%) and 10 (2%) parents reported that their children gained or lost weight during the pandemic, respectively. Eighty-one (19%) parents reported a regression in their children's developmental milestones, particularly in toileting, speech, and social interaction. The GAD-7 mean scores increased by 2.9 points (95% CI [2.5, 3.25]; P < .001) in comparison with prepandemic scores. Adjusted multivariable analysis showed that having children with psychological conditions and a maternal education level less than a university degree were significantly associated with higher parental anxiety.

Quality and credibility of clinical practice guidelines recommendations for the management of neonatal hypoglycemia. A protocol for a systematic review and recommendations' synthesis.

INTRODUCTION: Hypoglycemia is one of the most frequent metabolic conditions in neonates. Clinical practice guidelines (CPGs) influence clinical practice as high-quality CPGs facilitate the use of evidence in practice. This proposed study aims to systematically identify and appraise CPGs and CPG recommendations (CPGRs) for treating neonatal hypoglycemia (NH). METHODS AND ANALYSIS: We will conduct searches in MEDLINE, EMBASE, CINAHL, Cochrane Library, LILACS (Latin American & Caribbean Health Sciences Literature), and Epistemonikos. Authors will search CPGs-specific databases and grey literature. Two reviewers will independently perform the titles and abstract screening, full-text review, and data extraction. Two appraisers will assess the quality of the CPGs and their recommendations using AGREE II (Appraisal of Guidelines Research and Evaluation) and AGREE-REX (Appraisal of Guidelines Research and Evaluation-Recommendations Excellence) instruments. Scores of ≥ 60% in the rigour of development domain will be considered for defining high-quality with AGREE II tool. CPGRs with scores >60% in the three domains will be used to determine high quality with the AGREE REX tool. We will perform a synthesis of the CPGRs to identify the consistency among the CPGRs and the methodological quality of primary studies that support them. ETHICS AND DISSEMINATION: The results will help us to identify the methodological and quality gaps in the existing CPGs for the treatment of NH. Our findings will be submitted to peer-review journals and presented at academic conferences. Based on the study design, approval from the institutional ethics board is not required for this project. TRIAL REGISTRATIONS: Systematic Review Registration Number (PROSPERO): CRD 42021239921.

Medications for the treatment of pulmonary arterial hypertension: a systematic review and network meta-analysis.

BACKGROUND: There is no consensus on the most effective treatments of pulmonary arterial hypertension (PAH). Our objective was to compare effects of medications for PAH. METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrials.gov from inception to December 2021. We performed a frequentist random-effects network meta-analysis on all included trials. We rated the certainty of the evidence using the Grades of Recommendation, Assessment, Development, and Evaluation approach. RESULTS: We included 53 randomised controlled trials with 10 670 patients. Combination therapy with endothelin receptor antagonist (ERA) plus phosphodiesterase-5 inhibitors (PDE5i) reduced clinical worsening (120.7 fewer events per 1000, 95% CI 136.8-93.4 fewer; high certainty) and was superior to either ERA or PDE5i alone, both of which reduced clinical worsening, as did riociguat monotherapy (all high certainty). PDE5i (24.9 fewer deaths per 1000, 95% CI 35.2 fewer to 2.1 more); intravenous/subcutaneous prostanoids (18.3 fewer deaths per 1000, 95% CI 28.6 fewer deaths to 0) and riociguat (29.1 fewer deaths per 1000, 95% CI 38.6 fewer to 8.7 more) probably reduce mortality as compared to placebo (all moderate certainty). Combination therapy with ERA+PDE5i (49.9 m, 95% CI 25.9-73.8 m) and riociguat (49.5 m, 95% CI 17.3-81.7 m) probably increase 6-min walk distance as compared to placebo (moderate certainty). CONCLUSION: Current PAH treatments improve clinically important outcomes, although the degree and certainty of benefit vary between treatments.

Outcomes of long-term von Willebrand factor prophylaxis use in von Willebrand disease: A systematic literature review.

BACKGROUND: Von Willebrand Disease (VWD) is a common inherited bleeding disorder. Patients with VWD suffering from severe bleeding may benefit from the use of secondary long-term prophylaxis. AIM: Systematically summarize the evidence on the clinical outcomes of secondary long-term prophylaxis in patients with VWD and severe recurrent bleedings. METHODS: We searched Medline and EMBASE through October 2019 for relevant randomized clinical trials (RCTs) and comparative observational studies (OS) assessing the effects of secondary long-term prophylaxis in patients with VWD. We used Cochrane Risk of Bias (RoB) tool and the RoB for Non-Randomized Studies of interventions (ROBINS-I) tool to assess the quality of the included studies. We conducted random-effects meta-analyses and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: We included 12 studies. Evidence from one placebo controlled RCT suggested that VWD prophylaxis as compared to no prophylaxis reduced the rate of bleeding episodes (Rate ratio [RR], .24; 95% confidence interval [CI], .17-.35; low certainty evidence), and of epistaxis (RR, .38; 95%CI, .21-.67; moderate certainty evidence), and may increase serious adverse events RR 2.73 (95%CI .12-59.57; low certainty). Evidence from four before-and-after studies in which researchers reported comparative data suggested that VWD prophylaxis reduced the rate of bleeding (RR .34; 95%CI, .25-.46; very low certainty evidence). CONCLUSION: VWD prophylaxis treatment seems to reduce the risk of spontaneous bleeding, epistaxis, and hospitalizations. More RCTs should be conducted to increase the certainty in these benefits.

