Bifidobacterium infantis as a probiotic in preterm infants: a systematic review and meta-analysis.

BACKGROUND: Bifidobacterium infantis has special abilities to utilise human milk oligosaccharides. Hence we hypothesised that probiotic supplements containing B. infantis may confer greater benefits to preterm infants than probiotic supplements without B. infantis. METHODS: A systematic review with meta-analysis was conducted according to standard guidelines. We selected RCTs evaluating probiotics compared to placebo or no treatment in preterm and/or low birth weight infants. Probiotic effects on Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS) and Mortality were analysed separately for RCTs in which the supplemented probiotic product contained B. infantis and those that did not contain B. infantis. RESULTS: 67 RCTs were included (n = 14,606), of which 16 used probiotics containing B. infantis (Subgroup A) and 51 RCTs did not (Subgroup B) Meta-analysis of all RCTs indicated that probiotics reduced the risk of NEC, LOS, and mortality. The subgroup meta-analysis demonstrated greater reduction in the incidence of NEC in subgroup A than subgroup B [(relative risk in subgroup A: 0.38; 95% CI, 0.27-0.55) versus (0.67; 95% CI, 0.55-0.81) in subgroup B; p value for subgroup difference: 0.01]. CONCLUSIONS: These results provide indirect evidence that probiotic supplements that include B. infantis may be more beneficial for preterm infants. Well-designed RCTs are necessary to confirm these findings. IMPACT: Evidence is emerging that beneficial effects of probiotics are species and strain specific. This systematic review analyses if B. infantis supplementation provides an advantage to preterm infants. This is the first systematic review evaluating the effects of probiotics containing B. infantis in preterm infants. The results of this systematic review provides indirect evidence that probiotics that include B. infantis may be more beneficial for preterm infants. These results will help in guiding future research and clinical practice for using B. infantis as a probiotic in preterm infants.

Early or delayed parenteral nutrition for infants: what evidence is available?

PURPOSE OF REVIEW: To review the current evidence evaluating early versus delayed commencement of parenteral nutrition in infants. RECENT FINDINGS: Recent studies in very premature infants (<32 weeks gestation) have shown that early commencement of parenteral nutrition immediately after birth improves physical growth. However, there are concerns that early use of very high dose of amino-acids (>3.5 g/kg/day immediately after birth) may cause metabolic acidosis, elevated blood urea, slower head growth and refeeding-hypophosphatemia syndrome. A recent multicentre randomized controlled trial found that commencement of parenteral nutrition within 24-h of admission increases the risk of infections and prolongs the duration of ventilation and ICU stay in full-term neonates, older infants and children. The study also found that delaying to day 8 of admission increased the risk of hypoglycaemia. SUMMARY: Benefits of commencing parenteral nutrition on the first day of life appear to outweigh risks in very premature infants; however, it is prudent to avoid early very high doses of amino acids (>3.5 g/kg/day) in the first few days of life. In moderate to late preterm infants, if enteral feeds are not tolerated by 72 h, it is reasonable to commence parenteral nutrition. In full-term and older infants, it is preferable to avoid parenteral nutrition within 24 h of admission and consider delaying by further few days. Diligent monitoring of blood glucose, serum phosphate and other parameters is essential while on parenteral nutrition.

Gut microbiota in neonates with congenital gastrointestinal surgical conditions: a prospective study.

BACKGROUND: There is limited information on gut microbiota of neonates with congenital gastrointestinal surgical conditions (CGISCs) available. METHODS: This study compared stool microbiota and short-chain fatty acids (SCFAs) of 37 term infants with CGISCs with 36 term healthy infants (HIs). Two stool samples were collected from each infant: as soon as possible after birth (week 1) and 10-14 days of life (week 2). RESULTS: Bacterial richness and alpha diversity were comparable between CGISCs and HIs at week 1 and week 2 (all p > 0.05). Beta diversity analysis revealed that at week 1, CGISCs had similar community structures to HIs (p = 0.415). However, by week 2, community structures of CGISCs were significantly different from HIs (p = 0.003). At week 1, there were no significant differences in the relative abundances of genera Bifidobacterium and Bacteroides between CGISCs and HIs. At week 2, the relative abundance of Bifidobacterium was significantly lower in CGISCs (mean percentage 7.21 ± 13.49 vs. 28.96 ± 19.6; p = 0.002). Bacteroides were also less abundant in the CGISC group (mean percentage 0.12 ± 0.49 vs. 6.59 ± 8.62; p = 0.039). Relative abundance of genera Pseudomonas and Escherichia-Shigella were higher in CGISCs. At week 2, stool concentrations of all SCFAs were lower in CGISCs (all p < 0.001). CONCLUSIONS: During hospitalization, neonates with CGISCs develop gut dysbiosis and deficiency of SCFAs. IMPACT: During hospitalisation, neonates with congenital gastrointestinal surgical conditions develop gut dysbiosis with deficiency of Bifidobacteria and Bacteroides and increased abundance of Escherichia-Shigella and Pseudomonas. They also have low levels of short chain fatty acids in their stools compared to healthy infants. This is the first study evaluating the gut microbiota using 16S ribosomal RNA sequencing methods and stool short chain fatty acids in neonates with congenital gastrointestinal surgical conditions and comparing them to healthy infants. The findings of this study will pave the way for randomised trials of bifidobacterial supplementation in neonates with congenital gastrointestinal surgical conditions.

Early versus late parenteral nutrition for critically ill term and late preterm infants.

