Intermittent phototherapy versus continuous phototherapy for neonatal jaundice.

BACKGROUND: Phototherapy is a widely accepted, effective first-line therapy for neonatal jaundice. It is traditionally used continuously but intermittent phototherapy has been proposed as an equally effective alternative with practical advantages of improved maternal feeding and bonding. The effectiveness of intermittent phototherapy compared with continuous phototherapy is unknown. OBJECTIVES: To assess the safety and effectiveness of intermittent phototherapy compared with continuous phototherapy. SEARCH METHODS: Searches were conducted on 31 January 2022 in the following databases: CENTRAL via CRS Web, MEDLINE and Embase via Ovid. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: We included RCTs, cluster-RCTs and quasi-RCTs comparing intermittent phototherapy with continuous phototherapy in jaundiced infants (both term and preterm) up to the age of 30 days. We compared intermittent phototherapy with continuous phototherapy by any method and at any dose and duration as defined by the authors. DATA COLLECTION AND ANALYSIS: Three review authors independently selected trials, assessed trial quality and extracted data from included studies. We performed fixed-effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs). Our primary outcomes of interest were rate of decline of serum bilirubin, and kernicterus. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 12 RCTs (1600 infants) in the review. There is one ongoing study and four awaiting classification. There was little or no difference between intermittent phototherapy and continuous phototherapy with respect to rate of decline of bilirubin in jaundiced newborn infants (MD -0.09 micromol/L/hr, 95% CI -0.21 to 0.03; I² = 61%; 10 studies; 1225 infants; low-certainty evidence). One study involving 60 infants reported no incidence of bilirubin induced brain dysfunction (BIND). It is uncertain whether either intermittent or continuous phototherapy reduces BIND because the certainty of this evidence is very low. There was little or no difference in treatment failure (RD 0.03, 95% CI 0.08 to 0.15; RR 1.63, 95% CI 0.29 to 9.17; 1 study; 75 infants; very low-certainty evidence) or infant mortality (RD -0.01, 95% CI -0.03 to 0.01; RR 0.69, 95% CI 0.37 to 1.31 I² = 0%; 10 studies, 1470 infants; low-certainty evidence).  AUTHORS' CONCLUSIONS: The available evidence detected little or no difference between intermittent and continuous phototherapy with respect to rate of decline of bilirubin. Continuous phototherapy appears to be more effective in preterm infants, however, the risks of continuous phototherapy and the potential benefits of a slightly lower bilirubin level are unknown. Intermittent phototherapy is associated with a decrease in the total number of hours of phototherapy exposure. There are theoretical benefits to intermittent regimens but there are important safety outcomes that were inadequately addressed. Large, well designed, prospective trials are needed in both preterm and term infants before it can be concluded that intermittent and continuous phototherapy regimens are equally effective.

Reference values for diaphragm electrical activity (Edi) in newborn infants.

BACKGROUND: Neurally adjusted ventilatory assist is an emerging mode of respiratory support that uses the electrical activity of the diaphragm (Edi) to provide synchronised inspiratory pressure support, proportional to an infant's changing inspiratory effort. Data on Edi reference values for neonates are limited. The objective of this study was to establish reference Edi values for preterm and term neonates who are not receiving respiratory support. METHODS: This was a prospective observational study of newborn infants breathing spontaneously in room air. The Edi waveform was monitored by a specialised naso/orogastric feeding tube with embedded electrodes positioned at the level of the diaphragm. Edi minimums and peaks were recorded continuously for 4 h without changes to routine clinical handling. RESULTS: Twenty-four newborn infants (16 preterm [< 37 weeks' gestation]; 8 term) were studied. All infants were breathing comfortably in room air at the time of study. Edi data were successfully captured in all infants. The mean (±SD) Edi minimum was 3.02 (±0.94) µV and the mean Edi peak was 10.13 (±3.50) µV. In preterm infants the mean (±SD) Edi minimum was 3.05 (±0.91) µV and the mean Edi peak was 9.36 (±2.13) µV. In term infants the mean (±SD) Edi minimum was 2.97 (±1.05) µV and the mean Edi peak was 11.66 (±5.14) µV. CONCLUSION: Reference Edi values were established for both preterm and term neonates. These values can be used as a guide when monitoring breathing support and when using diaphragm-triggered modes of respiratory support in newborn infants.

Early PARacetamol (EPAR) Trial: A Randomized Controlled Trial of Early Paracetamol to Promote Closure of the Ductus Arteriosus in Preterm Infants.

