Cochrane Neonatal Review Group Research Articles

Cerebral near-infrared spectroscopy monitoring for prevention of brain injury in very preterm infants.

Cerebral injury and long-term neurodevelopmental impairment is common in extremely preterm infants. Cerebral near-infrared spectroscopy (NIRS) enables continuous estimation of cerebral oxygenation. This diagnostic method coupled with appropriate interventions if NIRS is out of normal range (that is cerebral oxygenation within the 55% to 85% range) may offer benefits without causing more harms. Therefore, NIRS coupled with appropriate responses to abnormal findings on NIRS needs assessment in a systematic review of randomised clinical trials and quasi-randomised studies. To evaluate the benefits and harms of interventions that attempt to alter cerebral oxygenation guided by cerebral NIRS monitoring in order to prevent cerebral injury, improve neurological outcome, and increase survival in preterm infants born more than 8 weeks preterm. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 8), MEDLINE via PubMed (1966 to 10 September 2016), Embase (1980 to 10 September 2016), and CINAHL (1982 to 10 September 2016). We also searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised clinical trials and quasi-randomised studies. Randomised clinical trials and quasi-randomised clinical studies comparing continuous cerebral NIRS monitoring for at least 24 hours versus blinded NIRS or versus no NIRS monitoring. Two review authors independently selected, assessed the quality of, and extracted data from the included trials and studies. If necessary, we contacted authors for further information. We conducted assessments of risks of bias; risks of design errors; and controlled the risks of random errors with Trial Sequential Analysis. We assessed the quality of the evidence with GRADE. One randomised clinical trial met inclusion criteria, including infants born more than 12 weeks preterm. The trial employed adequate methodologies and was assessed at low risk of bias. One hundred and sixty-six infants were randomised to start continuous cerebral NIRS monitoring less than 3 hours after birth until 72 hours after birth plus appropriate interventions if NIRS was out of normal range according to a guideline versus conventional monitoring with blinded NIRS. There was no effect of NIRS plus guideline of mortality until term-equivalent age (RR 0.50, 95% CI 0.29 to 1.00; one trial; 166 participants). There were no effects of NIRS plus guideline on intraventricular haemorrhages: all grades (RR 0.93, 95% CI 0.65 to 1.34; one trial; 166 participants); grade III/IV (RR 0.57, 95% CI 0.25 to 1.31; one trial; 166 participants); and cystic periventricular leukomalacia (which did not occur in either group). Likewise, there was no effect of NIRS plus guideline on the occurrence of a patent ductus arteriosus (RR 1.96, 95% CI 0.94 to 4.08; one trial; 166 participants); chronic lung disease (RR 1.27, 95% CI 0.94 to 1.50; one trial; 166 participants); necrotising enterocolitis (RR 0.83, 95% CI 0.33 to 1.94; one trial; 166 participants); and retinopathy of prematurity (RR 1.64, 95% CI 0.75 to 3.00; one trial; 166 participants). There were no serious adverse events in any of the intervention groups. NIRS plus guideline caused more skin marks from the NIRS sensor in the control group than in the experimental group (unadjusted RR 0.31, 95% CI 0.10 to 0.92; one trial; 166 participants). There are no data regarding neurodevelopmental outcome, renal impairment or air leaks.The quality of evidence for all comparisons discussed above was assessed as very low apart from all-cause mortality and adverse events: these were assessed as low and moderate, respectively. The validity of all comparisons is hampered by a small sample of randomised infants, risk of bias due to lack of blinding, and indirectness of outcomes. The only eligible randomised clinical trial did not demonstrate any consistent effects of NIRS plus a guideline on the assessed clinical outcomes. The trial was, however, only powered to detect difference in cerebral oxygenation, not morbidities or mortality. Our systematic review did not reach sufficient power to prove or disprove effects on clinical outcomes. Further randomised clinical trials with low risks of bias and low risks of random errors are needed.

Fluid supplementation for neonatal unconjugated hyperbilirubinaemia.

Fluid supplementation for neonatal unconjugated hyperbilirubinaemia.

Oral dextrose gel to prevent hypoglycaemia in at-risk neonates

Background Neonatal hypoglycaemia is a common condition that can be associated with brain injury. Current practice usually includes early identification of at-risk infants (e.g. infants of diabetic mothers; preterm, small- or large-for-gestational-age infants), and prophylactic measures are advised. However, these measures often involve use of formula milk or admission to the neonatal unit. Dextrose gel is non-invasive, inexpensive, and effective for treatment of neonatal hypoglycaemia. Use of prophylactic dextrose gel can prevent neonatal hypoglycaemia, thus potentially reducing separation of mother and baby and supporting breastfeeding, as well as preventing brain injury. Objectives To assess the effectiveness and safety of oral dextrose gel in preventing hypoglycaemia among newborn infants at risk of hypoglycaemia and in reducing long-term neurodevelopmental impairment. Search methods We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12), MEDLINE via PubMed (1966 to 23 January 2017), Embase (1980 to 23 January 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 23 January 2017). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Selection criteria We included randomised and quasi-randomised studies comparing dextrose gel versus placebo, no intervention, or other therapies for prevention of neonatal hypoglycaemia. Data collection and analysis We used standard methodological procedures as expected by the Cochrane Collaboration. Two review authors independently assessed trial quality and extracted data. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to assess the quality of evidence. Main results We included one trial comparing oral dextrose gel versus placebo in 416 infants at risk of hypoglycaemia. We judged this trial to be at low risk of bias. Using the GRADE method, we determined that evidence ranged from high quality to moderate quality. For outcomes selected for the GRADE analysis, we found the following. • Oral dextrose gel prophylaxis (any dose) is associated with reduced risk of neonatal hypoglycaemia compared with placebo (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.62 to 0.94; one RCT; n = 415 infants; high-quality evidence). The risk difference (RD) is -0.13 (95% CI -0.23 to -0.03), and on average, 8.3 infants would have to receive prophylactic dextrose gel to prevent one additional case of neonatal hypoglycaemia. • Investigators found no statistically significant differences between dextrose gel and placebo groups in the number of adverse events (RR 1.09, 95% CI 0.55 to 2.17; one RCT; n = 413 infants; moderate-quality evidence); separation from mother for treatment of hypoglycaemia (RR 0.46, 95% CI 0.21 to 1.01; one RCT, n = 415 infants; moderate-quality evidence); exclusive breastfeeding at discharge (RR 1.00, 95% CI 0.86 to 1.15; one RCT; n = 415 women; moderate-quality evidence); or breastfeeding at six weeks postpartum (RR 1.06, 95% CI 0.88 to 1.29; one RCT; n = 386 women; moderate-quality evidence). • Researchers provided no data for the other prespecified GRADE outcomes for this review (major neurological disability at two years of age or older; receipt of treatment for hypoglycaemia during initial hospital stay; receipt of intravenous treatment for hypoglycaemia). Authors' conclusions Oral dextrose gel reduced the risk of neonatal hypoglycaemia in at-risk infants in a single trial. Results showed no statistically significant differences in the number of adverse events or in risk of separation of infant from mother for treatment of hypoglycaemia between babies who received oral dextrose gel and those given placebo. Caution is suggested in interpreting data for the latter two outcomes owing to low event rates. Available evidence is limited to a cohort of at-risk infants, most of whom were infants of diabetic mothers and were treated on the postnatal ward. Minimal data available for many of the prespecified outcomes of this review showed no long-term neurodevelopmental and disability outcomes. Additional evidence is needed to assess the efficacy and safety of dextrose gel for prevention of neonatal hypoglycaemia.