BACKGROUND: Recently conducted randomised controlled trials (RCTs) suggest that late commencement of parenteral nutrition (PN) may have clinical benefits in critically ill adults and children. However, there is currently limited evidence regarding the optimal timing of commencement of PN in critically ill term and late preterm infants. OBJECTIVES: To evaluate the benefits and safety of early versus late PN in critically ill term and late preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (5 April 2019), MEDLINE Ovid (1966 to 5 April 2019), Embase Ovid (1980 to 5 April 2019), EMCare (1995 to 5 April 2019) and MEDLINE via PubMed (1966 to 5 April 2019). We searched for ongoing or recently completed clinical trials, and also searched the grey literature and reference lists of relevant publications. SELECTION CRITERIA: We included RCTs comparing early versus late initiation of PN in term and late preterm infants. We defined early PN as commencing within 72 hours of admission, and late PN as commencing after 72 hours of admission. Infants born at 37 weeks' gestation or more were defined as term, and infants born between 34 and 36+6 weeks' gestation were defined as late preterm. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the trials, extracted the data and assessed the risk of bias. Treatment effects were expressed using risk ratio (RR) and risk difference (RD) for dichotomous outcomes and mean difference (MD) for continuous data. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: Two RCTs were eligible for inclusion. Data were only available from a subgroup (including 209 term infants) from one RCT in children (aged from birth to 17 years) conducted in Belgium, the Netherlands and Canada. In that RCT, children with medium to high risk of malnutrition were included if a stay of 24 hours or more in the paediatric intensive care unit (PICU) was expected. Early PN and late PN were defined as initiation of PN within 24 hours and after day 7 of admission to PICU, respectively. The risk of bias for the study was considered to be low for five domains and high for two domains. The subgroup of term infants that received late PN had significantly lower risk of in-hospital all-cause mortality (RR 0.35, 95% confidence interval (CI) 0.14 to 0.87; RD -0.10, 95% CI -0.18 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) = 10; 1 trial, 209 participants) and neonatal mortality (death from any cause in the first 28 days since birth) (RR 0.29, 95% CI 0.10 to 0.88; RD -0.09, 95% CI -0.16 to -0.01; NNTB = 11; 1 trial, 209 participants). There were no significant differences in rates of healthcare-associated blood stream infections, growth parameters and duration of hospital stay between the two groups. Neurodevelopmental outcomes were not reported. The quality of evidence was considered to be low for all outcomes, due to imprecision (owing to the small sample size and wide confidence intervals) and high risk of bias in the included studies. AUTHORS' CONCLUSIONS: Whilst late commencement of PN in term and late preterm infants may have some benefits, the quality of the evidence was low and hence our confidence in the results is limited. Adequately powered RCTs, which evaluate short-term as well as long-term neurodevelopmental outcomes, are needed.

Cuffed endotracheal tubes in infants less than 3 kg: A retrospective cohort study.

BACKGROUND: Cuffed endotracheal tubes are being increasingly used in infants; however, current evidence in the literature mostly includes infants ≥ 3-kg weight. AIMS: The aim of this observational study was to compare the short-term outcomes with the use of Microcuff® cuffed vs uncuffed endotracheal tubes in neonates < 3 kg. METHODS: We performed a retrospective cohort study in a single-centre, tertiary children's hospital neonatal intensive care unit. The study included all infants < 3 kg receiving Microcuff® cuffed endotracheal tubes over the period January 2015 to January 2016. Controls were all infants 2000-2999 g receiving an uncuffed endotracheal tube over the period September 2015 to January 2016. RESULTS: Twenty-three patients < 3 kg were intubated with cuffed endotracheal tubes. All were inserted in the operating room. Of 23 patients, 14 (60.9%) patients had the cuff inflated in the operating room and none subsequently in the neonatal intensive care unit. The group receiving cuffed endotracheal tubes was compared with 23 patients with uncuffed endotracheal tubes. There was no difference in weight (median 2620 g vs 2590 g, diff in median = 10, 95% CI -120, 130) or duration of intubation (median 27 vs 44 hours, diff in median = 17, 95% CI -5, 46). However, there was a significant difference in gestational age (median 37 vs 35 weeks, diff in median = -1, 95% CI -2, 0) and age at intubation (median 6 vs 0 days, diff in median = -4, 95% CI -10, -1). There were no significant differences in the rates of: change of endotracheal tube to find correct size (0/23 vs 4/23, P = .109, OR = 0.13, 95% CI 0.01, 1.41); median ventilator leak reading (0% [IQR 0%-12%] vs 0% [IQR 0%-5.5%], P = .201, diff in median = 0, 95% CI -5.5, 0); unplanned extubations (0/23 vs 2/23; atelectasis (4/23 vs 0/23; endotracheal tube blockage (0/23 vs 0/23; pneumonia (0/23 vs 0/23; or postextubation stridor (1/23 vs 2/23). CONCLUSION: This retrospective study with a small sample size found that Microcuff® cuffed endotracheal tubes may be safe in neonates < 3 kg. Well-designed randomized controlled trials are needed to address this issue definitively.

Long chain polyunsaturated fatty acid supplementation in infants born at term.

