Clinical practice guidelines for neonatal hypoxic-ischemic encephalopathy: A systematic review using the appraisal of guidelines for research and evaluation (AGREE) II instrument.

Background and Objective: To systematically review, critically appraise the quality of recent clinical practice guidelines (CPGs) for neonatal hypoxic ischemic encephalopathy (HIE), and map their recommendations. Data Sources: CPG databases (GIN, ECRI, NICE, SIGN, DynaMed), Bibliographic databases (PubMed, Embase, CINAHL), and related specialized professional societies (e.g., AAP, CPS, BAPM, RCPCH, and SNS). Study Selection: Original de-novo developed evidence-based CPGs for HIE, group authorship, Arabic or English languages, and international or national scope. The systematic review was drafted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement and Johnston et al methodological guide. Data Extraction: Quality assessment of the included HIE CPGs by the Appraisal of Guidelines for REsearch & Evaluation II (AGREE II) Instrument and report their characteristics, AGREE II ratings, and recommendations. Data Synthesis: Our search retrieved 2,489 citations, of which two recent HIE CPGs were eligible and appraised: Canadian Paediatric Society (CPS) and Queensland Maternity and Neonatal Services (QMN). The overall assessment of the QMN CPG was superior (83%). Domain 1 (Scope & Purpose) scored (47%, 63%), Domain 2 (Stakeholder Involvement) (72%, 39%), Domain 3 (Rigour of Development) (48%, 43%), Domain 4 (Clarity & Presentation) (100%, 96%), Domain 5 (Applicability) (59%, 9%), and Domain 6 (Editorial Independence) (67%, 17%) for the QMN and CPS CPGs respectively. All appraisers recommended the QMN CPG for use in practice. Conclusion: The methodological quality of the QMN CPG was superior with the relevant recommendations for its use in neonatal practice. Limitations: limited to Arabic and English languages. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=258291, identifier: CRD42021258291.

Quality assessment of clinical practice guidelines for neonatal sepsis using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument: A systematic review of neonatal guidelines.

Background and objective: Neonatal sepsis (NS) continues to be a critical healthcare priority for the coming decades worldwide. The aim of this study was to critically appraise the quality of recent clinical practice guidelines (CPGs) for neonatal sepsis and to summarize and compare their recommendations. Methods: This study involves a systematic review of CPGs. We identified clinical questions and eligibility criteria and searched and screened for CPGs using bibliographic and CPG databases and professional societies. Each included CPG was assessed by four independent appraisers using the Appraisal of Guidelines for REsearch & Evaluation II (AGREE II) instrument. We summarized the recommendations in a comparison practical table. The systematic review was drafted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Its protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (ID: CRD42021258732). Results: Our search retrieved 4,432 citations; of which five CPGs were eligible and appraised: American Academy of Pediatrics (AAP 2018) (35 and 34 weeks); Canadian Pediatric Society (CPS 2017); National Institute for Health and Care Excellence (NICE 2021); and Queensland Maternity and Neonatal Services (QH 2020). Among these, the overall assessment of two evidence-based CPGs scored > 70% (NICE and QH), which was consistent with their higher scores in the six domains of the AGREE II instrument. In domain 3 (rigor of development), NICE and QH scored 99 and 60%, respectively. In domain 5 (applicability), they scored 96 and 74%, respectively, and in domain 6 (editorial independence), they scored 90 and 71%, respectively. Conclusion: The methodological quality of the NICE CPG was superior followed by the QH CPG with relevant recommendations for use in practice. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021258732, PROSPERO (CRD42021258732).

Diuretics for transient tachypnoea of the newborn.