Head midline position for preventing the occurrence or extension of germinal matrix-intraventricular hemorrhage in preterm infants.

Preterm birth is known to constitute the major risk factor for development of germinal matrix-intraventricular hemorrhage (GM-IVH). Head position may affect cerebral hemodynamics and thus may be involved indirectly in development of GM-IVH. Turning the head toward one side may functionally occlude jugular venous drainage on the ipsilateral side while increasing intracranial pressure and cerebral blood volume. Thus, it has been suggested that cerebral venous pressure is reduced and hydrostatic brain drainage improved if the patient is in supine midline position with the bed tilted 30°. The midline position might be achieved in the supine position and, with the use of physical aids, in the lateral position as well. Midline position should be kept, at least when the incidence of GM-IVH is greatest, that is, during the first two to three days of life. Primary objective To assess whether head midline position is more effective than any other head position for preventing or extending germinal matrix-intraventricular hemorrhage in infants born at ≤ 32 weeks' gestational age. Secondary objectives To perform subgroup analyses regarding gestational age, birth weight, intubated versus not intubated, and with or without GM-IVH at trial entry. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8), MEDLINE via PubMed (1966 to September 19, 2016), Embase (1980 to September 19,.2016), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to September 19, 2016). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. Randomized clinical controlled trials, quasi-randomized trials, and cluster-randomized controlled trials comparing placing very preterm infants in a head midline position versus placing them in a prone or lateral decubitus position, or undertaking a strategy of regular position change, or having no prespecified position. We included trials enrolling infants with existing GM-IVH and planned to assess extension of hemorrhage in a subgroup of infants. We planned to analyze horizontal (flat) versus head elevated positions separately for all body positions. We used standard methods of the Cochrane Neonatal Review Group. For each of the included trials, two review authors independently extracted data (e.g., number of participants, birth weight, gestational age, initiation and duration of head midline position, co-intervention with horizontal vs head elevated position, use of physical aids to maintain head position) and assessed risk of bias (e.g., adequacy of randomization, blinding, completeness of follow-up). The primary outcomes considered in this review are GM-IVH , severe IVH, and neonatal death. Our search strategy yielded 2696 references. Two review authors independently assessed all references for inclusion. Two randomized controlled trials, for a total of 110 infants, met the inclusion criteria of this review. Both trials compared supine midline head position with the bed at 0° versus supine head rotated 90° with the bed at 0°. We found no trials that compared supine versus prone midline head position, and no trials that compared effects of head tilting. We found no significant differences in rates of GM-IVH (typical risk ratio [RR] 1.14, 95% confidence interval [CI] 0.55 to 2.35; typical risk difference [RD] 0.03, 95% CI -0.13 to 0.18; two studies, 110 infants; I2 = 0% for RR and I2 = 0% for RD), severe IVH (typical RR 1.57, 95% CI 0.28 to 8.98; typical RD 0.02, 95% CI -0.06 to 0.10; two studies, 110 infants; I2 = 0% for RR and I2 = 0% for RD), and neonatal mortality (typical RR 0.52, 95% CI 0.16 to 1.65; typical RD -0.07, 95% CI -0.18 to 0.05; two studies, 110 infants; I2 = 28% for RR and I2 = 44% for RD). Among secondary outcomes, we found no significant differences in terms of cystic periventricular leukomalacia (one study; RR 3.25, 95% CI 0.14 to 76.01; RD 0.04, 95% CI -0.07 to 0.15), retinopathy of prematurity (one study; RR 2.27, 95% CI 0.85 to 6.11; RD 0.25, 95% CI -0.02 to 0.53), and severe retinopathy of prematurity (one study; RR 2.73, 95% CI 0.31 to 24.14; RD 0.09, 95% CI -0.09 to 0.26). None of the included trials reported on the other specified outcomes of this review (i.e., cerebellar hemorrhage, brain magnetic resonance imaging abnormalities, impairment in cerebral hemodynamics, long-term neurodevelopmental outcomes, and major neurodevelopmental disability). The quality of evidence supporting these findings is limited owing to the imprecision of the estimates. We identified no ongoing studies. Given the imprecision of the estimate, results of this systematic review are consistent with beneficial or detrimental effects of a supine head midline position versus a lateral position and do not provide a definitive answer to the review question.

Saline irrigation for the management of skin extravasation injury in neonates.