BACKGROUND: The long chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid (DHA) and arachidonic acid (AA) are considered essential for maturation of the developing brain, retina and other organs in newborn infants. Standard infant milk formulae are not supplemented with LCPUFA; they contain only alpha-linolenic acid and linoleic acid, from which formula-fed infants must synthesise their own DHA and AA, respectively. Over the past few years, some manufacturers have added LCPUFA to formula milk and have marketed these products as providing an advantage for the overall development of full-term infants. OBJECTIVES: To assess whether supplementation of formula milk with LCPUFA is both safe and beneficial for full-term infants, while focusing on effects on visual function, neurodevelopment and physical growth. SEARCH METHODS: Two review authors independently searched the Cochrane Central Register of Controlled Trials (CENTRAL; December 2016), MEDLINE (Ovid, 1966 to December 2016), Embase (Ovid, 1980 to December 2016), the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1980 to December 2016) and abstracts of the Pediatric Academic Societies (2000 to 2016). We applied no language restrictions. SELECTION CRITERIA: We reviewed all randomised controlled trials (RCTs) evaluating effects of LCPUFA supplemented versus non-supplemented formula milk on visual function, neurodevelopment and physical growth. We did not include trials reporting only biochemical outcomes. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. We assessed risk of bias of included studies using the guidelines of the Cochrane Neonatal Review Group. When appropriate, we conducted meta-analysis to determine a pooled estimate of effect. MAIN RESULTS: We identified 31 RCTs and included 15 of these in the review (N = 1889).Nine studies assessed visual acuity, six of which used visual evoked potentials (VEP), two Teller cards and one both. Four studies reported beneficial effects, and the remaining five did not. Meta-analysis of three RCTs showed significant benefit for sweep VEP acuity at 12 months (log of the minimum angle of resolution (logMAR)) (mean difference (MD) -0.15, 95% confidence interval (CI) -0.17 to -0.13; I2 = 0; three trials; N = 244), but meta-analysis of three other RCTs showed no benefit for visual acuity measured with Teller cards at 12 months (cycles/degree) (MD -0.01, 95% CI -0.12 to 0.11; I2 = 0; three trials; N = 256). GRADE analysis for the outcome of visual acuity indicated that the overall quality of evidence was low.Eleven studies measured neurodevelopmental outcomes at or before two years. Nine studies used Bayley Scales of Infant Development, version II (BSID-II), and only two of these studies reported beneficial effects. Meta-analysis revealed no significant differences between LCPUFA and placebo groups in BSID Mental Developmental Index (MDI) scores at 18 months (MD 0.06, 95% CI -2.01 to 2.14; I2 = 75%; four trials; N = 661) and no significant differences in BSID Psychomotor Development Index (PDI) scores at 18 months (MD 0.69, 95% CI -0.78 to 2.16; I2 = 61%; four trials; N = 661). Results showed no significant differences between the two groups in BSID-II scores at one year and two years of age. One study reported better novelty preference measured by the Fagan Infant Test at nine months. Another study reported better problem solving at 10 months. One study used the Brunet and Lezine test to assess the developmental quotient and found no beneficial effects. Follow-up of some infants in different studies at three, six and nine years of age revealed no beneficial effects of supplementation. GRADE analysis of these outcomes indicated that the overall quality of evidence was low.Thirteen studies measured physical growth; none found beneficial or harmful effects of supplementation. Meta-analysis of five RCTs showed that the supplemented group had lower weight (z scores) at one year of age (MD -0.23, 95% CI -0.40 to -0.06; I2 = 83%; N = 521) and that the two groups showed no significant differences with respect to length and head circumference (z scores). Meta-analysis at 18 months and at two years revealed no significant differences between the two groups with respect to weight (kg), length (cm) and head circumference (cm). GRADE analysis of these outcomes indicated that the overall quality of evidence was low. AUTHORS' CONCLUSIONS: Most of the included RCTs reported no beneficial effects or harms of LCPUFA supplementation on neurodevelopmental outcomes of formula-fed full-term infants and no consistent beneficial effects on visual acuity. Routine supplementation of full-term infant milk formula with LCPUFA cannot be recommended at this time.

Role of upper gastrointestinal contrast studies for suspected malrotation in neonatal population.

AIM: Upper gastrointestinal (UGI) contrast study is the preferred radiological investigation to diagnose malrotation of intestine. We aimed to review the role of UGI contrast in neonates (term and preterm) who were clinically suspected to have malrotation. METHODS: The study included a retrospective review of medical charts and radiology reports. RESULTS: A total of 164 newborn infants underwent UGI contrast study to rule out malrotation during the study period (2006-2015). Median gestational age at the time of presentation was 38 weeks (interquartile range: 35.5-39.6 weeks). Median age for clinical presentation was day 2 of life (interquartile range: 2-5 days). Out of the 164 contrast studies, 112 were normal, whereas 52 were reported to have malrotation. Of those 52 infants, 47 were confirmed to have malrotation on surgery (positive predictive value: 90). Of the 112 infants with normal UGI contrasts, nine infants underwent laparotomy for ongoing clinical symptoms out of which four infants were diagnosed to have malrotation on laparotomy. There were 22 infants born at gestational age <32 weeks, who underwent UGI contrast studies to rule out malrotation. Their clinical symptoms were similar to necrotising enterocolitis. Of 22 preterm contrast studies, six were reported to have malrotation; of these, five had surgically confirmed malrotation. No complications related to the contrast study were noted in both term and preterm infants. CONCLUSION: Current study reaffirms the role of UGI contrast study as the investigation of choice for diagnosis of malrotation, in both term and preterm infants. UGI contrast is safe and well tolerated even in preterm infants.

