Breastfeeding or breast milk for procedural pain in neonates.

BACKGROUND: Pain in the neonate is associated with acute behavioural and physiological changes. Cumulative pain is associated with morbidities, including adverse neurodevelopmental outcomes. Studies have shown a reduction in changes in physiological parameters and pain score measurements following pre-emptive analgesic administration in neonates experiencing pain or stress. Non-pharmacological measures (such as holding, swaddling and breastfeeding) and pharmacological measures (such as acetaminophen, sucrose and opioids) have been used for analgesia. This is an update of a review first published in 2006 and updated in 2012. OBJECTIVES: The primary objective was to evaluate the effectiveness of breastfeeding or supplemental breast milk in reducing procedural pain in neonates. The secondary objective was to conduct subgroup analyses based on the type of control intervention, gestational age and the amount of supplemental breast milk given. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL and trial registries (ICTRP, ISRCTN and clinicaltrials.gov) in August 2022; searches were limited from 2011 forwards. We checked the reference lists of included studies and relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs of breastfeeding or supplemental breast milk versus no treatment/other measures in neonates. We included both term (≥ 37 completed weeks postmenstrual age) and preterm infants (< 37 completed weeks' postmenstrual age) up to a maximum of 44 weeks' postmenstrual age. The study must have reported on either physiological markers of pain or validated pain scores. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of the trials using the information provided in the studies and by personal communication with the authors. We extracted data on relevant outcomes, estimated the effect size and reported this as a mean difference (MD). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Of the 66 included studies, 36 evaluated breastfeeding, 29 evaluated supplemental breast milk and one study compared them against each other. The procedures conducted in the studies were: heel lance (39), venipuncture (11), intramuscular vaccination (nine), eye examination for retinopathy of prematurity (four), suctioning (four) and adhesive tape removal as procedure (one). We noted marked heterogeneity in the control interventions and pain assessment measures amongst the studies. Since many studies included multiple arms with breastfeeding/supplemental breast milk as the main comparator, we were not able to synthesise all interventions together. Individual interventions are compared to breastfeeding/supplemental breast milk and reported. The numbers of studies/participants presented with the findings are not taken from pooled analyses (as is usual in Cochrane Reviews), but are the overall totals in each comparison. Overall, the included studies were at low risk of bias except for masking of intervention and outcome assessment, where nearly one-third of studies were at high risk of bias. Breastfeeding versus control Breastfeeding may reduce the increase in heart rate compared to holding by mother, skin-to-skin contact, bottle feeding mother's milk, moderate concentration of sucrose/glucose (20% to 33%) with skin-to-skin contact (low-certainty evidence, 8 studies, 784 participants). Breastfeeding likely reduces the duration of crying compared to no intervention, lying on table, rocking, heel warming, holding by mother, skin-to-skin contact, bottle feeding mother's milk and moderate concentration of glucose (moderate-certainty evidence, 16 studies, 1866 participants). Breastfeeding may reduce percentage time crying compared to holding by mother, skin-to-skin contact, bottle feeding mother's milk, moderate concentration sucrose and moderate concentration of sucrose with skin-to-skin contact (low-certainty evidence, 4 studies, 359 participants). Breastfeeding likely reduces the Neonatal Infant Pain Scale (NIPS) score compared to no intervention, holding by mother, heel warming, music, EMLA cream, moderate glucose concentration, swaddling, swaddling and holding (moderate-certainty evidence, 12 studies, 1432 participants). Breastfeeding may reduce the Neonatal Facial Coding System (NFCS) score compared to no intervention, holding, pacifier and moderate concentration of glucose (low-certainty evidence, 2 studies, 235 participants). Breastfeeding may reduce the Douleur Aigue Nouveau-né (DAN) score compared to positioning, holding or placebo (low-certainty evidence, 4 studies, 709 participants). In the majority of the other comparisons there was little or no difference between the breastfeeding and control group in any of the outcome measures. Supplemental breast milk versus control Supplemental breast milk may reduce the increase in heart rate compared to water or no intervention (low-certainty evidence, 5 studies, 336 participants). Supplemental breast milk likely reduces the duration of crying compared to positioning, massage or placebo (moderate-certainty evidence, 11 studies, 1283 participants). Supplemental breast milk results in little or no difference in percentage time crying compared to placebo or glycine (low-certainty evidence, 1 study, 70 participants). Supplemental breast milk results in little or no difference in NIPS score compared to no intervention, pacifier, moderate concentration of sucrose, eye drops, gentle touch and verbal comfort, and breast milk odour and verbal comfort (low-certainty evidence, 3 studies, 291 participants). Supplemental breast milk may reduce NFCS