Extravasation injury, a complication commonly seen in the neonatal intensive care unit, can result in scarring with cosmetic and functional sequelae. A wide variety of treatments are available, including subcutaneous irrigation with saline (with or without hyaluronidase), liposuction, use of specific antidotes, topical applications, and normal wound care with dry or wet dressings. All such treatments aim to prevent or reduce the severity of complications. Primary objective To compare the efficacy and safety of saline irrigation or saline irrigation with prior hyaluronidase infiltration versus no intervention or normal wound care for tissue healing in neonates with extravasation injury. Secondary objectives To evaluate by subgroup analysis of controlled trials the influence of type of extravasate, timing of irrigation following extravasation, and postmenstrual age (PMA) of the neonate at the time of injury on outcomes and adverse effects.Specifically, we planned to perform subgroup analysis for the primary outcome, if appropriate, by examining:1. time to irrigation from identified extravasation injury (< 1 hour or ≥ 1 hour);2. type of extravasate (parenteral nutrition fluid or other fluids or medications);3. amount of saline used (< 500 mL or ≥ 500 mL); and4. PMA at injury (< 37 completed weeks or ≥ 37 completed weeks). We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1), MEDLINE via PubMed (1966 to 2 February 2017), Embase (1980 to 2 February 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 2 February 2017). We also searched clinical trial databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We used the Google Scholar search tool for reverse citations of relevant articles. Randomised controlled trials (RCTs) and quasi-randomised controlled trials comparing saline irrigation with or without hyaluronidase infiltration versus no intervention or normal wound care for the management of extravasation injury in neonates. Three review authors independently reviewed and identified articles for possible inclusion in this review. We used the GRADE approach to assess the quality of evidence. We found no eligible studies. Our search revealed 10 case reports or case series describing successful outcomes with different interventions for this condition. To date, no RCTs have examined the effects of saline irrigation with or without prior hyaluronidase infiltration for management of extravasation injury in neonates. Saline irrigation is frequently reported in the literature as an intervention for management of extravasation injury in neonates. Research should focus first on evaluating the efficacy and safety of this intervention through RCTs. It will also be important for investigators to determine effect size by examining the timing of the intervention, the nature of the infusate, and severity of injury at the time of intervention.

Sustained versus standard inflations during neonatal resuscitation to prevent mortality and improve respiratory outcomes.

At birth, infants' lungs are fluid-filled. For newborns to have a successful transition, this fluid must be replaced by air to enable effective breathing. Some infants are judged to have inadequate breathing at birth and are resuscitated with positive pressure ventilation (PPV). Giving prolonged (sustained) inflations at the start of PPV may help clear lung fluid and establish gas volume within the lungs. To assess the efficacy of an initial sustained (> 1 second duration) lung inflation versus standard inflations (≤ 1 second) in newly born infants receiving resuscitation with intermittent PPV. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1), MEDLINE via PubMed (1966 to 17 February 2017), Embase (1980 to 17 February 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 17 February 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles to identify randomised controlled trials and quasi-randomised trials. Randomised controlled trials (RCTs) and quasi-RCTs comparing initial sustained lung inflation (SLI) versus standard inflations given to infants receiving resuscitation with PPV at birth. We assessed the methodological quality of included trials using Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria (assessing randomisation, blinding, loss to follow-up, and handling of outcome data). We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data and mean, standard deviation (SD), and weighted mean difference (WMD) for continuous data. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Eight trials enrolling 941 infants met our inclusion criteria. Investigators in seven trials (932 infants) administered sustained inflation with no chest compressions. Use of sustained inflation had no impact on the primary outcomes of this review - mortality in the delivery room (typical RR 2.66, 95% confidence interval (CI) 0.11 to 63.40; participants = 479; studies = 5; I² not applicable) and mortality during hospitalisation (typical RR 1.01, 95% CI 0.67 to 1.51; participants = 932; studies = 7; I² = 19%); the quality of the evidence was low for death in the delivery room (limitations in study design and imprecision of estimates) and was moderate for death before discharge (limitations in study design of most included trials). Amongst secondary outcomes, duration of mechanical ventilation was shorter in the SLI group (mean difference (MD) -5.37 days, 95% CI -6.31 to -4.43; participants = 524; studies = 5; I² = 95%; low-quality evidence). Heterogeneity, statistical significance, and magnitude of effects of this outcome are largely influenced by a single study: When this study was removed from the analysis, the effect was largely reduced (MD -1.71 days, 95% CI -3.04 to -0.39, I² = 0%). Results revealed no differences in any of the other secondary outcomes (e.g. rate of endotracheal intubation outside the delivery room by 72 hours of age (typical RR 0.93, 95% CI 0.79 to 1.09; participants = 811; studies = 5; I² = 0%); need for surfactant administration during hospital admission (typical RR 0.97, 95% CI 0.86 to 1.10; participants = 932; studies = 7; I² = 0%); rate of chronic lung disease (typical RR 0.95, 95% CI 0.74 to 1.22; participants = 683; studies = 5; I² = 47%); pneumothorax (typical RR 1.44, 95% CI 0.76 to 2.72; studies = 6, 851 infants; I² = 26%); or rate of patent ductus arteriosus requiring pharmacological treatment (typical RR 1.08, 95% CI 0.90 to 1.30; studies = 6, 745 infants; I² = 36%). The quality of evidence for these secondary outcomes was moderate (limitations in study design of most included trials - GRADE) except for pneumothorax (low quality: limitations in study design and imprecision of estimates - GRADE). Sustained inflation was not better than intermittent ventilation for reducing mortality in the delivery room and during hospitalisation. The number of events across trials was limited, so differences cannot be excluded. When considering secondary outcomes, such as need for intubation, need for or duration of respiratory support, or bronchopulmonary dysplasia, we found no evidence of relevant benefit for sustained inflation over intermittent ventilation. The duration of mechanical ventilation was shortened in the SLI group. This result should be interpreted cautiously, as it can be influenced by study characteristics other than the intervention. Future RCTs should aim to enrol infants who are at higher risk of morbidity and mortality, should stratify participants by gestational age, and should provide more detailed monitoring of the procedure, including measurements of lung volume and presence of apnoea before or during the SLI.

Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants.

Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. Primary objective 1. To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates Secondary objectives 1. To determine the effects of lactoferrin supplementation to enteral feeds to prevent neonatal sepsis and/or NEC on duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later2. To determine the adverse effects of lactoferrin supplementation for prophylaxis of neonatal sepsis and/or NECWhen data were available, we analyzed the following subgroups.1. Gestational age < 32 weeks and 32 to 36 weeks2. Birth weight < 1000 g (extremely low birth weight (ELBW) infants) and birth weight < 1500 g (very low birth weight (VLBW) infants)3. Type of feeding: breast milk versus formula milk SEARCH METHODS: We used the search strategy of the Cochrane Neonatal Review Group (CNRG) to update our search in December 2016. We searched the databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PREMEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as trial registries and conference proceedings. Randomized controlled trials (RCTs) evaluating oral lactoferrin at any dose or duration to prevent sepsis or NEC in preterm neonates. Review authors used standard methods of the CNRG. This review includes six RCTs. Trial results show that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical risk ratio (RR) 0.59, 95% confidence interval (CI) 0.40 to 0.87; typical risk difference (RD) -0.06, 95% CI -0.10 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 17, 95% CI 10 to 50; six trials, 886 participants; low-quality evidence) and NEC stage II or III (typical RR 0.40, 95% CI 0.18 to 0.86; typical RD -0.04, 95% CI -0.06 to -0.01; NNTB 25, 95% CI 17 to 100; four studies, 750 participants; low-quality evidence). Lactoferrin supplementation did not have an effect on "all-cause mortality" (typical RR 0.65, 95% CI 0.37 to 1.11; typical RD -0.02, 95% CI -0.05 to 0; six studies, 1041 participants; low-quality evidence).Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.27, 95% CI 0.12 to 0.60; RD -0.13, 95% CI -0.19 to -0.06; NNTB 8, 95% CI 5 to 17; one study, 321 participants; low-quality evidence) and NEC stage II or III (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; one study, 496 participants; low-quality evidence), but not "all-cause mortality" (low-quality evidence).Lactoferrin supplementation to enteral feeds with or without probiotics decreased bacterial and fungal sepsis but not CLD or length of hospital stay (low-quality evidence). Investigators reported no adverse effects and did not evaluate long-term neurological outcomes and PVL. Evidence of low quality suggests that lactoferrin supplementation to enteral feeds with or without probiotics decreases late-onset sepsis and NEC stage II or III in preterm infants without adverse effects. Completed ongoing trials will provide data from more than 6000 preterm neonates, which may enhance the quality of the evidence. Clarification regarding optimal dosing regimens, types of lactoferrin (human or bovine), and long-term outcomes is needed.

Orotracheal intubation in infants performed with a stylet versus without a stylet.

Neonatal endotracheal intubation is a common and potentially life-saving intervention. It is a mandatory skill for neonatal trainees, but one that is difficult to master and maintain. Intubation opportunities for trainees are decreasing and success rates are subsequently falling. Use of a stylet may aid intubation and improve success. However, the potential for associated harm must be considered. To compare the benefits and harms of neonatal orotracheal intubation with a stylet versus neonatal orotracheal intubation without a stylet. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE; Embase; the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and previous reviews. We also searched cross-references, contacted expert informants, handsearched journals, and looked at conference proceedings. We searched clinical trials registries for current and recently completed trials. We conducted our most recent search in April 2017. All randomised, quasi-randomised, and cluster-randomised controlled trials comparing use versus non-use of a stylet in neonatal orotracheal intubation. Two review authors independently assessed results of searches against predetermined criteria for inclusion, assessed risk of bias, and extracted data. We used the standard methods of the Cochrane Collaboration, as documented in the Cochrane Handbook for Systemic Reviews of Interventions, and of the Cochrane Neonatal Review Group. We included a single-centre non-blinded randomised controlled trial that reported a total of 302 intubation attempts in 232 infants. The median gestational age of enrolled infants was 29 weeks. Paediatric residents and fellows performed the intubations. We judged the study to be at low risk of bias overall. Investigators compared success rates of first-attempt intubation with and without use of a stylet and reported success rates as similar between stylet and no-stylet groups (57% and 53%) (P = 0.47). Success rates did not differ between groups in subgroup analyses by provider level of training and infant weight. Results showed no differences in secondary review outcomes, including duration of intubation, number of attempts, participant instability during the procedure, and local airway trauma. Only 25% of all intubations took less than 30 seconds to perform. Study authors did not report neonatal morbidity nor mortality. We considered the quality of evidence as low on GRADE analysis, given that we identified only one unblinded study. Current available evidence suggests that use of a stylet during neonatal orotracheal intubation does not significantly improve the success rate among paediatric trainees. However, only one brand of stylet and one brand of endotracheal tube have been tested, and researchers performed all intubations on infants in a hospital setting. Therefore, our results cannot be generalised beyond these limitations.

WITHDRAWN: Infant formulas containing hydrolysed protein for prevention of allergic disease and food allergy.

Allergy is common and may be associated with foods, including cow's milk formula (CMF). Formulas containing hydrolysed proteins have been used to treat infants with allergy. However, it is unclear whether hydrolysed formulas can be advocated for prevention of allergy in infants. To compare effects on allergy and food allergy when infants are fed a hydrolysed formula versus CMF or human breast milk. If hydrolysed formulas are effective, to determine what type of hydrolysed formula is most effective, including extensively or partially hydrolysed formula (EHF/PHF). To determine which infants at low or high risk of allergy and which infants receiving early, short-term or prolonged formula feeding may benefit from hydrolysed formulas. We used the standard search strategy of the Cochrane Neonatal Review Group supplemented by cross referencing of previous reviews and publications (updated August 2016). We searched for randomised and quasi-randomised trials that compared use of a hydrolysed formula versus human milk or CMF. Trials with ≥ 80% follow-up of participants were eligible for inclusion. We independently assessed eligibility of studies for inclusion, methodological quality and data extraction. Primary outcomes included clinical allergy, specific allergy and food allergy. We conducted meta-analysis using a fixed-effect (FE) model. Two studies assessed the effect of three to four days' infant supplementation with an EHF whilst in hospital after birth versus pasteurised human milk feed. Results showed no difference in infant allergy or childhood cow's milk allergy (CMA). No eligible trials compared prolonged hydrolysed formula versus human milk feeding.Two studies assessed the effect of three to four days infant supplementation with an EHF versus a CMF. One large quasi-random study reported a reduction in infant CMA of borderline significance among low-risk infants (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.38 to 1.00).Prolonged infant feeding with a hydrolysed formula compared with a CMF was associated with a reduction in infant allergy (eight studies, 2852 infants; FE RR 0.82, 95% CI 0.72 to 0.95; risk difference (RD) -0.04, 95% CI -0.08 to -0.01; number needed to treat for an additional beneficial outcome (NNTB) 25, 95% CI 12.5 to 100) and infant CMA (two studies, 405 infants; FE RR 0.38, 95% CI 0.16 to 0.86). We had substantial methodological concerns regarding studies and concerns regarding publication bias, as substantial numbers of studies including those in high-risk infants have not comprehensively reported allergy outcomes (GRADE quality of evidence 'very low').Prolonged infant feeding with a hydrolysed formula compared with a CMF was not associated with a difference in childhood allergy and led to no differences in specific allergy, including infant and childhood asthma, eczema and rhinitis and infant food allergy. Many of the analyses assessing specific allergy are underpowered.Subroup analyses showed that infant allergy was reduced in studies that enrolled infants at high risk of allergy who used a hydrolysed formula compared with a CMF; used a PHF compared with a CMF; used prolonged and exclusive feeding of a hydrolysed formula compared with a CMF; and used a partially hydrolysed whey formula compared with a CMF. Studies that enrolled infants at high risk of allergy; used a PHF compared with a CMF; used prolonged and exclusive feeding of a hydrolysed formula compared with a CMF; and used a partially hydrolysed whey formula compared with a CMF found a reduction in infant CMA. We found no evidence to support short-term or prolonged feeding with a hydrolysed formula compared with exclusive breast feeding for prevention of allergy. Very low-quality evidence indicates that short-term use of an EHF compared with a CMF may prevent infant CMA.In infants at high risk of allergy not exclusively breast fed, very low-quality evidence suggests that prolonged hydrolysed formula feeding compared with CMF feeding reduces infant allergy and infant CMA. Studies have found no difference in childhood allergy and no difference in specific allergy, including infant and childhood asthma, eczema and rhinitis and infant food allergy.Very low-quality evidence shows that prolonged use of a partially hydrolysed formula compared with a CMF for partial or exclusive feeding was associated with a reduction in infant allergy incidence and CMA incidence, and that prolonged use of an EHF versus a PHF reduces infant food allergy.