INTRODUCTION: This study aimed to investigate whether early treatment with paracetamol reduces the number of infants requiring intervention for patent ductus arteriosus (PDA) and assess the safety profile of paracetamol during the early postnatal period. METHODS: This was a double-blind, parallel, randomized, placebo-controlled trial. Preterm infants born at <29-week gestation with a ductus arteriosus >0.9 mm at 6 h of life were randomized to either (1) intravenous paracetamol (15 mg/kg initially and then 7.5 mg/kg every 6 h) or (2) intravenous dextrose for 5 days. The primary outcome was the need for any intervention for PDA up to 5 days. Secondary outcomes included ductal closure at 5 days, ductal size at 48 h, ductal reopening, mortality, and significant morbidities. RESULTS: Of 58 infants randomized, 29 were allocated to the intervention and 29 to the control group. The trial was stopped for benefit at 50% recruitment after reaching the prespecified stopping criteria. Less infants in the intervention group required intervention for PDA up to 5 days (6 [21%] vs. 17 [59%] infants [p = 0.003]; relative risk reduction 0.35 [95% CI 0.16-0.77; NNT 2.6]). The intervention group had a higher rate of ductal closure (20 [69%] vs. 8 [28%] infants [p = 0.002]) and smaller ductal size (1.0 mm [±0.8] vs. 1.4 mm [±0.9]; p = 0.04). Three deaths occurred (2 in the intervention group), which were not attributed to the intervention. No other adverse events were reported. DISCUSSION/CONCLUSION: Early paracetamol treatment reduced the number of infants requiring intervention for PDA. Short-term safety data were reassuring, acknowledging the small number of infants involved in the study.

FEEding DURing red cell transfusion (FEEDUR RCT): a multi-arm randomised controlled trial.

BACKGROUND: Necrotising Enterocolitis (NEC) is a devastating neonatal disease. A temporal association between red cell transfusion and NEC has been recognized and there have been concerns about the effects of feeding during transfusion. We aimed to assess the effect of different enteral feeding regimens on splanchnic oxygenation in preterm infants receiving red cell transfusions. METHODS: This was an open, multi-arm, parallel-group, randomised controlled trial conducted in a single centre in Australia. We compared three different enteral feeding regimes during a single red cell transfusion in preterm infants < 35 weeks gestational age at birth. Infants were randomised to either: (1) Withholding enteral feeds for 12 h from the start of transfusion or; (2) Continuing enteral feeds or; (3) Restriction of enteral feed volume to 120 ml/kg/day (maximum 20 kcal/30 ml) for 12 h. The primary outcome was mean splanchnic-cerebral oxygenation ratio (SCOR) and mean splanchnic fractional oxygen extraction (FOE) before (1 h prior), during (1 h into transfusion) and after (end of transfusion; 12 and 24 h post) transfusion. RESULTS: There were 60 transfusion episodes (20 transfusion episodes in each group) included in the analysis. 41 infants with a median gestational age at birth of 27 weeks (range 23-32 weeks) were enrolled. The median postnatal age was 43 days (range 19-94 days) and the median pre-transfusion haematocrit was 0.27 (range 0.22-0.32). All three groups were similar at baseline. There were no differences in mean SCOR and mean splanchnic FOE at any of the pre-specified time points. There were also no differences in clinical outcomes. There were no episodes of NEC in any infant. Across all groups the mean SCOR increased from the start to the end of each transfusion (0.97 [CI95% 0.96-0.98] vs 1.00 [CI95% 0.99-1.01]; p = 0.04) and the mean FOE decreased from the start to the end of each transfusion (0.22 [CI95% 0.21-0.23] vs 0.17 [CI95% 0.16-0.18]; p < 0.001). CONCLUSIONS: There were no differences in splanchnic oxygenation when enteral feeds were either withheld, continued or restricted during a transfusion. However, the successful conduct of this study supports the feasibility of a large trial powered to assess clinical outcomes. TRIAL REGISTRATION: ANZCTR, ACTRN12616000160437. Registered 10 February 2016, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370069.