score compared to glycine (overall low-certainty evidence, 1 study, 40 participants). DAN scores were lower when compared to massage and water; no different when compared to no intervention, EMLA and moderate concentration of sucrose; and higher when compared to rocking or pacifier (low-certainty evidence, 2 studies, 224 participants). Due to the high number of comparator interventions, other measures of pain were assessed in a very small number of studies in both comparisons, rendering the evidence of low certainty. The majority of studies did not report on adverse events, considering the benign nature of the intervention. Those that reported on adverse events identified none in any participants. Subgroup analyses were not conducted due to the small number of studies. AUTHORS' CONCLUSIONS: Moderate-/low-certainty evidence suggests that breastfeeding or supplemental breast milk may reduce pain in neonates undergoing painful procedures compared to no intervention/positioning/holding or placebo or non-pharmacological interventions. Low-certainty evidence suggests that moderate concentration (20% to 33%) glucose/sucrose may lead to little or no difference in reducing pain compared to breastfeeding. The effectiveness of breast milk for painful procedures should be studied in the preterm population, as there are currently a limited number of studies that have assessed its effectiveness in this population.

Inhaled versus systemic corticosteroids for the treatment of bronchopulmonary dysplasia in ventilated very low birth weight preterm infants.

BACKGROUND: This is an update of a review published in 2012. A related review "Inhaled versus systemic corticosteroids for preventing bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates" has been updated as well. Bronchopulmonary dysplasia (BPD) is a serious and common problem among very low birth weight infants, despite the use of antenatal steroids and postnatal surfactant therapy to decrease the incidence and severity of respiratory distress syndrome. Due to their anti-inflammatory properties, corticosteroids have been widely used to treat or prevent BPD. However, the use of systemic steroids has been associated with serious short- and long-term adverse effects. Administration of corticosteroids topically through the respiratory tract may result in beneficial effects on the pulmonary system with fewer undesirable systemic side effects. OBJECTIVES: To compare the effectiveness of inhaled versus systemic corticosteroids administered to ventilator-dependent preterm neonates with birth weight ≤ 1500 g or gestational age ≤ 32 weeks after 7 days of life on the incidence of death or BPD at 36 weeks' postmenstrual age. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 1), MEDLINE via PubMed (1966 to 23 February 2017), Embase (1980 to 23 February 2017), and CINAHL (1982 to 23 February 2017). We also searched clinical trials registers, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing inhaled versus systemic corticosteroid therapy (irrespective of dose and duration) starting after the first week of life in ventilator-dependent very low birth weight infants. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. MAIN RESULTS: We included three trials that involved a total of 431 participants which compared inhaled versus systemic corticosteroids to treat BPD. No new trials were included for the 2017 update.Although one study randomised infants at < 72 hours (N = 292), treatment started when infants were aged > 15 days. In this larger study, deaths were included from the point of randomisation and before treatment started. Two studies (N = 139) randomised and started treatment at 12 to 21 days.Two trials reported non-significant differences between groups for the primary outcome: incidence of death or BPD at 36 weeks' postmenstrual age among all randomised infants. Estimates for the largest trial were Relative risk (RR) 1.04 (95% Confidence interval (CI) 0.86 to 1.26), Risk difference (RD) 0.03 (95% CI -0.09 to 0.15); (moderate-quality evidence). Estimates for the other trial reporting the primary outcome were RR 0.94 (95% CI 0.83 to 1.05), RD -0.06 (95% CI -0.17 to 0.05); (low-quality evidence).Secondary outcomes that included data from all three trials showed no significant differences in the duration of mechanical ventilation or supplemental oxygen, length of hospital stay, or the incidence of hyperglycaemia, hypertension, necrotising enterocolitis, gastrointestinal bleed, retinopathy of prematurity or culture-proven sepsis moderate- to low-quality evidence).In a subset of 75 surviving infants who were enrolled from the United Kingdom and Ireland, there were no significant differences in developmental outcomes at seven years of age between groups (moderate-quality evidence). One study received grant support and the industry provided aerochambers and metered dose inhalers of budesonide and placebo for the same study. No conflict of interest was identified. AUTHORS' CONCLUSIONS: We found no evidence that inhaled corticosteroids confer net advantages over systemic corticosteroids in the management of ventilator-dependent preterm infants. There was no evidence of difference in effectiveness or adverse event profiles for inhaled versus systemic steroids.A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing adverse events.To resolve this issue, studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for administration of these medications. The long-term effects of inhaled steroids, with particular attention to neurodevelopmental outcomes, should be addressed in future studies.