Clonidine for sedation and analgesia for neonates receiving mechanical ventilation.

Although routine administration of pharmacologic sedation or analgesia during mechanical ventilation in preterm neonates is not recommended, its use in clinical practice remains common. Alpha-2 agonists, mainly clonidine and dexmedetomidine, are used as adjunctive (or alternative) sedative agents alongside opioids and benzodiazepines. Clonidine has not been systematically assessed for use in neonatal sedation during ventilation. To assess whether clonidine administered to term and preterm newborn infants receiving mechanical ventilation reduces morbidity and mortality rates. To compare the intervention versus placebo, no treatment, and dexmedetomidine; and to assess the safety of clonidine infusion for potential harms.To perform subgroup analyses according to gestational age; birth weight; administration method (infusion or bolus therapy); dose, duration, and route of clonidine administration; and pharmacologic sedation as a co-intervention. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12) in the Cochrane Library, MEDLINE via PubMed (1966 to January 10, 2017), Embase (1980 to January 10, 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to January 10, 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. We searched for randomized controlled trials, quasi-randomized controlled trials, and cluster trials comparing clonidine versus placebo, no treatment, or dexmedetomidine administered to term and preterm newborns receiving mechanical ventilation via an endotracheal tube. For the included trial, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, all-cause death during initial hospitalization, duration of respiratory support, sedation scale, duration of hospital stay) and assessed risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). This review considered primary outcomes of all-cause neonatal death, all-cause death during initial hospitalization, and duration of mechanical ventilation in days. One trial, which included 112 infants, met the inclusion criteria for this review. Term newborn infants on mechanical ventilation with the need for continuous analgesia and sedation with fentanyl and midazolam were eligible for enrollment during the first 96 hours of ventilation. Study authors administered clonidine 1 μg/kg/h or placebo on day 4 after intubation.We found no differences between the two groups in all-cause death during hospitalization (risk ratio [RR] 0.69, 95% confidence interval [CI] 0.12 to 3.98). The quality of the evidence supporting these findings is low owing to imprecision of the estimates (one study; few events). The median (interquartile range) duration of mechanical ventilation was 7.1 days (5.7 to 9.1 days) in the clonidine group and 5.8 days (4.9 to 7.9 days) in the placebo group, respectively (P = 0.070). Among secondary outcomes, we found no differences in terms of duration of stay in the intensive care unit. Sedation scale values (COMFORT) and analgesia scores (Hartwig) during the first 72 hours of infusion of study medication were lower in the clonidine group than in the placebo group. At present, evidence is insufficient to show the efficacy and safety of clonidine for sedation and analgesia in term and preterm newborn infants receiving mechanical ventilation.

Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis.

Recombinant human erythropoietin (rhEPO) is a promising pharmacological agent for neuroprotection in neonates. To investigate whether prophylactic rhEPO administration in very preterm infants improves neurodevelopmental outcomes in a meta-analysis of randomized controlled trials (RCTs). Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched in December 2016 and complemented by other sources. RCTs investigating the use of rhEPO in preterm infants versus a control group were selected if they were published in a peer-reviewed journal and reported neurodevelopmental outcomes at 18 to 24 months' corrected age. Data extraction and analysis followed the standard methods of the Cochrane Neonatal Review Group. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Secondary outcomes included a Psychomotor Development Index <70, cerebral palsy, visual impairment, and hearing impairment. Four RCTs, comprising 1133 infants, were included in the meta-analysis. Prophylactic rhEPO administration reduced the incidence of children with an MDI <70, with an odds ratio (95% confidence interval) of 0.51 (0.31-0.81), P < .005. The number needed to treat was 14. There was no statistically significant effect on any secondary outcome. Prophylactic rhEPO improved the cognitive development of very preterm infants, as assessed by the MDI at a corrected age of 18 to 24 months, without affecting other neurodevelopmental outcomes. Current and future RCTs should investigate optimal dosing and timing of prophylactic rhEPO and plan for long-term neurodevelopmental follow-up.

Routine oro/nasopharyngeal suction versus no suction at birth.