Evaluation of a Modified SBAR Report to Physician Tool to Standardize Communication on Neonatal Transport.

OBJECTIVE: SBAR (situation, background, assessment and recommendation) is a structured format for the effective communication of critically relevant information. This tool was developed as a generic template to provide structure to the communication of clinical information between health care providers. Neonatal transport often presents clinically stressful circumstances where concise and accurate information is required to be shared clearly between multidisciplinary health care providers. A modified SBAR communication tool was designed to facilitate structured communication between nonphysician bedside care providers operating from remote sites and physicians providing decision-making support at receiving care facilities. Prospective interventional study was designed to evaluate the reliability of a "SBAR report to physician tool" in sharing clinically relevant information between multidisciplinary care providers on neonatal transport. STUDY DESIGN: The study was conducted between 2011 and 2014 by a dedicated neonatal transport service based at McMaster Children's Hospital which provides care for approximately 500 infants in Southern Ontario annually. In the preintervention phase, 50 calls were randomly selected for the evaluation and 115 consecutively recorded transport calls following adoption of the reporting tool. The quality of calls prior to and after the intervention was assessed by reviewers independently. Inter-rater agreement was also assessed for both periods. RESULTS: Inter-rater agreement between raters was moderate to perfect in most components of the SBAR "report to the physician tool" except for the assessment component, which showed fair agreement during both preintervention and postintervention periods. There was an improvement in global score (primary outcome) with a mean difference of 0.95 (95% confidence interval [CI]: 0.77-1.14; p < 0.001) and in cumulative score with a mean difference of 8.55 (95% CI: 7.26-9.84; p < 0.001) in postintervention period. CONCLUSION: The use of the SBAR report to physician tool improved the quality of clinical information shared between nonphysician members of the neonatal transport team and neonatal transport physicians. KEY POINTS: · Long-Accurate and concise information sharing is crucial for decision-making in neonatal transport.. · Information sharing between multidisciplinary teams can be enhanced by using a commonly understood information sharing template.. · The SBAR report to physician tool improves the quality of information shared between multidisciplinary team members in neonatal transport..

Gynecologic and obstetric management of women with von Willebrand disease: summary of 3 systematic reviews of the literature.

von Willebrand disease (VWD) disproportionately affects women because of the potential for heavy menstrual bleeding (HMB), delivery complications, and postpartum hemorrhage (PPH). To systematically synthesize the evidence regarding first-line management of HMB, treatment of women requiring or desiring neuraxial analgesia, and management of PPH. We searched Medline and EMBASE through October 2019 for randomized trials, comparative observational studies, and case series comparing the effects of desmopressin, hormonal therapy, and tranexamic acid (TxA) on HMB; comparing different von Willebrand factor (VWF) levels in women with VWD who were undergoing labor and receiving neuraxial anesthesia; and measuring the effects of TxA on PPH. We conducted duplicate study selection, data abstraction, and appraisal of risk of bias. Whenever possible, we conducted meta-analyses. We assessed the quality of the evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We included 1 randomized trial, 3 comparative observational studies, and 10 case series. Moderate-certainty evidence showed that desmopressin resulted in a smaller reduction of menstrual blood loss (difference in mean change from baseline, 41.6 [95% confidence interval, 16.6-63.6] points in a pictorial blood assessment chart score) as compared with TxA. There was very-low-certainty evidence about how first-line treatments compare against each other, the effects of different VWF levels in women receiving neuraxial anesthesia, and the effects of postpartum administration of TxA. Most of the evidence relevant to the gynecologic and obstetric management of women with VWD addressed by most guidelines is very low quality. Future studies that address research priorities will be key when updating such guidelines.