BACKGROUND: Transient tachypnoea of the newborn (TTN) results from delayed clearance of lung liquid and is a common cause of admission of full-term infants to neonatal intensive care units. The condition is particularly common after elective caesarean section. Conventional treatment involves appropriate oxygen administration and continuous positive airway pressure in some cases. Most infants receive antibiotic therapy. Hastening the clearance of lung liquid may shorten the duration of the symptoms and reduce complications. OBJECTIVES: To determine whether diuretic administration reduces the duration of oxygen therapy and respiratory symptoms and shortens hospital stay in term infants presenting with transient tachypnoea of the newborn. SEARCH METHODS: An updated search was carried out in September 2015 of the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 9, 2015), MEDLINE via Ovid, EMBASE, PubMed, and CINAHL via OVID. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that compared the effect of diuretics administration versus placebo or no treatment in infants of less than seven days of age, born at 37 or more weeks of gestation with the clinical picture of transient tachypnoea of the newborn. DATA COLLECTION AND ANALYSIS: We extracted and analysed data according to the methods outlined in the latest Cochrane Handbook for Systematic Reviews of Interventions. Two review authors assessed trial quality in each potentially eligible manuscript and two review authors extracted data. MAIN RESULTS: Our previous systematic review included two trials enrolling a total of 100 infants with transient tachypnoea of the newborn (Wiswell 1985; Karabayir 2006). The updated search revealed no new trials. Wiswell 1985 randomised 50 infants to receive either oral furosemide (2 mg/kg body weight at time of diagnosis followed by a 1 mg/kg dose 12 hours later if the tachypnoea persisted) or placebo. Karabayir 2006 randomised 50 infants to receive either intravenous furosemide (2 mg/kg body weight) or an equal volume of normal saline placebo. Neither trial reported on the need for respiratory support. Neither trial demonstrated a statistically significant impact of furosemide on transient tachypnoea of the newborn regarding duration of symptoms or length of hospitalisation. AUTHORS' CONCLUSIONS: Diuretics cannot be recommended as treatment for transient tachypnoea of the newborn and it should not be used unless additional data become available. This finding suggests that either furosemide is not effective in promoting resorption of lung fluid, or factors other than delayed resorption of this fluid contribute to the pathogenesis of transient tachypnoea of the newborn. The question remains as to whether furosemide given to the infant (or even to the mother before caesarean section) might shorten the duration of the illness. As elective caesarean section continues at a high level, these two interventions might be worthy of trials.

Glycerin laxatives for prevention or treatment of feeding intolerance in very low birth weight infants.

BACKGROUND: Feeding intolerance is a common clinical problem among preterm infants. It may be an early sign of necrotising enterocolitis, sepsis or other serious gastrointestinal conditions, or it may result from gut immaturity with delayed passage of meconium. Glycerin laxatives stimulate passage of meconium by acting as an osmotic dehydrating agent and increasing osmotic pressure in the gut; they stimulate rectal contraction, potentially reducing the incidence of feeding intolerance. OBJECTIVES: To assess the effectiveness and safety of glycerin laxatives (enemas/suppositories) for prevention or treatment of feeding intolerance in very low birth weight (VLBW) infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 4), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We restricted our search to all randomised controlled trials and applied no language restrictions. We searched the references of identified studies and reviews on this topic and handsearched for additional articles. We searched the database maintained by the US National Institutes of Health (www.clinicaltrials.gov) and European trial registries to identify ongoing trials. SELECTION CRITERIA: We considered only randomised or quasi-randomised controlled trials that enrolled preterm infants < 32 weeks' gestational age (GA) and/or < 1500 g birth weight. We included trials if they administered glycerin laxatives and measured at least one prespecified clinical outcome. DATA COLLECTION AND ANALYSIS: We used standard methods of The Cochrane Collaboration and its Neonatal Group to assess methodological quality of trials, to collect data and to perform analyses. MAIN RESULTS: We identified three trials that evaluated use of prophylactic glycerin laxatives in preterm infants. We identified no trials that evaluated therapeutic use of glycerin laxatives for feeding intolerance. Our review showed that prophylactic administration of glycerin laxatives did not reduce the time required to achieve full enteral feeds and did not influence secondary outcomes, including duration of hospital stay, mortality and weight at discharge. Prophylactic administration of glycerin laxatives resulted in failure of fewer infants to pass stool over the first 48 hours. Included trials reported no adverse events. AUTHORS' CONCLUSIONS: Our review of available evidence for glycerin laxatives does not support the routine use of prophylactic glycerin laxatives in clinical practice. Additional studies are needed to confirm or refute the effectiveness and safety of glycerin laxatives for prevention or treatment of feeding intolerance in VLBW infants.

Probiotics for prevention of necrotizing enterocolitis in preterm infants.