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

BACKGROUND: Animal studies and trials in older children and adults suggest that a 'one dose per day' regimen of gentamicin is superior to a 'multiple doses per day' regimen. OBJECTIVES: To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. SEARCH METHODS: Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3) in the Cochrane Library (searched 8 April 2016), MEDLINE (1966 to 8 April 2016), Embase (1980 to 8 April 2016), and CINAHL (December 1982 to 8 April 2016). SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing one dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin to newborn infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI -0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD -0.13, 95% CI -0.19 to -0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD -0.22, 95% CI -0.29 to -0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD -0.57, 95% CI -0.69 to -0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups (typical RR 1.69, 95% CI 0.18 to 16.25; typical RD 0.01, 95% CI -0.04 to 0.05; 5 trials; N = 214). Nephrotoxicity was not noted with either of the treatment regimens. Overall, the quality of evidence was considered to be moderate on GRADE analysis, given the small sample size and unclear/high risk of bias in some of the domains in a few of the included studies. AUTHORS' CONCLUSIONS: There is insufficient evidence from the currently available RCTs to conclude whether a 'once a day' or a 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggest that pharmacokinetic properties of a 'once a day' gentamicin regimen are superior to a 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There was no change in nephrotoxicity or auditory toxicity. Based on the assessment of pharmacokinetics, a 'once a day regimen' may be superior in treating sepsis in neonates of more than 32 weeks' gestation.

Longchain polyunsaturated fatty acid supplementation in preterm infants.

BACKGROUND: Controversy exists over whether longchain polyunsaturated fatty acids (LCPUFA) are essential nutrients for preterm infants because they may not be able to synthesise sufficient amounts of LCPUFA to meet the needs of the developing brain and retina. OBJECTIVES: To assess whether supplementation of formula milk with LCPUFA is safe and of benefit to preterm infants. The main areas of interest were the effects of supplementation on the visual function, development and growth of preterm infants. SEARCH METHODS: Trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 28 February 2016), MEDLINE Ovid (1966 to 28 February 2016), Embase Ovid (1980 to 28 February 2016), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1980 to 28 February 2016), MEDLINE In Process & Other Non-indexed Citations (1966 to 28 February 2016) and by checking reference lists of articles and conference proceedings. We also searched ClinicalTrials.gov (13 April 2016). No language restrictions were applied. SELECTION CRITERIA: All randomised trials evaluating the effect of LCPUFA-supplemented formula in enterally-fed preterm infants (compared with standard formula) on visual development, neurodevelopment and physical growth. Trials reporting only biochemical outcomes were not included. DATA COLLECTION AND ANALYSIS: All authors assessed eligibility and trial quality, two authors extracted data separately. Study authors were contacted for additional information. MAIN RESULTS: Seventeen trials involving 2260 preterm infants were included in the review. The risk of bias varied across the included trials with 10 studies having low risk of bias in a majority of the domains. The median gestational age (GA) in the included trials was 30 weeks and median birth weight (BW) was 1300 g. The median concentration of docosahexaenoic acid (DHA) was 0.33% (range: 0.15% to 1%) and arachidonic acid (AA) 0.37% (range: 0.02% to 0.84%). Visual acuity Visual acuity over the first year was measured by Teller or Lea acuity cards in eight studies, by visual evoked potential (VEP) in six studies and by electroretinogram (ERG) in two studies. Most studies found no significant differences in visual acuity between supplemented and control infants. The form of data presentation and the varying assessment methods precluded the use of meta-analysis. A GRADE analysis for this outcome indicated that the overall quality of evidence was low. Neurodevelopment Three out of seven studies reported some benefit of LCPUFA on neurodevelopment at different postnatal ages. Meta-analysis of four studies evaluating Bayley Scales of Infant Development at 12 months (N = 364) showed no significant effect of supplementation (Mental Development Index (MDI): MD 0.96, 95% CI -1.42 to 3.34; P = 0.43; I² = 71% - Psychomotor DeveIopment Index (PDI): MD 0.23, 95% CI -2.77 to 3.22; P = 0.88; I² = 81%). Furthermore, three studies at 18 months (N = 494) also revealed no significant effect of LCPUFA on neurodevelopment (MDI: MD 2.40, 95% CI -0.33 to 5.12; P = 0.08; I² = 0% - PDI: MD 0.74, 95% CI -1.90 to 3.37; P = 0.58; I² = 54%). A GRADE analysis for these outcomes indicated that the overall quality of evidence was low. Physical growth Four out of 15 studies reported benefits of LCPUFA on growth of supplemented infants at different postmenstrual ages (PMAs), whereas two trials suggested that LCPUFA-supplemented infants grow less well. One trial reported mild reductions in length and weight z scores at 18 months. Meta-analysis of five studies (N = 297) showed increased weight and length at two months post-term in supplemented infants (Weight: MD 0.21, 95% CI 0.08 to 0.33; P = 0.0010; I² = 69% - Length: MD 0.47, 95% CI 0.00 to 0.94; P = 0.05; I² = 0%). Meta-analysis of four studies at a corrected age of 12 months (N = 271) showed no significant effect of supplementation on growth outcomes (Weight: MD -0.10, 95% CI -0.31 to 0.12; P = 0.34; I² = 65% - Length: MD 0.25; 95% CI -0.33 to 0.84; P = 0.40; I² = 71% - Head circumference: MD -0.15, 95% CI -0.53 to 0.23; P = 0.45; I² = 0%). No significant effect of LCPUFA on weight, length or head circumference was observed on meta-analysis of two studies (n = 396 infants) at 18 months (Weight: MD -0.14, 95% CI -0.39 to 0.10; P = 0.26; I² = 66% - Length: MD -0.28, 95% CI -0.91 to 0.35; P = 0.38; I² = 90% - Head circumference: MD -0.18, 95% CI -0.53 to 0.18; P = 0.32; I² = 0%). A GRADE analysis for this outcome indicated that the overall quality of evidence was low. AUTHORS' CONCLUSIONS: Infants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. On pooling of results, no clear long-term benefits or harms were demonstrated for preterm infants receiving LCPUFA-supplemented formula.