Surgical management of patients with von Willebrand disease: summary of 2 systematic reviews of the literature.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD who are undergoing surgeries is crucial to prevent bleeding complications. We systematically summarized the evidence on the management of patients with VWD who are undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE from inception through October 2019 for randomized clinical trials (RCTs), comparative observational studies, and case series that compared maintaining factor VIII (FVIII) levels or von Willebrand factor (VWF) levels at >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and those with options for perioperative management of patients undergoing minor surgery. Two authors screened and abstracted data and assessed the risk of bias. We conducted meta-analyses when possible. We evaluated the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We included 7 case series for major surgeries and 2 RCTs and 12 case series for minor surgeries. Very-low-certainty evidence showed that maintaining FVIII levels or VWF levels of >0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74% to 100% of major surgeries. Low- to very-low-certainty evidence showed that prescribing tranexamic acid and increasing VWF levels to 0.50 IU/mL resulted in fewer bleeding complications after minor procedures compared with increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence for guiding management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD who are undergoing surgical and invasive procedures.

Intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia: A systematic review.

To compare the effectiveness and safety of intensive antileukemic therapy to less-intensive therapy in older adults with acute myeloid leukemia (AML) and intermediate or adverse cytogenetics, we searched the literature in Medline, Embase, and CENTRAL to identify relevant studies through July 2020. We reported the pooled hazard ratios (HRs), risk ratios (RRs), mean difference (MD) and their 95% confidence intervals (CIs) using random-effects meta-analyses and the certainty of evidence using the GRADE approach. Two randomized trials enrolling 529 patients and 23 observational studies enrolling 7296 patients proved eligible. The most common intensive interventions included cytarabine-based intensive chemotherapy, combination of cytarabine and anthracycline, or daunorubicin/idarubicin, and cytarabine plus idarubicin. The most common less-intensive therapies included low-dose cytarabine alone, or combined with clofarabine, azacitidine, and hypomethylating agent-based chemotherapy. Low certainty evidence suggests that patients who receive intensive versus less-intensive therapy may experience longer survival (HR 0.87; 95% CI, 0.76-0.99), a higher probability of receiving allogeneic hematopoietic stem cell transplantation (RR 6.14; 95% CI, 4.03-9.35), fewer episodes of pneumonia (RR, 0.25; 95% CI, 0.06-0.98), but a greater number of severe, treatment-emergent adverse events (RR, 1.34; 95% CI, 1.03-1.75), and a longer duration of intensive care unit hospitalization (MD, 6.84 days longer; 95% CI, 3.44 days longer to 10.24 days longer, very low certainty evidence). Low certainty evidence due to confounding in observational studies suggest superior overall survival without substantial treatment-emergent adverse effect of intensive antileukemic therapy over less-intensive therapy in older adults with AML who are candidates for intensive antileukemic therapy.

Efficacy and Safety of EMLA Cream for Pain Control Due to Venipuncture in Infants: A Meta-analysis.

: media-1vid110.1542/5852339542001PEDS-VA_2018-1173Video Abstract CONTEXT: The eutectic mixture of lidocaine (EMLA) cream has been used to reduce the pain during venipuncture in infants. OBJECTIVE: To determine the efficacy and safety of EMLA in infants <3 months of age requiring venipuncture in comparison with nonpharmacological interventions in terms of pain reduction, change in physiologic variables, and methemoglobinemia. DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Web of Science, and gray literature were searched from inception to August 2017, without language restrictions. STUDY SELECTION: We selected randomized controlled trials in which researchers compared EMLA with nonpharmacological interventions. DATA EXTRACTION: Two reviewers independently performed abstract screening and full-text review, and extracted the data and assessed the risk of bias. RESULTS: Ten randomized controlled trials (907 infants) were included. EMLA revealed little or no effect in reduction of pain (standardized mean difference: 0.14; 95% confidence interval [CI]: -0.17 to 0.45; 6 trials, n = 742; moderate-quality evidence) when EMLA was compared with sucrose, breastfeeding, or placebo. In comparison with placebo, EMLA revealed a small-to-moderate effect on increasing methemoglobin levels (mean difference: 0.35; 95% CI: 0.04 to 0.66; 2 trials, n = 134; low-quality evidence). There was an increased risk of blanching of the skin in the EMLA group (relative risk: 2.63; 95% CI: 1.58 to 4.38; 2 trials, n = 123; I2 = 84%, very low-quality evidence). LIMITATIONS: Our results may not be applicable to older infants. CONCLUSIONS: EMLA reveals minimal benefits in terms of reduction of pain due to venipuncture procedure in comparison with placebo and no benefit in comparison with sucrose and/or breastfeeding. Moreover, it produced an elevation in methemoglobin levels and skin blanching.

Comparative Effectiveness of Prophylactic Therapies for Necrotizing Enterocolitis in Preterm Infants: Protocol for a Network Meta-analysis of Randomized Trials.