BACKGROUND: Necrotizing enterocolitis (NEC) and nosocomial sepsis are associated with increased morbidity and mortality in preterm infants. Through prevention of bacterial migration across the mucosa, competitive exclusion of pathogenic bacteria, and enhancing the immune responses of the host, prophylactic enteral probiotics (live microbial supplements) may play a role in reducing NEC and the associated morbidity. OBJECTIVES: To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC or sepsis, or both, in preterm infants. SEARCH METHODS: For this update, searches were made of MEDLINE (1966 to October 2013), EMBASE (1980 to October 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 10), and abstracts of annual meetings of the Society for Pediatric Research (1995 to 2013). SELECTION CRITERIA: Only randomized or quasi-randomized controlled trials that enrolled preterm infants < 37 weeks gestational age or < 2500 g birth weight, or both, were considered. Trials were included if they involved enteral administration of any live microbial supplement (probiotics) and measured at least one prespecified clinical outcome. DATA COLLECTION AND ANALYSIS: Standard methods of The Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials and for data collection and analysis. MAIN RESULTS: Twenty-four eligible trials were included. Included trials were highly variable with regard to enrolment criteria (that is birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) (typical relative risk (RR) 0.43, 95% confidence interval (CI) 0.33 to 0.56; 20 studies, 5529 infants) and mortality (typical RR 0.65, 95% CI 0.52 to 0.81; 17 studies, 5112 infants). There was no evidence of significant reduction of nosocomial sepsis (typical RR 0.91, 95% CI 0.80 to 1.03; 19 studies, 5338 infants). The included trials reported no systemic infection with the supplemental probiotics organism. Probiotics preparations containing either lactobacillus alone or in combination with bifidobacterium were found to be effective. AUTHORS' CONCLUSIONS: Enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. Our updated review of available evidence strongly supports a change in practice. Head to head comparative studies are required to assess the most effective preparations, timing, and length of therapy to be utilized. PLAIN LANGUAGE SUMMARY: Probiotics for prevention of necrotizing enterocolitis in preterm infants Necrotizing enterocolitis (NEC) is a serious disease that affects the bowel of premature infants in the first few weeks of life. Although the cause of NEC is not entirely known, milk feeding and bacterial growth play a role. Probiotics (dietary supplements containing potentially beneficial bacteria or yeast) have been used to prevent NEC. Our review of studies found that the use of probiotics reduces the occurrence of NEC and death in premature infants born weighing less than 1500 grams. There is insufficient data with regard to the benefits and potential adverse effects in the most at risk infants weighing less than 1000 grams at birth.

Probiotics for prevention of necrotizing enterocolitis in preterm infants.

BACKGROUND: Necrotizing enterocolitis (NEC) and nosocomial sepsis are associated with increased morbidity and mortality in preterm infants. Through prevention of bacterial migration across the mucosa, competitive exclusion of pathogenic bacteria, and enhancing the immune responses of the host, prophylactic enteral probiotics (live microbial supplements) may play a role in reducing NEC and the associated morbidity. OBJECTIVES: To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC or sepsis, or both, in preterm infants. SEARCH METHODS: For this update, searches were made of MEDLINE (1966 to October 2013), EMBASE (1980 to October 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 10), and abstracts of annual meetings of the Society for Pediatric Research (1995 to 2013). SELECTION CRITERIA: Only randomized or quasi-randomized controlled trials that enrolled preterm infants < 37 weeks gestational age or < 2500 g birth weight, or both, were considered. Trials were included if they involved enteral administration of any live microbial supplement (probiotics) and measured at least one prespecified clinical outcome. DATA COLLECTION AND ANALYSIS: Standard methods of The Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials and for data collection and analysis. MAIN RESULTS: Twenty-four eligible trials were included. Included trials were highly variable with regard to enrolment criteria (that is birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) (typical relative risk (RR) 0.43, 95% confidence interval (CI) 0.33 to 0.56; 20 studies, 5529 infants) and mortality (typical RR 0.65, 95% CI 0.52 to 0.81; 17 studies, 5112 infants). There was no evidence of significant reduction of nosocomial sepsis (typical RR 0.91, 95% CI 0.80 to 1.03; 19 studies, 5338 infants). The included trials reported no systemic infection with the supplemental probiotics organism. Probiotics preparations containing either lactobacillus alone or in combination with bifidobacterium were found to be effective. AUTHORS' CONCLUSIONS: Enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. Our updated review of available evidence strongly supports a change in practice. Head to head comparative studies are required to assess the most effective preparations, timing, and length of therapy to be utilized.