Endothelin receptor antagonists for persistent pulmonary hypertension in term and late preterm infants.

BACKGROUND: Endothelin, a powerful vasoconstrictor, is one of the mediators in the causation of persistent pulmonary hypertension of the newborn (PPHN). Theoretically, endothelin receptor antagonists (ETRA) have the potential to improve the outcomes of infants with PPHN. OBJECTIVES: To assess the efficacy and safety of ETRA in the treatment of PPHN in full-term, post-term and late preterm infants.To assess the efficacy and safety of selective ETRAs (which block only the ETA receptors) and non-selective ETRAs (which block both ETA and ETB receptors) separately. SEARCH METHODS: CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE and CINAHL databases were searched until December 2015. SELECTION CRITERIA: Randomised, cluster-randomised or quasi-randomised controlled trials were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently searched the literature, selected the studies, assessed the risk of bias and extracted the data. A fixed-effect model was used for meta-analysis. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. MAIN RESULTS: Two randomised controlled trials of ETRA met the inclusion criteria. Both studies utilized oral Bosentan. The first study was done in a setting where inhaled nitric oxide (iNO) therapy was not available. Forty-seven infants (≥ 34 weeks' gestation) were randomised to receive either Bosentan or placebo. The second study was a multicentre study where iNO therapy was the standard of care for PPHN. Twenty-one infants were randomised to receive either 'iNO plus Bosentan' or 'iNO plus placebo'.In the first study, there was no significant difference in the incidence of death before hospital discharge between the Bosentan and placebo groups (1/23 vs 3/14; RR 0.20, 95% CI 0.02 to 1.77; RD -0.17, 95% CI -0.40 to 0.06). A higher proportion of infants in the Bosentan group showed improvement in oxygenation index (OI) at the end of therapy (21/24 vs 3/15; RR 4.38, 95% CI 1.57 to 12.17; RD 0.68, 95% CI 0.43 to 0.92; number needed to treat for a beneficial outcome (NNTB) 1.5). The duration of mechanical ventilation was lower in the Bosentan group (4.3 ± 0.9 vs 11.5 ± 0.6 days; MD -7.20, 95% CI -7.64 to -6.76). There was no significant difference in adverse neurological outcomes at six months (0/23 vs 4/14; RR 0.07, 95% CI 0.00 to 1.20; RD -0.29, 95% CI -0.52 to -0.05). The study suffered from a high risk of attrition bias since 8/23 infants in the placebo group were excluded from various analyses. Since the protocol for the study could not be accessed, the study suffered from unclear risk of reporting bias.In the second study, there was no significant difference in the incidence of treatment failure needing extracorporeal membrane oxygenation (ECMO) between the 'iNO plus Bosentan' vs 'iNO plus placebo' groups (1/13 vs 0/8; RR 1.93, 95% CI 0.09 to 42.35; RD 0.08, 95% CI -0.14 to 0.30). There was no significant difference in the median time to wean from iNO ('iNO plus Bosentan': 3.7 days (95% CI 1.17 to 6.95); 'iNO plus placebo': 2.9 days (95% CI 1.26 to 4.23); P = 0.34). There were no significant differences in the OI 0, 3, 5, 12, 24, 48 and 72 hours of treatment between the groups. There were no significant differences in the time to complete weaning from mechanical ventilation (median 10.8 days (CI 3.21 to 12.21) versus 8.6 days (CI 3.71 to 9.66); P = 0.24). The study had unequal distribution to the Bosentan group (N = 13) and the placebo group (N = 8). The methods used for generating random sequence numbers and allocation concealment were unclear, resulting in unclear risk of selection bias.Both studies reported that Bosentan was well tolerated and no major adverse effects were noted. Data from the two studies was not pooled given the heterogenous nature of the clinical settings and the modalities used for the treatment of PPHN.Overall, the quality of evidence was considered low, given the small sample size of the included studies, the numerical imbalance between the groups due to randomisation and attrition, and unclear risk of bias on some of the important domains. AUTHORS' CONCLUSIONS: There is inadequate evidence to support the use of ETRAs either as stand-alone therapy or as adjuvant to inhaled nitric oxide in PPHN. Adequately powered RCTs are needed.

Does continuous positive airway pressure for extubation in congenital tracheoesophageal fistula increase the risk of anastomotic leak? A retrospective cohort study.