The effect of lactoferrin supplementation on death or major morbidity in very low birthweight infants (LIFT): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Very low birthweight or preterm infants are at increased risk of adverse outcomes including sepsis, necrotising enterocolitis, and death. We assessed whether supplementing the enteral diet of very low-birthweight infants with lactoferrin, an antimicrobial protein, reduces all-cause mortality or major morbidity. METHODS: We did a multicentre, double-blind, pragmatic, randomised superiority trial in 14 Australian and two New Zealand neonatal intensive care units. Infants born weighing less than 1500 g and aged less than 8 days, were eligible and randomly assigned (1:1) using minimising web-based randomisation to receive once daily 200 mg/kg pasteurised bovine lactoferrin supplements or no lactoferrin supplement added to breast or formula milk until 34 weeks' post-menstrual age (or for 2 weeks, if longer), or until discharge from the study hospital if that occurred first. Designated nurses preparing the daily feeds were not masked to group assignment, but other nurses, doctors, parents, caregivers, and investigators were unaware. The primary outcome was survival to hospital discharge or major morbidity (defined as brain injury, necrotising enterocolitis, late-onset sepsis at 36 weeks' post-menstrual age, or retinopathy treated before discharge) assessed in the intention-to-treat population. Safety analyses were by treatment received. We also did a prespecified, PRISMA-compliant meta-analysis, which included this study and other relevant randomised controlled trials, to estimate more precisely the effects of lactoferrin supplementation on late-onset sepsis, necrotising enterocolitis, and survival. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12611000247976. FINDINGS: Between June 27, 2014, and Sept 1, 2017, we recruited 1542 infants; 771 were assigned to the intervention group and 771 to the control group. One infant who had consent withdrawn before beginning lactoferrin treatment was excluded from analysis. In-hospital death or major morbidity occurred in 162 (21%) of 770 infants in the intervention group and in 170 (22%) of 771 infants in the control group (relative risk [RR] 0·95, 95% CI 0·79-1·14; p=0·60). Three suspected unexpected serious adverse reactions occurred; two in the lactoferrin group, namely unexplained late jaundice and inspissated milk syndrome, but were not attributed to the intervention and one in the control group had fatal inspissated milk syndrome. Our meta-analysis identified 13 trials completed before Feb 18, 2020, including this Article, in 5609 preterm infants. Lactoferrin supplements significantly reduced late-onset sepsis (RR 0·79, 95% CI 0·71-0·88; p<0·0001; I2=58%), but not necrotising enterocolitis or all-cause mortality. INTERPRETATION: Lactoferrin supplementation did not improve death or major morbidity in this trial, but might reduce late-onset sepsis, as found in our meta-analysis of over 5000 infants. Future collaborative studies should use products with demonstrated biological activity, be large enough to detect moderate and clinically important effects reliably, and assess greater doses of lactoferrin in infants at increased risk, such as those not exclusively receiving breastmilk or infants of extremely low birthweight. FUNDING: Australian National Health and Medical Research Council.

Diaphragm-triggered non-invasive respiratory support in preterm infants.

BACKGROUND: Diaphragm-triggered non-invasive respiratory support, commonly referred to as NIV-NAVA (non-invasive neurally adjusted ventilatory assist), uses the electrical activity of the crural diaphragm to trigger the start and end of a breath. It provides variable inspiratory pressure that is proportional to an infant's changing inspiratory effort. NIV-NAVA has the potential to provide effective, non-invasive, synchronised, multilevel support and may reduce the need for invasive ventilation; however, its effects on short- and long-term outcomes, especially in the preterm infant, are unclear. OBJECTIVES: To assess the effectiveness and safety of diaphragm-triggered non-invasive respiratory support in preterm infants (< 37 weeks' gestation) when compared to other non-invasive modes of respiratory support (nasal intermittent positive pressure ventilation (NIPPV); nasal continuous positive airway pressure (nCPAP); high-flow nasal cannulae (HFNC)), and to assess preterm infants with birth weight less than 1000 grams or less than 28 weeks' corrected gestation at the time of intervention as a sub-group. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 5), MEDLINE via PubMed (1946 to 10 May 2019), Embase (1947 to 10 May 2019), and CINAHL (1982 to 10 May 2019). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared diaphragm-triggered non-invasive versus other non-invasive respiratory support in preterm infants. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality and extracted data from included studies. We performed fixed-effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR), and risk difference (RD) with 95% confidence intervals (CIs). We used the generic inverse variance method to analyse specific outcomes for cross-over trials. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: There were two small randomised controlled trials including a total of 23 infants eligible for inclusion in the review. Only one trial involving 16 infants included in the analysis reported on either of the primary outcomes of the review. This found no difference in failure of modality between NIV-NAVA and NIPPV (RR 0.33, 95% CI 0.02 to 7.14; RD -0.13, 95% CI -0.41 to 0.16; 1 study, 16 infants; heterogeneity not applicable). Both trials reported on secondary outcomes of the review, specific for cross-over trials (total 22 infants; 1 excluded due to failure of initial modality). One study involving seven infants reported a significant reduction in maximum FiO2 with NIV-NAVA compared to NIPPV (MD -4.29, 95% CI -5.47 to -3.11; heterogeneity not applicable). There was no difference in maximum electric activity of the diaphragm (Edi) signal between modalities (MD -1.75, 95% CI -3.75 to 0.26; I² = 0%) and a significant increase in respiratory rate with NIV-NAVA compared to NIPPV (MD 7.22, 95% CI 0.21 to 14.22; I² = 72%) on a meta-analysis of two studies involving a total of 22 infants. The included studies did not report on other outcomes of interest. AUTHORS' CONCLUSIONS: Due to limited data and very low certainty evidence, we were unable to determine if diaphragm-triggered non-invasive respiratory support is effective or safe in preventing respiratory failure in preterm infants. Large, adequately powered randomised controlled trials are needed to determine if diaphragm-triggered non-invasive respiratory support in preterm infants is effective or safe.

Standardised neonatal parenteral nutrition formulations - Australasian neonatal parenteral nutrition consensus update 2017.