Probiotics for infantile colic: a systematic review.

BACKGROUND: Infantile colic is a common paediatric condition which causes significant parental distress. Increased intestinal coliform colonization in addition to alteration in Lactobacillus abundance and distribution may play an important role in its pathogenesis. The objectives of this systematic review are to evaluate the efficacy of probiotic supplementation in the reduction of crying time and successful treatment of infantile colic. METHODS: Literature searches were conducted of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. Only randomized controlled trials enrolling term, healthy infants with colic were included. A meta-analysis of included trials was performed utilizing the Cochrane Collaboration methodology. RESULTS: Three trials that enrolled 220 breastfed infants met inclusion criteria, of which 209 infants were available for analysis. Two of the studies were assessed as good quality. Lactobacillus reuteri (strains-American Type Culture Collection Strain 55730 and DSM 17 938) was the only species utilized in the therapeutic intervention. Two of the trials were industry funded. Probiotic supplementation compared to simethicone or placebo significantly and progressively shortened crying times to 7 days reaching a plateau at three weeks post initiation of therapy [mean difference -56.03 minutes; 95% CI (-59.92, -52.15)]. Similarly, probiotics compared to placebo significantly increased the treatment success of infantile colic with a relative risk (RR) of 0.06; 95% CI (0.01, 0.25) and a number needed to treat of 2. CONCLUSIONS: Although L. reuteri may be effective as a treatment strategy for crying in exclusively breastfed infants with colic, the evidence supporting probiotic use for the treatment of infant colic or crying in formula-fed infants remains unresolved. Results from larger rigorously designed studies will help draw more definitive conclusions.

Furosemide for transient tachypnoea of the newborn.

BACKGROUND: Transient tachypnoea of the newborn (TTN) results from delayed clearance of lung liquid and is a common cause of admission of full term infants to neonatal intensive care units. The condition is particularly common after elective caesarean section. Conventional treatment involves appropriate oxygen administration and continuous positive airway pressure in some cases. Most infants receive antibiotic therapy. Hastening the clearance of lung liquid may shorten the duration of the symptoms and reduce complications. OBJECTIVES: To determine whether furosemide administration reduces the duration of oxygen therapy and respiratory symptoms and shortens hospital stay in term infants with transient tachypnoea of the newborn. SEARCH METHODS: An updated search was carried out in January 2013 of the following databases: The Cochrane Library issue 1, 2013 (CENTRAL, The Cochrane Central Register of Controlled Trials), PubMed, MEDLINE via Ovid, CINAHL via OVID and EMBASE. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that compared the effect of furosemide administration versus placebo or no treatment in infants of less than seven days of age, born at 37 or more weeks of gestation with the clinical picture of transient tachypnoea of the newborn. DATA COLLECTION AND ANALYSIS: We extracted and analysed data according to the methods outlined in the latest Cochrane Handbook for Systematic Reviews of Interventions. Two review authors assessed trial quality in each potentially eligible manuscript and two review authors extracted data. MAIN RESULTS: Our updated review includes two completed trials. Wiswell 1985 and Karabayir 2006 investigated 100 infants with transient tachypnoea of the newborn. Wiswell 1985 randomised 50 infants to receive either oral furosemide (2 mg/kg body weight at time of diagnosis followed by a 1 mg/kg dose 12 hours later if the tachypnoea persisted) or placebo. Karabayir 2006 randomised 50 infants to receive either intravenous furosemide (2 mg/kg body weight) or an equal volume of normal saline placebo. Neither trial reported on the need for respiratory support. Neither trial demonstrated a statistically significant impact of furosemide on transient tachypnoea of the newborn regarding duration of symptoms or length of hospitalisation. AUTHORS' CONCLUSIONS: Oral or intravenous furosemide cannot be recommended as treatment for transient tachypnoea of the newborn and it should not be used unless additional data become available. This finding suggests that either furosemide is not effective in promoting resorption of lung fluid, or factors other than delayed resorption of this fluid contribute to the pathogenesis of transient tachypnoea of the newborn. The question remains as to whether furosemide given to the infant (or even to the mother before caesarean section) might shorten the duration of the illness. As elective caesarean section continues at a high level, these two interventions might be worthy of trials.