Oro/nasopharyngeal suction is a method used to clear secretions from the oropharynx and nasopharynx through the application of negative pressure via a suction catheter or bulb syringe. Traditionally, airway oro/nasopharyngeal suction at birth has been used routinely to remove fluid rapidly from the oropharynx and nasopharynx in vigorous and non-vigorous infants at birth. Concerns relating to the reported adverse effects of oro/nasopharyngeal suctioning led to a practice review and routine oro/nasopharyngeal suctioning is no longer recommended for vigorous infants. However, it is important to know whether there is any clear benefit or harm for infants whose oro/nasopharyngeal airway is suctioned compared to infants who are not suctioned. To evaluate the effect of routine oropharyngeal/nasopharyngeal suction compared to no suction on mortality and morbidity in newly born infants. We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 3), MEDLINE via PubMed (1966 to April 18, 2016), Embase (1980 to April 18, 2016), and CINAHL (1982 to April 18, 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised, quasi-randomised controlled trials and cluster randomised trials that evaluated the effect of routine oropharyngeal/nasopharyngeal suction compared to no suction on mortality and morbidity in newly born infants with and without meconium-stained amniotic fluid. The review authors extracted from the reports of the clinical trials, data regarding clinical outcomes including mortality, need for resuscitation, admission to neonatal intensive care, five minute Apgar score, episodes of apnoea and length of hospital stay. Eight randomised controlled trials met the inclusion criteria and only included term infants (n = 4011). Five studies included infants with no fetal distress and clear amniotic fluid, one large study included vigorous infants with clear or meconium-stained amniotic fluid, and two large studies included infants with thin or thick meconium-stained amniotic fluid. Overall, there was no statistical difference between oro/nasopharyngeal suction and no oro/nasopharyngeal suction for all reported outcomes: mortality (typical RR 2.29, 95% CI 0.94 to 5.53; typical RD 0.01, 95% CI -0.00 to 0.01; I2 = 0%, studies = 2, participants = 3023), need for resuscitation (typical RR 0.85, 95% CI 0.69 to 1.06; typical RD -0.01, 95% CI -0.03 to 0.00; I2 = 0%, studies = 5, participants = 3791), admission to NICU (typical RR 0.82, 95% CI 0.62 to 1.08; typical RD -0.03, 95% CI -0.08 to 0.01; I2 = 27%, studies = 2, participants = 997) and Apgar scores at five minutes (MD -0.03, 95% CI -0.08 to 0.02; I2 not estimated, studies = 3, participants = 330). The currently available evidence does not support or refute the benefits or harms of routine oro/nasopharyngeal suction over no suction. Further high-quality studies are required in preterm infants or term newborn infants with thick meconium amniotic fluid. Studies should investigate long-term effects such as neurodevelopmental outcomes.

Infant pacifiers for reduction in risk of sudden infant death syndrome.

Sudden infant death syndrome (SIDS) has been most recently defined as the sudden unexpected death of an infant less than one year of age, with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation, including the performance of a complete autopsy and a review of the circumstances of death and clinical history. Despite the success of several prevention campaigns, SIDS remains a leading cause of infant mortality. In 1994, a 'triple risk model' for SIDS was proposed that described SIDS as an event that results from the intersection of three factors: a vulnerable infant; a critical development period in homeostatic control (age related); and an exogenous stressor. The association between pacifier (dummy) use and reduced incidence of SIDS has been shown in epidemiological studies since the early 1990s. Pacifier use, given its low cost, might be a cost-effective intervention for SIDS prevention if it is confirmed effective in randomised controlled trials. To determine whether the use of pacifiers during sleep versus no pacifier during sleep reduces the risk of SIDS. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2), MEDLINE via PubMed, Embase, and CINAHL to 16 March 2016. We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Published and unpublished controlled trials using random and quasi-random allocations of infants born at term and at preterm (less than 37 weeks' gestation) or with low birth weight (< 2500 g). Infants must have been randomised by one month' postmenstrual age. We planned to include studies reported only by abstracts, and cluster and cross-over randomised trials. Two review authors independently reviewed studies from searches. We found no eligible studies. We identified no randomised controlled trials examining infant pacifiers for reduction in risk of SIDS. We found no randomised control trial evidence on which to support or refute the use of pacifiers for the prevention of SIDS.

Infant formulas containing hydrolysed protein for prevention of allergic disease and food allergy.

Allergy is common and may be associated with foods, including cow's milk formula (CMF). Formulas containing hydrolysed proteins have been used to treat infants with allergy. However, it is unclear whether hydrolysed formulas can be advocated for prevention of allergy in infants. To compare effects on allergy and food allergy when infants are fed a hydrolysed formula versus CMF or human breast milk. If hydrolysed formulas are effective, to determine what type of hydrolysed formula is most effective, including extensively or partially hydrolysed formula (EHF/PHF). To determine which infants at low or high risk of allergy and which infants receiving early, short-term or prolonged formula feeding may benefit from hydrolysed formulas. We used the standard search strategy of the Cochrane Neonatal Review Group supplemented by cross referencing of previous reviews and publications (updated August 2016). We searched for randomised and quasi-randomised trials that compared use of a hydrolysed formula versus human milk or CMF. Trials with ≥ 80% follow-up of participants were eligible for inclusion. We independently assessed eligibility of studies for inclusion, methodological quality and data extraction. Primary outcomes included clinical allergy, specific allergy and food allergy. We conducted meta-analysis using a fixed-effect (FE) model. Two studies assessed the effect of three to four days' infant supplementation with an EHF whilst in hospital after birth versus pasteurised human milk feed. Results showed no difference in infant allergy or childhood cow's milk allergy (CMA). No eligible trials compared prolonged hydrolysed formula versus human milk feeding.Two studies assessed the effect of three to four days' infant supplementation with an EHF versus a CMF. One large quasi-random study reported a reduction in infant CMA of borderline significance among low-risk infants (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.38 to 1.00).Prolonged infant feeding with a hydrolysed formula compared with a CMF was associated with a reduction in infant allergy (eight studies, 2852 infants; FE RR 0.82, 95% CI 0.72 to 0.95; risk difference (RD) -0.04, 95% CI -0.08 to -0.01; number needed to treat for an additional beneficial outcome (NNTB) 25, 95% CI 12.5 to 100) and infant CMA (two studies, 405 infants; FE RR 0.38, 95% CI 0.16 to 0.86). We had substantial methodological concerns regarding studies and concerns regarding publication bias, as substantial numbers of studies including those in high-risk infants have not comprehensively reported allergy outcomes (GRADE quality of evidence 'very low').Prolonged infant feeding with a hydrolysed formula compared with a CMF was not associated with a difference in childhood allergy and led to no differences in specific allergy, including infant and childhood asthma, eczema and rhinitis and infant food allergy. Many of the analyses assessing specific allergy are underpowered.Subroup analyses showed that infant allergy was reduced in studies that enrolled infants at high risk of allergy who used a hydrolysed formula compared with a CMF; used a PHF compared with a CMF; used prolonged and exclusive feeding of a hydrolysed formula compared with a CMF; and used a partially hydrolysed whey formula compared with a CMF. Studies that enrolled infants at high risk of allergy; used a PHF compared with a CMF; used prolonged and exclusive feeding of a hydrolysed formula compared with a CMF; and used a partially hydrolysed whey formula compared with a CMF found a reduction in infant CMA. We found no evidence to support short-term or prolonged feeding with a hydrolysed formula compared with exclusive breast feeding for prevention of allergy. Very low-quality evidence indicates that short-term use of an EHF compared with a CMF may prevent infant CMA.In infants at high risk of allergy not exclusively breast fed, very low-quality evidence suggests that prolonged hydrolysed formula feeding compared with CMF feeding reduces infant allergy and infant CMA. Studies have found no difference in childhood allergy and no difference in specific allergy, including infant and childhood asthma, eczema and rhinitis and infant food allergy.Very low-quality evidence shows that prolonged use of a partially hydrolysed formula compared with a CMF for partial or exclusive feeding was associated with a reduction in infant allergy incidence and CMA incidence, and that prolonged use of an EHF versus a PHF reduces infant food allergy.