BACKGROUND: The first consensus standardised neonatal parenteral nutrition formulations were implemented in many neonatal units in Australia in 2012. The current update involving 49 units from Australia, New Zealand, Singapore, Malaysia and India was conducted between September 2015 and December 2017 with the aim to review and update the 2012 formulations and guidelines. METHODS: A systematic review of available evidence for each parenteral nutrient was undertaken and new standardised formulations and guidelines were developed. RESULTS: Five existing preterm Amino acid-Dextrose formulations have been modified and two new concentrated Amino acid-Dextrose formulations added to optimise amino acid and nutrient intake according to gestation. Organic phosphate has replaced inorganic phosphate allowing for an increase in calcium and phosphate content, and acetate reduced. Lipid emulsions are unchanged, with both SMOFlipid (Fresenius Kabi, Australia) and ClinOleic (Baxter Healthcare, Australia) preparations included. The physicochemical compatibility and stability of all formulations have been tested and confirmed. Guidelines to standardise the parenteral nutrition clinical practice across facilities have also been developed. CONCLUSIONS: The 2017 PN formulations and guidelines developed by the 2017 Neonatal Parenteral Nutrition Consensus Group offer concise and practical instructions to clinicians on how to implement current and up-to-date evidence based PN to the NICU population.

Stopping enteral feeds for prevention of transfusion-associated necrotising enterocolitis in preterm infants.

BACKGROUND: Feeding practices around the time of packed red blood cell transfusion have been implicated in the subsequent development of necrotising enterocolitis (NEC) in preterm infants. Specifically, it has been suggested that withholding feeds around the time of transfusion may reduce the risk of subsequent NEC. It is important to determine if withholding feeds around transfusion reduces the risk of subsequent NEC and associated mortality. OBJECTIVES: • To assess the benefits and risks of stopping compared to continuing feed management before, during, and after blood transfusion in preterm infants • To assess the effects of stopping versus continuing feeds in the following subgroups of infants: infants of different gestations; infants with symptomatic and asymptomatic anaemia; infants who received different feeding schedules, types of feed, and methods of feed delivery; infants who were transfused with different blood products, at different blood volumes, via different routes of delivery; and those who received blood transfusion with and without co-interventions such as use of diuretics • To determine the effectiveness and safety of stopping feeds around the time of a blood transfusion in reducing the risk of subsequent necrotising enterocolitis (NEC) in preterm infants SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11), in the Cochrane Library; MEDLINE (1966 to 14 November 2018); Embase (1980 to 14 November 2018); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 14 November 2018). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials (RCTs), cluster-RCTs, and quasi-RCTs. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared stopping feeds versus continuing feeds around the time of blood transfusion in preterm infants. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality, and extracted data from the included studies. MAIN RESULTS: The search revealed seven studies that assessed effects of stopping feeds during blood transfusion. However, only one RCT involving 22 preterm infants was eligible for inclusion in the review. This RCT had low risk of selection bias but high risk of performance bias, as care personnel were not blinded to the study allocation. The primary objective of this trial was to investigate changes in mesenteric blood flow, and no cases of NEC were reported in any of the infants included in the trial. We were unable to draw any conclusions from this single study. The overall GRADE rating for quality of evidence was very low. AUTHORS' CONCLUSIONS: Randomised controlled trial evidence is insufficient to show whether stopping feeds has an effect on the incidence of subsequent NEC or death. Large, adequately powered RCTs are needed to address this issue.

Early PARacetamol (EPAR) trial: a study protocol for a randomised controlled trial of early paracetamol to promote closure of the ductus arteriosus in preterm infants.

INTRODUCTION: The optimal management of patent ductus arteriosus (PDA) remains contentious. The medications used to treat PDA are often non-steroidal anti-inflammatory drugs, which are associated with a number of unwanted adverse effects. Paracetamol is a medication with an excellent safety profile in infants and has been suggested as a safe alternative medication in situations where other medications have failed or are contraindicated. There are limited data on the use of early, intravenous paracetamol in preterm infants. METHODS AND ANALYSIS: This trial aims to address whether early treatment with paracetamol will reduce the number of infants requiring intervention for PDA. This is a randomised, double-blind, placebo-controlled trial in preterm infants <29 weeks' gestation. At 6 hours of life, infants with a ductus arteriosus >0.9 mm will be randomised to receive either (1) intravenous paracetamol at a dose of 15 mg/kg initially, followed by every 6 hours at a dose of 7.5 mg/kg for 5 days; or (2) intravenous 5% dextrose every 6 hours for 5 days. The primary outcome is the need for any intervention for management of PDA up to 5 days. Secondary outcomes include closure of the ductus arteriosus at 5 days, size of the ductus arteriosus, ductal reopening, systemic blood flow, mortality and significant morbidities. The target sample size of 100 infants yields >80% power, at the two-sided 5% level significance, to detect a 50% reduction in the need for intervention assuming that approximately 60% of infants in this study would otherwise have required intervention for PDA. ETHICS AND DISSEMINATION: A report on the results of the planned analyses will be prepared. The results of the primary analysis of all end points will be presented at medical conferences and submitted for publication in peer-reviewed journals. Separate manuscripts pertaining to the second aim of the study may be written, and these will also be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12616001517460.