Fluid restriction and prophylactic indomethacin in extremely low birth weight infants.

Although survival of extremely low birth weight (ELBW) infants dramatically improved over last decades, bronchopulmonary dysplasia (BPD) rate has not changed. The use of indomethacin prophylaxis in ELBW infants results in improved short-term outcomes with no effect on long-term outcomes. The addition of fluid restriction to the indomethacin prophylaxis policy could result in a reduction of BPD and improve long-term survival without neurosensory impairment at 18 months corrected age. To determine the effect of a policy of fluid restriction compared with a policy of no fluid restriction on morbidity and mortality in ELBW infants receiving indomethacin prophylaxis. The standard search strategy for the Cochrane Neonatal Review Group was used. This included search of OVID MEDLINE-National Library of Medicine, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 8, 2011). Additional search included conference proceedings, references in articles, and unpublished data. All randomized or quasi-randomized trials that compared fluid restriction and indomethacin prophylaxis vs. indomethacin prophylaxis alone in ELBW infants were included. Standard methods of the Cochrane Neonatal Review Group were planned to assess the methodological quality of the trials. Review Manager 5 software was planned to be used for statistical analysis. We found no randomized controlled trials to investigate the possible interaction between fluid restriction and indomethacin prophylaxis vs. indomethacin prophylaxis alone in ELBW infants. A well-designed randomized trial is needed to address this question.

Success rate and neonatal morbidities associated with early extubation in extremely low birth weight infants.

BACKGROUND AND OBJECTIVES: Mechanical ventilation improves survival of preterm infants with respiratory failure. The aim of this study was to determine the success rate and short-term neonatal morbidities of early extubation in extremely low birth weight (ELBW) infants in a tertiary care neonatal intensive care unit (NICU). DESIGN AND SETTING: Retrospective cohort study of ELBW infants admitted to a tertiary. neonatal intensive care referral unit from January 1 st to December 31 st , 2005. PATIENTS AND METHODS: The primary outcome was the success rate of early extubation in ELBW infants who were intubated at delivery, extubated in the first 48 hours of life, and did not require reintubation within 72 hours following extubation. RESULTS: Thirty of the 95 eligible infants were extubated early; of these 30 infants, 24 (80%) had a successful extubation. Infants extubated early had a higher mean birth weight (855 vs 745 g; P<.0001) and gestational age (27.3 vs 25.6 weeks; P<.0001). ELBW infants who were extubated early had lower rates of death (relative risk [RR], 0.05; 95% CI, (0.0, 0.79); P=.003), intraventricular hemorrhage (IVH) (RR, 0.23; 95% CI, 0.08, 0.70; P=.008), and patent ductus arteriosus (PDA) (RR, 0.76; 95% CI, 0.60, 0.98; P=.03) compared with those who remained ventilated beyond the first 48 hours of life. CONCLUSION: The rate of successful early extubation in our unit exceeded the sole previously reported rate. Successful early extubation was associated with lower rates of death, IVH, and PDA in ELBW infants.

Fluid restriction and prophylactic indomethacin versus prophylactic indomethacin alone for prevention of morbidity and mortality in extremely low birth weight infants.

BACKGROUND: Although survival of extremely low birth weight (ELBW) infants has dramatically improved over the last decades, the rate of bronchopulmonary dysplasia (BPD) has not changed. The use of indomethacin prophylaxis in ELBW infants results in improved short-term outcomes with no effect on long-term outcomes. The addition of fluid restriction to the indomethacin prophylaxis policy could result in a reduction of BPD and improve long-term survival without neurosensory impairment at eighteen months corrected age. OBJECTIVES: To determine the effect of a policy of fluid restriction compared with a policy of no fluid restriction on morbidity and mortality in ELBW infants receiving indomethacin prophylaxis. SEARCH STRATEGY: We used the standard search strategy for the Cochrane Neonatal Review Group (CNRG). This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL) ( The Cochrane Library 2010, Issue 1), MEDLINE (1966 to December 2010), and EMBASE (1980 to December 2010). Additional searches included conference proceedings, references in articles and unpublished data. SELECTION CRITERIA: We planned to include all randomized or quasi-randomized trials that compared fluid restriction and indomethacin prophylaxis versus indomethacin prophylaxis alone in ELBW infants. DATA COLLECTION AND ANALYSIS: If we had identified any eligible studies, we would have assessed the methodological quality of the trials using the standard methods of the CNRG. We planned to use Review Manager 5 software for statistical analysis. MAIN RESULTS: We did not identify any eligible trials. AUTHORS' CONCLUSIONS: We found no randomized controlled trials to investigate the possible interaction between fluid restriction and indomethacin prophylaxis versus indomethacin prophylaxis alone in ELBW infants. A well-designed randomized trial is needed to address this question.