Necrotizing enterocolitis (NEC) is a common and devastating disease with high morbidity and mortality in premature infants. Current literature on the prevention of NEC has limitations including lack of direct and indirect comparisons of available therapies. We will search MEDLINE, EMBASE, Science Citation Index Expanded, Social Sciences Citation Index, CINAHL, Scopus, ProQuest Dissertations and Theses database, and grey literature sources to identify eligible trials evaluating NEC preventive therapies. Eligible studies will (1) enroll preterm (gestational age <37 weeks) and/or low birth weight (birth weight <2500 g) infants, (2) randomize infants to any preventive intervention or a placebo, or alternative active or nonactive intervention. Our outcomes of interest are severe NEC (stage II or more, based on Bell's criteria), all-cause mortality, NEC-related mortality, late-onset sepsis, duration of hospitalization, weight gain, time to establish full enteral feeds, and treatment-related adverse events. Two reviewers will independently screen trials for eligibility, assess risk of bias, and extract data. All discrepancies will be resolved by discussion. We will specify a priori explanations for heterogeneity between studies. For available comparisons between treatment and no treatment, and direct comparisons of treatments, we will conduct conventional meta-analysis using a random effects model. We will conduct a network meta-analysis using a random effects model within the Bayesian framework using Markov chain Monte Carlo methods to assess relative effects of eligible interventions. We will assess the certainty in direct, indirect, and network estimates using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: We will disseminate our findings through a peer-reviewed publication and conference presentations.

Guidelines for feeding very low birth weight infants.

Despite the fact that feeding a very low birth weight (VLBW) neonate is a fundamental and inevitable part of its management, this is a field which is beset with controversies. Optimal nutrition improves growth and neurological outcomes, and reduces the incidence of sepsis and possibly even retinopathy of prematurity. There is a great deal of heterogeneity of practice among neonatologists and pediatricians regarding feeding VLBW infants. A working group on feeding guidelines for VLBW infants was constituted in McMaster University, Canada. The group listed a number of important questions that had to be answered with respect to feeding VLBW infants, systematically reviewed the literature, critically appraised the level of evidence, and generated a comprehensive set of guidelines. These guidelines form the basis of this state-of-art review. The review touches upon trophic feeding, nutritional feeding, fortification, feeding in special circumstances, assessment of feed tolerance, and management of gastric residuals, gastro-esophageal reflux, and glycerin enemas.

Standardizing umbilical catheter usage in preterm infants.

BACKGROUND AND OBJECTIVE: Absence of guidelines on umbilical arterial catheter (UAC) and umbilical venous catheter (UVC) use and inability to predict the hospital course may sway the frontline staff to overuse umbilical catheters in preterm infants. Our objective was to evaluate the feasibility of implementing guidelines standardizing the use of umbilical catheters and its impact on the incidence of sepsis and resource use. METHODS: All inborn infants delivered at <33 weeks' gestation and admitted to the NICU were included in this quality improvement study. The primary outcome was proportion of infants receiving umbilical catheters. Secondary outcomes were central venous catheter (CVC) use and central line-associated bloodstream infection (CLABSI). RESULTS: The proportion of infants receiving UACs and UVCs was significantly lower in postintervention (sustainment) phase than in the preintervention phase (93 [42.3%] vs 52 [23.6%], P = .0001) and (137 [62.6%] vs 93 [42.3%], P = .0001), respectively. There was no corresponding increase in the proportion of infants receiving peripherally inserted central catheters (PICCs) or surgical CVCs (SCVCs) during the sustainment phase. There was a significant reduction in the proportion of infants receiving CVCs (UVC, PICC, and SCVC) in the sustainment phase. The incidence of CLABSI was similar in the preintervention and sustainment phases. CONCLUSIONS: Implementation of guidelines standardizing the use of umbilical catheters in the NICU is feasible. Fewer infants were exposed to the risk of UVC or UAC, and fewer resources were used.

Severe hypernatremic dehydration and metabolic acidosis due to neonatal intestinal microvillus inclusion disease.

Neonatal microvillus inclusion disease (MID) is a congenital secretory diarrhea diagnosed by morphological enterocyte abnormalities on histology. The secretory diarrhea associated with MID occurs within the first few hours of birth and is exacerbated by enteral feeding. Affected newborns will die of dehydration and acid-base disturbances if MID is not rapidly recognized and treated with massive intravenous fluid replacement and gut rest. We report a case of a 4-day-old neonate presenting with 18% weight loss, hypernatremic dehydration and metabolic acidosis. Despite aggressive fluid resuscitation (206 ml/kg for the first 24 h), the dehydration and metabolic acidosis were only minimally improved. The diapers were found soaked with clear, non-odorous fluid on repeated examinations. Persistent secretory diarrhea was suspected. Stool electrolytes analyses showed a high NaCl content typical of secretory diarrhea and intestinal biopsy with electron microscopy was diagnostic of MID.