Hypertriglyceridaemia in extremely preterm infants receiving parenteral lipid emulsions.

BACKGROUND: Lipid emulsions (LE) are routinely administered as part of parenteral nutrition in neonates. There is a wide variation in clinical practice of plasma triglyceride monitoring during LE therapy. Our aim was to evaluate the incidence of hypertriglyceridaemia (Plasma triglyceride > 2.8 mmol/L) and its association with mortality and major morbidities in extremely preterm infants on parenteral nutrition. METHODS: A retrospective review of 195 infants < 29 weeks gestation. Lipid emulsion was commenced at 1 g/kg/day soon after birth and increased by 1 g/kg daily up to 3 g/kg/day and continued until the infant was on at least 120 ml/kg/day of enteral feeds. Plasma triglyceride concentrations were measured at each increment and the lipid emulsion dosage was adjusted to keep plasma triglyceride concentrations ≤2.8 mmol/L. RESULTS: Hypertriglyceridemia was noted in 38 neonates (32.5% in 23-25 weeks and 16.1% in 26-28 weeks). Severe hypertriglyceridemia (> 4.5 mmol/L) was noted in 11 infants (10.0% in 23-25 weeks and 4.5% in 26-28 weeks). Hypertriglyceridemia was associated with an increase in mortality (unadjusted OR 3.5; 95% CI 1.13-10.76; 0.033) and severe retinopathy of prematurity (unadjusted OR 4.06; 95% CI 1.73-9.59; 0.002) on univariate analysis. However, this association became non-significant in multivariate analysis with adjustment for gestation and birthweight. CONCLUSIONS: Hypertriglyceridemia is common in extremely preterm infants receiving parenteral lipid emulsions. Regular monitoring and prompt adjustment of lipid intake in the presence of hypertriglyceridemia, minimising the length of exposure to hypertriglyceridemia, may mitigate potential consequences.

Higher versus lower amino acid intake in parenteral nutrition for newborn infants.

BACKGROUND: Sick newborn and preterm infants frequently are not able to be fed enterally, necessitating parenteral fluid and nutrition. Potential benefits of higher parenteral amino acid (AA) intake for improved nitrogen balance, growth, and infant health may be outweighed by the infant's ability to utilise high intake of parenteral AA, especially in the days after birth. OBJECTIVES: The primary objective is to determine whether higher versus lower intake of parenteral AA is associated with improved growth and disability-free survival in newborn infants receiving parenteral nutrition.Secondary objectives include determining whether:• higher versus lower starting or initial intake of amino acids is associated with improved growth and disability-free survival without side effects;• higher versus lower intake of amino acids at maximal intake is associated with improved growth and disability-free survival without side effects; and• increased amino acid intake should replace non-protein energy intake (glucose and lipid), should be added to non-protein energy intake, or should be provided simultaneously with non-protein energy intake.We conducted subgroup analyses to look for any differences in the effects of higher versus lower intake of amino acids according to gestational age, birth weight, age at commencement, and condition of the infant, or concomitant increases in fluid intake. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (2 June 2017), MEDLINE (1966 to 2 June 2017), Embase (1980 to 2 June 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 2 June 2017). We also searched clinical trials databases, conference proceedings, and citations of articles. SELECTION CRITERIA: Randomised controlled trials of higher versus lower intake of AAs as parenteral nutrition in newborn infants. Comparisons of higher intake at commencement, at maximal intake, and at both commencement and maximal intake were performed. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality, and extracted data from included studies. We performed fixed-effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR), and risk difference (RD) with 95% confidence intervals (CIs) and assessed the quality of evidence using the GRADE approach. MAIN RESULTS: Thirty-two studies were eligible for inclusion. Six were short-term biochemical tolerance studies, one was in infants at > 35 weeks' gestation, one in term surgical newborns, and three yielding no usable data. The 21 remaining studies reported clinical outcomes in very preterm or low birth weight infants for inclusion in meta-analysis for this review.Higher AA intake had no effect on mortality before hospital discharge (typical RR 0.90, 95% CI 0.69 to 1.17; participants = 1407; studies = 14; I2 = 0%; quality of evidence: low). Evidence was insufficient to show an effect on neurodevelopment and suggest no reported benefit (quality of evidence: very low). Higher AA intake was associated with a reduction in postnatal growth failure (< 10th centile) at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3; I2 = 22%; typical RD -0.15, 95% CI -0.27 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 4 to 50; quality of evidence: very low). Subgroup analyses found reduced postnatal growth failure in infants that commenced on high amino acid intake (> 2 to ≤ 3 g/kg/day); that occurred with increased amino acid and non-protein caloric intake; that commenced on intake at < 24 hours' age; and that occurred with early lipid infusion.Higher AA intake was associated with a reduction in days needed to regain birth weight (MD -1.14, 95% CI -1.73 to -0.56; participants = 950; studies = 13; I2 = 77%). Data show varying effects on growth parameters and no consistent effects on anthropometric z-scores at any time point, as well as increased growth in head circumference at discharge (MD 0.09 cm/week, 95% CI 0.06 to 0.13; participants = 315; studies = 4; I2 = 90%; quality of evidence: very low).Higher AA intake was not associated with effects on days to full enteral feeds, late-onset sepsis, necrotising enterocolitis, chronic lung disease, any or severe intraventricular haemorrhage, or periventricular leukomalacia. Data show a reduction in retinopathy of prematurity (typical RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4; I2 = 31%; quality of evidence: very low) but no difference in severe retinopathy of prematurity.Higher AA intake was associated with an increase in positive protein balance and nitrogen balance. Potential biochemical intolerances were reported, including risk of abnormal blood urea nitrogen (typical RR 2.77, 95% CI 2.13 to 3.61; participants = 688; studies = 7; I2 = 6%; typical RD 0.26, 95% CI 0.20 to 0.32; number needed to treat for an additional harmful outcome (NNTH) 4; 95% CI 3 to 5; quality of evidence: high). Higher amino acid intake in parenteral nutrition was associated with a reduction in hyperglycaemia (> 8.3 mmol/L) (typical RR 0.69, 95% CI 0.49 to 0.96; participants = 505; studies = 5; I2 = 68%), although the incidence of hyperglycaemia treated with insulin was not different. AUTHORS' CONCLUSIONS: Low-quality evidence suggests that higher AA intake in parenteral nutrition does not affect mortality. Very low-quality evidence suggests that higher AA intake reduces the incidence of postnatal growth failure. Evidence was insufficient to show an effect on neurodevelopment. Very low-quality evidence suggests that higher AA intake reduces retinopathy of prematurity but not severe retinopathy of prematurity. Higher AA intake was associated with potentially adverse biochemical effects resulting from excess amino acid load, including azotaemia. Adequately powered trials in very preterm infants are required to determine the optimal intake of AA and effects of caloric balance in parenteral nutrition on the brain and on neurodevelopment.