AIM: Immediate post-operative care of tracheoesophageal fistula (TEF) and oesophageal atresia (EA) requires mechanical ventilation. Early extubation is preferred, but subsequent respiratory distress may warrant re-intubation. Continuous positive airway pressure (CPAP) is a well-established modality to prevent extubation failures in preterm infants. However, it is not favoured in TEF/EA, because of the theoretical risk of oesophageal anastomotic leak (AL). The aim of this study was to find out if post-extubation CPAP is associated with increased risk of AL. METHODS: Retrospective cohort study (2007-2014). RESULTS: Fifty-one infants underwent primary repair in the newborn period. Median age at surgery was 24 h (interquartile range: 12, 24). In the post-extubation period, 10 received CPAP, whereas 41 did not. The median post-operative day at the commencement of CPAP was 2.5 days (interquartile range: 1, 6 days). Zero out of 10 in the CPAP group and 4/41 in the 'no CPAP' group developed AL on routine post-operative contrast studies (P = 0.57). Zero out of 10 in the CPAP group and 1/41 in the 'no CPAP group' developed recurrence of TEF necessitating re-surgery (P = 1.00). The neonate with recurrent fistula also had coarctation of aorta and needed protracted hospitalisation of 6 months, mainly because of the recurrence of TEF. CONCLUSION: The use of CPAP in the immediate post-extubation period after corrective surgery for TEF/EA appears to be safe and may not be associated with increased risk of AL or recurrence of the fistula. Information from other centres, surveys and large databases is needed to define the benefits and risks of use of CPAP in these infants.

Prevalence of symptomatic tracheal morbidities after fetoscopic endoluminal tracheal occlusion: a systematic review and meta-analysis.

BACKGROUND: Fetoscopic endoluminal tracheal occlusion (FETO) has been shown to improve survival of infants with congenital diaphragmatic hernia (CDH). However, there are concerns that FETO may lead to tracheomegaly, tracheomalacia and related complications. METHODS: A systematic review was conducted to estimate the prevalence of symptomatic tracheal complications in infants who underwent FETO for CDH. Presence of one or more of the following was considered as tracheal complication: tracheomalacia, stenosis, laceration or tracheomegaly with symptoms such as stridor, effort-induced barking cough, recurrent chest infections or the need for tracheostomy, tracheal suturing, or stenting. Isolated tracheomegaly on imaging or routine bronchoscopy without clinical symptoms was not considered as tracheal morbidity. Statistical analysis was performed using the metaprop command on Stata V.16.0. RESULTS: A total of 10 studies (449 infants) were included (6 retrospective cohort, 2 prospective cohort and 2 randomised controlled trials). There were 228 infants who survived to discharge. Prevalence rates of tracheal complications in infants born alive were 6% (95% CI 2% to 12%) and 12% (95% CI 4% to 22%) in those who survived to discharge. The spectrum of severity ranged from relatively mild symptoms such as effort-induced barking cough to the need for tracheostomy/tracheal stenting. CONCLUSION: A significant proportion of FETO survivors have symptomatic tracheal morbidities of varying severity. Units that are planning to adopt FETO for managing CDH should consider ongoing surveillance of survivors to enable early identification of upper airway issues. Inventing FETO devices that minimise tracheal injury is needed.

Mortality and neurodevelopmental outcomes of infants with spontaneous intestinal perforation: a systematic review and meta-analysis.

BACKGROUND: There is limited information about the mortality and neurodevelopmental outcomes of very preterm infants (<32 weeks) with spontaneous intestinal perforation (SIP). OBJECTIVE: To explore the association between SIP and neurodevelopmental outcomes and mortality in very preterm infants. DATA SOURCES: Medline, EMBASE, Cochrane Library, EMCARE and MedNar. STUDY SELECTION: Databases were searched until September 2021. Studies comparing outcomes of 'SIP' versus 'no SIP or necrotising enterocolitis (NEC)' were included. DATA EXTRACTION: Neurodevelopmental outcomes at ≥1 year corrected age were extracted as the main outcome measure. Data were pooled separately for adjusted and unadjusted ORs using the random-effects model. The evidence level was assessed using the GRADE (Grading of Recommendations, Assessments, Development and Evaluations) framework. RESULTS: Eighteen cohort studies (13 606 infants) were included. Meta-analysis of unadjusted ORs showed that SIP was significantly associated with increased odds of mortality, cerebral palsy, composite outcome of death or disability, visual impairment and hearing impairment. However, pooling of adjusted ORs (aOR) found significant associations only for mortality (aOR (95% CI) 2.27 (2.07 to 2.49); I2: 0%; four studies (n=10 695)), severe disability (aOR (95% CI) 2.06 (1.38 to 3.08); I2: 0%; two studies (n=321)) and composite outcome of 'death or disability' (aOR (95% CI) 2.18 (1.55 to 3.06); I2: 0%; two studies (n=321)). The level of evidence was 'low' or 'very low'. LIMITATIONS: Lack of information on aORs from many studies. CONCLUSIONS: SIP in very preterm infants is associated with higher odds of mortality, severe disability, and death or disability.

Local nitroglycerin to facilitate peripheral arterial cannulation in children: systematic review and meta-analysis.

BACKGROUND: Neonates and children admitted to intensive care units require peripheral arterial cannulation to monitor their blood pressures and for blood sampling, but many times it is unsuccessful. OBJECTIVE: To conduct a systematic review and meta-analysis to evaluate the efficacy and safety of local nitroglycerin (NTG) to facilitate peripheral artery cannulation in neonates and children. REVIEW METHODS: PubMed, EMBASE, CINAHL, Emcare and Cochrane library were searched till August 2021. Grey literature was searched through Mednar. Data were extracted by two reviewers independently using a prespecified form and the risk of bias was assessed. Meta-analysis was conducted using a random-effects model. The I2 statistic was used to quantify statistical heterogeneity. Certainty of evidence was assessed using the criteria of inconsistency, imprecision, indirectness, publication bias and size of effect as per the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines. RESULTS: Two randomised controlled trials (RCTs) were included in this meta-analysis (n=153). One was conducted in children 2-8 years of age and the other was in children <2 years. Both trials found increased success rates with the use of local NTG. Pooling of the two studies found that the first-attempt success rate was significantly higher in the NTG group (risk difference: 0.44, 95% CI 0.05 to 0.83; I2=89%). Overall procedure time was significantly lower in the NTG group (mean difference: -100.28 s, 95% CI -136.74 to -63.82; I2=0%). No major complications secondary to the use of NTG were noted. The GRADE of evidence was very low. CONCLUSION: Local NTG may be useful in facilitating peripheral arterial cannulation in children. Adequately powered RCTs are needed to confirm these findings.