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

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. 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. 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. 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. 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. 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. 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.

Calcium and phosphorus supplementation of human milk for preterm infants.

Preterm infants are born with low skeletal stores of calcium and phosphorus. Preterm human milk provides insufficient calcium and phosphorus to meet the estimated needs of preterm infants for adequate growth. Supplementation of human milk with calcium and phosphorus may improve growth and development of preterm infants. To determine whether addition of calcium and phosphorus supplements to human milk leads to improved growth and bone metabolism of preterm infants without significant adverse effects. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3), MEDLINE via PubMed (1966 to 14 April 2016), Embase (1980 to 14 April 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 14 April 2016). We also searched clinical trials databases (11 May 2016) and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised and quasi-randomised trials comparing supplementation of human milk with calcium and/or phosphorus versus no supplementation in hospitalised preterm infants were eligible for inclusion in this review. Two review authors (JB, JW) independently extracted data and assessed trial quality using standard methods of the Cochrane Neonatal Review Group. We reported dichotomous data as risk ratios (RRs) and continuous data as mean differences (MDs) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. This is an update of a 2001 review that identified no eligible trials. One trial including 40 infants met the inclusion criteria for this review. Using GRADE criteria, we judged the quality of the evidence as low owing to risk of bias (inadequate reporting of methods of randomisation, allocation concealment and/or blinding) and imprecision (wide confidence intervals and data from a single small trial). We found no evidence of a difference between calcium and phosphorus supplementation versus no supplementation for neonatal growth outcomes (weight, length, head circumference) at any time point reported (two, four or six weeks postnatal age). At six weeks postnatal age, supplementation with calcium/phosphorus was associated with a decrease in serum alkaline phosphatase concentration (MD -56.85 IU/L, 95% CI -101.27 to -12.43; one randomised controlled trial (RCT); n = 40 infants). Investigators provided no data on growth at 12 to 18 months, neonatal fractures, feed intolerance, breastfeeding or any of the prespecified childhood outcomes for this review (fractures, growth, neurodevelopmental outcomes). We identified one small trial including only 40 infants that compared supplementation of human milk with calcium and phosphorus versus no supplementation in hospitalised preterm infants. We judged the evidence to be of low quality and found no evidence of differences between groups for clinically important outcomes including growth and fractures. Although serum alkaline phosphatase concentration was reduced in the group receiving supplementation at six weeks postnatal age, this difference is unlikely to be of clinical significance. We conclude that evidence is insufficient to determine whether benefit or harm ensues when human milk is supplemented with calcium and/or phosphorus for the hospitalised preterm infant. We see no advantage of conducting further trials of this intervention because with the advent of multi-component human milk fortifier, supplementation of human milk with calcium and/or phosphorus alone is no longer common practice. Future trials should consider assessing effects of multi-component fortifiers with different mineral compositions on clinically important outcomes during the neonatal period and in later childhood.

Neonatal vitamin A supplementation for the prevention of mortality and morbidity in term neonates in low and middle income countries.

Vitamin A deficiency is a major public health problem in low and middle income countries. Vitamin A supplementation in children six months of age and older has been found to be beneficial, but no effect of supplementation has been noted for children between one and five months of age. Supplementation during the neonatal period has been suggested to have an impact by increasing body stores in early infancy. To evaluate the role of vitamin A supplementation for term neonates in low and middle income countries with respect to prevention of mortality and morbidity. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE via PubMed (1966 to 13 March 2016), Embase (1980 to 13 March 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 13 March 2016). We also searched clinical trials databases, conference proceedings and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised and quasi-randomised controlled trials. Also trials with a factorial design. Two review authors independently assessed trial quality and extracted study data. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. We included 12 trials (168,460 neonates) in this review, with only a few trials reporting disaggregated data for term infants. Therefore, we analysed data and presented estimates for term infants (when specified) and for all infants.Data for term neonates from three studies did not show a statistically significant effect on the risk of infant mortality at six months in the vitamin A group compared with the control group (typical risk ratio (RR) 0.80; 95% confidence interval (CI) 0.54 to 1.18; I2 = 63%). Analysis of data for all infants from 11 studies revealed no evidence of a significant reduction in the risk of infant mortality at six months among neonates supplemented with vitamin A compared with control neonates (typical RR 0.98, 95% CI 0.89 to 1.07; I2 = 47%). We observed similar results for infant mortality at 12 months of age with no significant effect of vitamin A compared with control (typical RR 1.04, 95% CI 0.94 to 1.15; I2 = 47%). Limited data were available for the outcomes of cause-specific mortality and morbidity, vitamin A deficiency, anaemia and adverse events. Given the high burden of death among children younger than five years of age in low and middle income countries, and the fact that mortality in infancy is a major contributory cause, it is critical to obtain sound scientific evidence of the effect of vitamin A supplementation during the neonatal period on infant mortality and morbidity. Evidence provided in this review does not indicate a potential beneficial effect of vitamin A supplementation among neonates at birth in reducing mortality during the first six months or 12 months of life. Given this finding and the absence of a clear indication of the biological mechanism through which vitamin A could affect mortality, along with substantial conflicting findings from individual studies conducted in settings with potentially varying levels of maternal vitamin A deficiency and infant mortality, absence of follow-up studies assessing any long-term impact of a bulging fontanelle after supplementation and the finding of a potentially harmful effect among female infants, additional research is warranted before a decision can be reached regarding policy recommendations for this intervention.