Defining normal neonatal abdominal wall musculature with ultrasonography.

INTRODUCTION: The development of new surgical approaches for the management of congenital abdominal wall defects may be facilitated by using an animal model. However, because the anatomy of the neonatal abdominal wall has not been described, a suitable model is yet to be identified. We aimed to evaluate and define the neonatal abdominal wall musculature using ultrasound, to be used as a reference to identify an appropriate animal model for the neonatal abdominal wall in the future. METHODS: Infants with a postconceptual age of less than one month weighing between 2 and 3 kg were eligible. With ethical approval, ultrasonography of three abdominal wall locations bilaterally was performed. The depth of the skin to external oblique and the thickness of the three abdominal wall muscles, external oblique (EO), internal oblique (IO) and transversus abdominis (TA), were measured. RESULTS: Ten males and seven females were recruited with median postconceptual age of 36 weeks (IQR 36-38), median postnatal age of 8 days (IQR 3-30) and median weight of 2.35kg (IQR 2.26-2.56). The mean depth of EO from skin was 2.06 mm (± 0.44). The mean thicknesses of the muscles were: EO 1.02 mm (± 0.33), IO 1.16 mm (± 0.39) and TA 1.02 mm (± 0.37). There was no statistical difference between the thickness of EO, IO or TA (p= 0.43). CONCLUSIONS: It is possible to consistently identify and measure the components of the neonatal abdominal wall musculature with ultrasonography. We hope this can aid in developing an appropriate animal model, with the ultimate aim of facilitating innovation in surgical management of neonatal abdominal wall pathology. LEVELS OF EVIDENCE: Study of Diagnostic test, Level IV.

Causes of death in very preterm infants cared for in neonatal intensive care units: a population-based retrospective cohort study.

BACKGROUND: While there are good data to describe changing trends in mortality and morbidity rates for preterm populations, there is very little information on the specific causes and pattern of death in terms of age of vulnerability. It is well established that mortality increases with decreasing gestational age but there are limited data on the specific causes that account for this increased mortality. The aim of this study was to establish the common causes of hospital mortality in a regional preterm population admitted to a neonatal intensive care unit (NICU). METHODS: Retrospective analysis of prospectively collected data of the Neonatal Intensive Care Units' (NICUS) Data Collection of all 10 NICUs in the region. Infants <32 weeks gestation without major congenital anomalies admitted from 2007 to 2011 were included. Three authors reviewed all cases to agree upon the immediate cause of death. RESULTS: There were 345 (7.7%) deaths out of 4454 infants. The most common cause of death across all gestational groups was major IVH (cause-specific mortality rate [CMR] 22 per 1000 infants), followed by acute respiratory illnesses [ARI] (CMR 21 per 1000 infants) and sepsis (CMR 12 per 1000 infants). The most common cause of death was different in each gestational group (22-25 weeks [ARI], 26-28 weeks [IVH] and 29-31 weeks [perinatal asphyxia]). Pregnancy induced hypertension, antenatal steroids and chorioamnionitis were all associated with changes in CMRs. Deaths due to ARI or major IVH were more likely to occur at an earlier age (median [quartiles] 1.4 [0.3-4.4] and 3.6 [1.9-6.6] days respectively) in comparison to NEC and miscellaneous causes (25.2 [15.4-37.3] and 25.8 [3.2-68.9] days respectively). CONCLUSIONS: Major IVH and ARI were the most common causes of hospital mortality in this extreme to very preterm population. Perinatal factors have a significant impact on cause-specific mortality. The varying timing of death provides insight into the prolonged vulnerability for diseases such as necrotising enterocolitis in our preterm population.