Outcomes of very preterm infants with neonatal hyperglycaemia: a systematic review and meta-analysis.

OBJECTIVE: To explore the association between hyperglycaemia and adverse outcomes in very preterm infants. DESIGN: Systematic review and meta-analysis. Data were pooled separately for adjusted and unadjusted odds ratios (ORs) using random-effects model. Subgroup analysis was conducted based on study design (cohort and case control). MAIN OUTCOME MEASURES: Association between hyperglycaemia in preterm neonates (<32 weeks or <1500 g) and mortality and morbidities. FINDINGS: Forty-six studies (30 cohort and 16 case control) with data from 34 527 infants were included. Meta-analysis of unadjusted ORs from cohort studies found hyperglycaemia to be significantly associated with mortality, any-grade intraventricular haemorrhage (IVH), severe IVH, any-stage retinopathy of prematurity (ROP), severe ROP, sepsis, chronic lung disease and disability. However, pooling of adjusted ORs found significant associations only for mortality (adjusted OR (CI): 2.37 (1.40 to 4.01); I2: 36%; 6 studies), 'Any grade IVH' (adjusted OR (CI): 2.60 (1.09 to 6.20); I2: 0%; 2 studies) and 'Any stage ROP' (adjusted OR (CI): 3.70 (1.55 to 8.84); I2: 0%; 2 studies). Meta-regression analysis found glucose levels >10 mmol/L to be associated with increased odds of mortality compared with <10 mmol/L. Pooled analysis from case-control studies were similar to cohort studies for most outcomes but limited by small sample size. Longer duration of hyperglycaemia was associated with adverse outcomes. GRADE of evidence was 'Low' or 'Very low'. CONCLUSION: Hyperglycaemia in very preterm infants is associated with higher odds of mortality, any-grade IVH and any-stage ROP. A limitation was lack of availability of adjusted ORs from many of the included studies. PROSPERO REGISTRATION NUMBER: CRD42020193016.

Evidence-based guidelines for use of probiotics in preterm neonates.

BACKGROUND: Current evidence indicates that probiotic supplementation significantly reduces all-cause mortality and definite necrotising enterocolitis without significant adverse effects in preterm neonates. As the debate about the pros and cons of routine probiotic supplementation continues, many institutions are satisfied with the current evidence and wish to use probiotics routinely. Because of the lack of detail on many practical aspects of probiotic supplementation, clinician-friendly guidelines are urgently needed to optimise use of probiotics in preterm neonates. AIM: To develop evidence-based guidelines for probiotic supplementation in preterm neonates. METHODS: To develop core guidelines on use of probiotics, including strain selection, dose and duration of supplementation, we primarily used the data from our recent updated systematic review of randomised controlled trials. For equally important issues including strain identification, monitoring for adverse effects, product format, storage and transport, and regulatory hurdles, a comprehensive literature search, covering the period 1966-2010 without restriction on the study design, was conducted, using the databases PubMed and EMBASE, and the proceedings of scientific conferences; these data were used in our updated systematic review. RESULTS: In this review, we present guidelines, including level of evidence, for the practical aspects (for example, strain selection, dose, duration, clinical and laboratory surveillance) of probiotic supplementation, and for dealing with non-clinical but important issues (for example, regulatory requirements, product format). Evidence was inadequate in some areas, and these should be a target for further research. CONCLUSION: We hope that these evidence-based guidelines will help to optimise the use of probiotics in preterm neonates. Continued research is essential to provide answers to the current gaps in knowledge about probiotics.

Long-chain polyunsaturated fatty acid supplementation in infants born at term.

BACKGROUND: The n-3 and n-6 fatty acids linolenic acid and linoleic acid are precursors of the n-3 and n-6 long chain fatty acids (LCPUFA). Infant formula has historically only contained the precursor fatty acids. Over the last few years, some manufacturers have added LCPUFA to formulae and marketed them as providing an advantage for the development of term infants. OBJECTIVES: To assess whether supplementation of formula with LCPUFA is safe and of benefit to term infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, April, 2011), MEDLINE (1966 to April 2011), EMBASE (1980 to April 2011), CINAHL (December 1982 to April 2011) and abstracts of the Society for Pediatric Research (1980 to 2010). No language restrictions were applied. SELECTION CRITERIA: Randomised and quasi randomised trials comparing LCPUFA supplemented vs. non-supplemented formula milk and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: Methodological quality of studies was assessed using the guidelines of Cochrane neonatal review group. Data were sought regarding effects on visual acuity, neurodevelopmental outcomes and physical growth. When appropriate, meta-analysis was conducted to provide a pooled estimate of effect. MAIN RESULTS: Twenty-five randomised studies were identified; fifteen were included (n = 1889) and ten excluded.Visual acuity was assessed by nine studies. Visual evoked potential was used in six studies, two used Teller cards and one used both. Four studies reported beneficial effects while the remaining five did not.Neurodevelopmental outcome was measured by eleven studies. Bayley scales of infant development (BSID) was used in nine studies; only two showed beneficial effects. Meta-analysis did not show significant benefits of supplementation. One study followed the infants up to nine years of age and did not find benefit of supplementation. One study reported better novelty preference measured by Fagan Infant test at nine months. Another study reported better problem solving at 10 months. One study used Brunet and Lezine test to assess the developmental quotient and did not find beneficial effects.Physical growth was measured by thirteen studies; none found beneficial or harmful effects of supplementation. Meta-analysis found that supplemented group may have marginally lower weight at one year of age. AUTHORS' CONCLUSIONS: Majority of the RCTS have not shown beneficial effects of LCPUFA supplementation on the neurodevelopmental outcomes of term infants. The beneficial effects on visual acuity have not been consistently demonstrated. Routine supplementation of term infant milk formula with LCPUFA can not be recommended.