Probiotics for prevention of necrotizing enterocolitis in preterm infants.

BACKGROUND: Necrotizing enterocolitis (NEC) and nosocomial sepsis are associated with increased morbidity and mortality in preterm infants. Through prevention of bacterial migration across the mucosa, competitive exclusion of pathogenic bacteria, and enhancing the immune responses of the host, prophylactic enteral probiotics (live microbial supplements) may play a role in reducing NEC and associated morbidity. OBJECTIVES: To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and/or sepsis in preterm infants. SEARCH STRATEGY: For this update, searches were made of MEDLINE (1966 to October 2010), EMBASE (1980 to October 2010), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2010), and abstracts of annual meetings of the Society for Pediatric Research (1995 to 2010). SELECTION CRITERIA: Only randomized or quasi-randomized controlled trials that enrolled preterm infants < 37 weeks gestational age and/or < 2500 g birth weight were considered. Trials were included if they involved enteral administration of any live microbial supplement (probiotics) and measured at least one prespecified clinical outcome. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials, data collection and analysis. MAIN RESULTS: Sixteen eligible trials randomizing 2842 infants were included. Included trials were highly variable with regard to enrollment criteria (i.e. birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. Data regarding extremely low birth weight infants (ELBW) could not be extrapolated. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) (typical RR 0.35, 95% CI 0.24 to 0.52) and mortality (typical RR 0.40, 95% CI 0.27 to 0.60). There was no evidence of significant reduction of nosocomial sepsis (typical RR 0.90, 95% CI 0.76 to 1.07). The included trials reported no systemic infection with the probiotics supplemental organism. The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant. AUTHORS' CONCLUSIONS: Enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. Our updated review of available evidence supports a change in practice. More studies are needed to assess efficacy in ELBW infants and assess the most effective formulation and dose to be utilized.

Probiotics reduce the risk of necrotizing enterocolitis in preterm infants: a meta-analysis.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common serious acquired disease of the gastrointestinal tract in preterm infants. Probiotic bacteria are live microbial supplements that colonize the gastrointestinal tract and potentially provide benefit to the host. OBJECTIVE: To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and other morbidities in preterm infants. METHODS: A meta-analysis was performed in accordance with the Cochrane Neonatal Review Group methods. Preterm infants <37 weeks' gestational age and/or <2,500 g birth weight were included. Literature searches were made of MEDLINE, EMBASE, Cochrane Library Controlled Trials Register (CENTRAL), and abstracts of annual meetings of the Society for Pediatric Research and the European Society of Pediatric Research. RESULTS: Nine eligible trials randomizing 1,425 infants were included. Included trials were highly variable with regard to enrollment criteria, baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. In a meta-analysis, enteral probiotics supplementation significantly reduced the incidence of severe NEC [typical RR 0.32 (95% CI 0.17, 0.60)] and mortality [typical RR 0.43 (95% CI 0.25, 0.75)]. There was no evidence of significant reduction of nosocomial sepsis [typical RR 0.93 (95% CI 0.73, 1.19)] or days on total parenteral nutrition [weighted mean difference -1.9 (95% CI -4.6, 0.77)]. The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant. Data regarding extremely low birth weight infants (ELBW) could not be extrapolated. The included trials reported no systemic infection with the probiotics supplemental organism. CONCLUSION: Enteral supplementation of probiotics reduces the risk of severe NEC and mortality in preterm infants. A large randomized controlled trial is required to investigate the benefit and safety profile of probiotics supplementation in ELBW infants.