Polyunsaturated fatty acid supplementation in infancy for the prevention of allergy.

BACKGROUND: Early dietary intakes may influence the development of allergic disease. It is important to determine if dietary polyunsaturated fatty acids (PUFAs) given as supplements or added to infant formula prevent the development of allergy. OBJECTIVES: To determine the effect of higher PUFA intake during infancy to prevent allergic disease. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 9), MEDLINE (1966 to 14 September 2015), EMBASE (1980 to 14 September 2015) and CINAHL (1982 to 14 September 2015). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared the use of a PUFA with no PUFA in infants for the prevention of allergy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality and extracted data from the included studies. We used fixed-effect analyses. The treatment effects were expressed as risk ratio (RR) with 95% confidence intervals (CI). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: The search found 17 studies that assessed the effect of higher versus lower intake of PUFAs on allergic outcomes in infants. Only nine studies enrolling 2704 infants reported allergy outcomes that could be used in meta-analyses. Of these, there were methodological concerns for eight.In infants up to two years of age, meta-analyses found no difference in incidence of all allergy (1 study, 323 infants; RR 0.96, 95% CI 0.73 to 1.26; risk difference (RD) -0.02, 95% CI -0.12 to 0.09; heterogeneity not applicable), asthma (3 studies, 1162 infants; RR 1.04, 95% CI 0.80 to 1.35, I2 = 0%; RD 0.01, 95% CI -0.04 to 0.05, I2 = 0%), dermatitis/eczema (7 studies, 1906 infants; RR 0.93, 95% CI 0.82 to 1.06, I2 = 0%; RD -0.02, 95% CI -0.06 to 0.02, I2 = 0%) or food allergy (3 studies, 915 infants; RR 0.81, 95% CI 0.56 to 1.19, I2 = 63%; RD -0.02, 95% CI -0.06 to 0.02, I2 = 74%). There was a reduction in allergic rhinitis (2 studies, 594 infants; RR 0.47, 95% CI 0.23 to 0.96, I2 = 6%; RD -0.04, 95% CI -0.08 to -0.00, I2 = 54%; number needed to treat for an additional beneficial outcome (NNTB) 25, 95% CI 13 to ∞).In children aged two to five years, meta-analysis found no difference in incidence of all allergic disease (2 studies, 154 infants; RR 0.69, 95% CI 0.47 to 1.02, I2 = 43%; RD -0.16, 95% CI -0.31 to -0.00, I2 = 63%; NNTB 6, 95% CI 3 to ∞), asthma (1 study, 89 infants; RR 0.45, 95% CI 0.20 to 1.02; RD -0.20, 95% CI -0.37 to -0.02; heterogeneity not applicable; NNTB 5, 95% CI 3 to 50), dermatitis/eczema (2 studies, 154 infants; RR 0.65, 95% CI 0.34 to 1.24, I2 = 0%; RD -0.09 95% CI -0.22 to 0.04, I2 = 24%) or food allergy (1 study, 65 infants; RR 2.27, 95% CI 0.25 to 20.68; RD 0.05, 95% CI -0.07 to 0.16; heterogeneity not applicable).In children aged two to five years, meta-analysis found no difference in prevalence of all allergic disease (2 studies, 633 infants; RR 0.98, 95% CI 0.81 to 1.19, I2 = 36%; RD -0.01, 95% CI -0.08 to 0.07, I2 = 0%), asthma (2 studies, 635 infants; RR 1.12, 95% CI 0.82 to 1.53, I2 = 0%; RD 0.02, 95% CI -0.04 to 0.09, I2 = 0%), dermatitis/eczema (2 studies, 635 infants; RR 0.81, 95% CI 0.59 to 1.09, I2 = 0%; RD -0.04 95% CI -0.11 to 0.02, I2 = 0%), allergic rhinitis (2 studies, 635 infants; RR 1.02, 95% CI 0.83 to 1.25, I2 = 0%; RD 0.01, 95% CI -0.06 to 0.08, I2 = 0%) or food allergy (1 study, 119 infants; RR 0.27, 95% CI 0.06 to 1.19; RD -0.10, 95% CI -0.20 to -0.00; heterogeneity not applicable; NNTB 10, 95% CI 5 to ∞). AUTHORS' CONCLUSIONS: There is no evidence that PUFA supplementation in infancy has an effect on infant or childhood allergy, asthma, dermatitis/eczema or food allergy. However, the quality of evidence was very low. There was insufficient evidence to determine an effect on allergic rhinitis.