Peritoneal drainage versus laparotomy as initial surgical treatment for perforated necrotizing enterocolitis or spontaneous intestinal perforation in preterm low birth weight infants.

BACKGROUND: Standard surgical management of infants with perforated necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) is laparotomy with the resection of the necrotic or perforated segments of the intestine. Peritoneal drainage is an alternative approach to the management of such infants. OBJECTIVES: To evaluate the benefits and risks of peritoneal drainage compared to laparotomy as the initial surgical treatment for perforated NEC or SIP in preterm infants. SEARCH STRATEGY: Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2010, Issue 3), MEDLINE (1966 to July 2010), EMBASE (1980 to July 2010), CINAHL (1982 to July 2010), previous reviews and cross-references were searched. Abstracts of paediatric academic society meetings were also searched (online: 2000 to 2009; handsearching Pediatric Research: 1995 to 2000). SELECTION CRITERIA: All randomised or quasi-randomised controlled trials in preterm (< 37 weeks gestation), low birth weight (< 2500 g) infants with perforated NEC or SIP allocated to peritoneal drainage or laparotomy as initial surgical treatment. DATA COLLECTION AND ANALYSIS: Data were excerpted from the trial reports and analysed according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Only two randomised controlled trials (RCT) met the eligibility criteria. Overall, no significant differences were seen between the peritoneal drainage and laparotomy groups regarding the incidence of mortality within 28 days of the primary procedure (28/90 versus 30/95; typical relative risk (RR) 0.99, 95% CI 0.64 to 1.52; N = 185, two trials); mortality by 90 days after the primary procedure (typical RR 1.05, 95% CI 0.71 to 1.55; N = 185, two trials) and the number of infants needing total parenteral nutrition for more than 90 days (typical RR 1.18, 95% CI 0.72 to 1.95; N = 116, two trials). Nearly 50% of the infants in the peritoneal drainage group could avoid the need for laparotomy during the study period (44/90 versus 95/96; typical RR 0.49, 95% CI 0.39 to 0.61; N = 186, two trials). One study found that the time to attain full enteral feeds in infants ≤ 1000 g was prolonged in the peritoneal drainage group (mean difference (MD) 20.77, 95% CI 3.62 to 37.92). AUTHORS' CONCLUSIONS: Evidence from two RCTs suggests no significant benefits or harms of peritoneal drainage over laparotomy. However, due to the very small sample size, clinically significant differences may have easily been missed. No firm recommendations can be made for clinicians. Large multicentre randomised controlled trials are needed to address this question definitively.

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

BACKGROUND: Animal studies and trials in older children and adults suggest that a one dose per day regimen of gentamicin is superior to a multiple doses per day regimen. OBJECTIVES: To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. SEARCH METHODS: Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, April 2011), MEDLINE (1966 to April 2011), EMBASE 1980 to April 2011, and CINAHL (December 1982 to April 2011). Abstracts of the Society for Pediatric Research were searched from 1980 to 2010 inclusive. SELECTION CRITERIA: All randomised or quasi randomised controlled trials comparing one dose per day ( 'once a day') compared to multiple doses per day ( 'multiple doses a day') of gentamicin to newborn infants < 28 days of life. DATA COLLECTION AND ANALYSIS: Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Eleven studies were included (N = 574) and nineteen excluded. All infants in both 'once a day' as well as 'multiple doses a day' regimen showed adequate clearance of sepsis [typical RD 0.00 (95% CI - 0.19 to 0.19); 3 trials; N = 36]. For the other primary outcome measures relating to gentamicin pharmacokinetics 'once a day' dosing of gentamicin was superior. 'Once a day' gentamicin regimen was associated with less failures to attain peak level of at least 5 µg/ml [typical RR 0.22 (95% CI 0.11 to 0.47); 9 trials; N = 422] and less failures to achieve trough levels of < 2 µg/ml [typical RR 0.38 (95% CI 0.27 to 0.55); 11 trials N = 503] compared to 'multiple doses a day' regimen.Ototoxicity and nephrotoxicity were not noted with either of the treatment regimens. AUTHORS' CONCLUSIONS: There is insufficient evidence from the currently available RCTs to conclude whether 'once a day' or 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggests that pharmacokinetic properties of 'once a day' gentamicin regimen are superior to 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There is no change in nephrotoxicity or auditory toxicity. Based on this assessment of pharmacokinetics, 'once a day regimen' may be superior in treating neonatal sepsis in neonates greater than 32 weeks gestation.