Skin-to-skin care for procedural pain in neonates.

Skin-to-skin care for procedural pain in neonates.

Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants.

Cochrane systematic reviews show that systemic postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia (BPD) in preterm infants. However, corticosteroids have also been associated with an increased risk of neurodevelopmental impairment. It is unknown whether these beneficial and adverse effects are modulated by differences in corticosteroid treatment regimens. To assess the effects of different corticosteroid treatment regimens on mortality, pulmonary morbidity, and neurodevelopmental outcome in very low birth weight (VLBW) infants. We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 21 March 2016), MEDLINE via PubMed (1966 to 21 March 2016), Embase (1980 to 21 March 2016), and CINAHL (1982 to 21 March 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials. Randomized controlled trials (RCTs) comparing two or more different treatment regimens of systemic postnatal corticosteroids in preterm infants at risk for BPD, as defined by the original trialists. Studies investigating one treatment regimen of systemic corticosteroids to a placebo or studies using inhalation corticosteroids were excluded. Two authors independently assessed eligibility and quality of trials and extracted data on study design, participant characteristics and the relevant outcomes. We asked the original investigators to verify if data extraction was correct and, if possible, to provide any missing data. The primary outcomes to be assessed were: mortality at 36 weeks' postmenstrual age (PMA) or at hospital discharge; BPD defined as oxygen dependency at 36 weeks' PMA; long-term neurodevelopmental sequelae, including cerebral palsy, measured by the Bayley Mental Developmental Index (MDI); and blindness or poor vision. Secondary outcomes were: duration of mechanical ventilation and failure to extubate at day 3 and 7 after initiating therapy; rescue treatment with corticosteroids outside the study period; and the incidence of hypertension, sepsis and hyperglycemia during hospitalizations. Data were analyzed using Review Manager 5 (RevMan 5). We used the GRADE approach to assess the quality of evidence. Fourteen studies were included in this review. Only RCTs investigating dexamethasone were identified. Eight studies enrolling a total of 303 participants investigated the cumulative dosage administered; three studies contrasted a high versus a moderate and five studies a moderate versus a low cumulative dexamethasone dose.Analysis of the studies investigating a moderate dexamethasone dose versus a high-dosage regimen showed an increased risk of BPD (typical risk ratio (RR) 1.50, 95% confidence interval (CI) 1.01 to 2.22; typical risk difference (RD) 0.26, 95% CI 0.03 to 0.49; number needed to treat for an additional harmful outcome (NNTH) 4, 95% CI 1.9 to 23.3; I² = 0%, 2 studies, 55 infants) as well as an increased risk of abnormal neurodevelopmental outcome (typical RR 8.33, 95% CI 1.63 to 42.48; RD 0.30, 95% CI 0.14 to 0.46; NNTH 4, 95% CI 2.2 to 7.3; I² = 68%, 2 studies, 74 infants) when using a moderate cumulative-dosage regimen. The composite outcomes of death or BPD and death or abnormal neurodevelopmental outcome showed similar results although the former only reached borderline significance.There were no differences in outcomes between a moderate- and a low-dosage regimen.Four other studies enrolling 762 infants investigated early initiation of dexamethasone therapy versus a moderately early or delayed initiation and showed no significant differences in the primary outcomes. The two RCTs investigating a continuous versus a pulse dexamethasone regimen showed an increased risk of the combined outcome death or BPD when using the pulse therapy. Finally, two trials investigating a standard regimen versus a participant-individualized course of dexamethasone showed no difference in the primary outcome and long-term neurodevelopmental outcomes.The quality of evidence for all comparisons discussed above was assessed as low or very low, because the validity of all comparisons is hampered by small samples of randomized infants, heterogeneity in study population and design, non-protocolized use of 'rescue' corticosteroids and lack of long-term neurodevelopmental data in most studies. Despite the fact that some studies reported a modulating effect of treatment regimens in favor of higher-dosage regimens on the incidence of BPD and neurodevelopmental impairment, recommendations on the optimal type of corticosteroid, the optimal dosage, or the optimal timing of initiation for the prevention of BPD in preterm infants cannot be made based on current level of evidence. A well-designed large RCT is urgently needed to establish the optimal systemic postnatal corticosteroid dosage regimen.

Body positioning for spontaneously breathing preterm infants with apnoea

It has been proposed that body positioning in preterm infants, as compared with other, more invasive measures, may be an effective method of reducing clinically significant apnoea.To determine effects of body positioning on cardiorespiratory parameters in spontaneously breathing preterm infants with clinically significant apnoea.Subgroup analyses examined effects of body positioning of spontaneously breathing preterm infants with apnoea from the following subgroups.• Gestational age < 28 weeks or birth weight less than 1000 grams.• Apnoea managed with methylxanthines.• Frequent apnoea (> 10 events/d).• Type of apnoea measured (central vs mixed vs obstructive)We used the standard search strategy of the Cochrane Neonatal Review Group (CNRG) to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10), MEDLINE via PubMed (1966 to 14 November 2016), Embase (1980 to 14 November 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 2016 November 14). We also searched clinical trials databases and conference proceedings for randomised controlled trials and quasi-randomised trials.Randomised and quasi-randomised controlled clinical trials with parallel, factorial or cross-over design comparing the impact of different body positions on apnoea in spontaneously breathing preterm infants were eligible for our review.We assessed trial quality, data extraction and synthesis of data using standard methods of the CNRG. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence.The search conducted in November 2016 identified no new studies. Five studies (N = 114) were eligible for inclusion. None of the individual studies nor meta-analyses showed a reduction in apnoea, bradycardia, oxygen desaturation or oxygen saturation with body positioning (supine vs prone; prone vs right lateral; prone vs left lateral; right lateral vs left lateral; prone horizontal vs prone head elevated; right lateral horizontal vs right lateral head elevated, left lateral horizontal vs left lateral head elevated).We found insufficient evidence to determine effects of body positioning on apnoea, bradycardia and oxygen saturation in preterm infants. No new studies have been conducted since the original review was published. Large, multi-centre studies are warranted to provide conclusive evidence, but it may be plausible to conclude that positioning of spontaneously breathing preterm infants has no effect on their cardiorespiratory parameters.