Basal ganglia perfusion in the preterm infant during transition.

BACKGROUND: The preterm brain is susceptible to changes in blood flow. Using power Doppler images, digital imaging techniques have been developed to measure the total amount of blood flow in a defined area, giving the index: fractional moving blood volume (FMBV). The aim of this study was to investigate temporal changes in basal ganglia perfusion during the transitional period after birth. METHODS: Twenty-four preterm infants were examined with serial cranial ultrasounds at four time points during the first 48 h of life. FMBV was calculated using power Doppler images at each time point. RESULTS: All infants had analyzable data and FMBV was successfully calculated at all time points. Twenty-three of the 24 infants had an increasing trend in FMBV over time. The median FMBV increased from 17% at 6 h to 25% at 48 h. One-way repeated measures ANOVA showed a significant increase in values at P < 0.001 at each of the four time points. CONCLUSION: We have demonstrated changes in basal ganglia blood flow as the cerebral circulation adapts to extrauterine life. With further investigation, this technique may be useful in the assessment of preterm circulatory adaptation, either alone or in conjunction with other modes of evaluating cerebral blood flow.

Spatiotemporal Image Correlation and Volumetric Impedance Indices in the Neonatal Brain: Proof of Concept and Preliminary Reproducibility.

OBJECTIVES: Changes in tissue perfusion can be critically important in the vulnerable neonate, but they are very difficult to assess at the bedside. Spatiotemporal image correlation (STIC) sonography is an exciting concept that allows assessment of blood flow by rearranging and merging multiple 2-dimensional color images to create serial 3-dimensional images showing regional blood flow throughout the cardiac cycle. Variations in tissue blood flow may reflect tissue impedance and perfusion. The aim of this study was to demonstrate that it is possible to use STIC images to evaluate tissue impedance in the neonatal brain. METHODS: Spatiotemporal image correlation data sets were acquired by cranial sonography in 19 neonates. Offline data analysis was performed by using virtual organ computer-aided analysis. With the use of STIC images from different phases of the cardiac cycle, impedance indices were calculated, based on maximum (systolic), minimum (diastolic), and mean virtual organ computer-aided analysis values, in the same way that resistive indices are calculated in 2-dimensional sonography. RESULTS: Volumetric indices for tissue impedance were obtained for all neonates. Intraclass correlation coefficients (95% confidence intervals) for volumetric impedance indices were as follows: systolic/diastolic ratio, 0.793 (0.615-0.906); pulsatility index, 0.790 (0.609-0.905); and resistive index, 0.783 (0.598-0.901). Interclass correlation coefficients for image processing and analysis were as follows: systolic/diastolic ratio, 0.868 (0.692-0.947); pulsatility index, 0.904 (0.772-0.962); and resistive index, 0.914 (0.794-0.966). CONCLUSIONS: This study shows that STIC data sets can be used to calculate volumetric impedance indices in the neonatal brain. Preliminary assessment shows that this technique appears reliable and allows evaluation of regional tissue impedance in the neonate.

Evaluation of neonatal regional cerebral perfusion using power Doppler and the index fractional moving blood volume.

BACKGROUND: The high cerebral morbidity of premature neonates is thought to be related to changes in tissue perfusion in vulnerable areas of the brain. Quantification of power Doppler (PD) images using the index fractional moving blood volume (FMBV) may allow measurement of regional cerebral perfusion. OBJECTIVE: To evaluate the reproducibility of calculating FMBV using PD ultrasound images to estimate cerebral perfusion. METHODS: Two experienced clinicians performed head ultrasounds on 24 normally-grown neonates at less than 33 weeks' gestation. Both clinicians independently acquired and stored three PD images in two different coronal planes. FMBV was calculated offline after selecting two predefined regions of interest within these planes (basal ganglia and subependymal regions). Reproducibility was evaluated by calculating the intraclass correlation coefficient (intraCC) and the interclass correlation coefficient (interCC). RESULTS: FMBV was successfully evaluated in 24/24 neonates by both clinicians. The intraCC for repeatability for observer A was 1.00 (95% CI 1.00-1.00) for the basal ganglia and 0.99 (95% CI 0.99-1.00) for the subependymal region, and for observer B was 0.99 (95% CI 0.99-1.00) for the basal ganglia and 0.96 (95% CI 0.92-0.98) for the subependymal region. The interCC was 0.86 (95% CI 0.68-0.94) for the basal ganglia and 0.93 (95% CI 0.86-0.97) for the subependymal region. CONCLUSION: Using standardised settings and a well-defined region of interest, the calculation of FMBV using PD images is a reproducible method of estimating neonatal regional cerebral perfusion.