Inhaled versus systemic corticosteroids for preventing bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains an important cause of mortality and morbidity in preterm infants and inflammation plays a significant role in its pathogenesis. The use of inhaled corticosteroids may modulate the inflammatory process without concomitant high systemic steroid concentrations and less risk of adverse effects. This is an update of a review published in 2012 (Shah 2012). We recently updated the related review on "Inhaled versus systemic corticosteroids for treating bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates". OBJECTIVES: To determine the effect of inhaled versus systemic corticosteroids started within the first 7 days of life on preventing death or BPD in ventilated very low birth weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 1), MEDLINE via PubMed (1966 to 23 February 2017), Embase (1980 to 23 February 2017), and CINAHL (1982 to 23 February 2017). We searched clinical trials registers, conference proceedings and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing inhaled versus systemic corticosteroid therapy (irrespective of dose and duration) starting in the first seven days of life in very low birth weight preterm infants receiving assisted ventilation. DATA COLLECTION AND ANALYSIS: Clinical outcomes data were extracted and analysed using Review Manager. When appropriate, meta-analysis was performed using typical relative risk (RR), typical risk difference (RD) and weighted mean difference (WMD). Meta-analyses were performed using typical relative risk, typical risk difference (RD), and weighted mean difference with their 95% confidence intervals (CI). If RD was statistically significant, the number needed to benefit or the number needed to harm was calculated. We assessed the quality of evidence was evaluated using GRADE principles. MAIN RESULTS: We included two trials that involved 294 infants. No new studies were included for the 2017 update. The incidence of death or BPD at 36 weeks' postmenstrual age was not statistically significantly different between infants who received inhaled or systemic steroids (RR 1.09, 95% CI 0.88 to 1.35; RD 0.05, 95% CI -0.07 to 0.16; 1 trial, N = 278). The incidence of BPD at 36 weeks' postmenstrual age among survivors was not statistically significant between groups (RR 1.34, 95% CI 0.94 to 1.90; RD 0.11, 95% CI -0.02 to 0.24; 1 trial, N = 206). There was no statistically significant difference in the outcomes of BPD at 28 days, death at 28 days or 36 weeks' postmenstrual age and the combined outcome of death or BPD by 28 days between groups (2 trials, N = 294). The duration of mechanical ventilation was significantly longer in the inhaled steroid group compared with the systemic steroid group (typical MD 4 days, 95% CI 0.2 to 8; 2 trials, N = 294; I² = 0%) as was the duration of supplemental oxygen (typical MD 11 days, 95% CI 2 to 20; 2 trials, N = 294; I² = 33%).The incidence of hyperglycaemia was significantly lower with inhaled steroids (RR 0.52, 95% CI 0.39 to 0.71; RD -0.25, 95% CI -0.37 to -0.14; 1 trial, N = 278; NNTB 4, 95% CI 3 to 7 to avoid 1 infant experiencing hyperglycaemia). The rate of patent ductus arteriosus increased in the group receiving inhaled steroids (RR 1.64, 95% CI 1.23 to 2.17; RD 0.21, 95% CI 0.10 to 0.33; 1 trial, N = 278; NNTH 5, 95% CI 3 to 10). In a subset of surviving infants in the United Kingdom and Ireland there were no significant differences in developmental outcomes at 7 years of age. However, there was a reduced risk of having ever been diagnosed as asthmatic by 7 years of age in the inhaled steroid group compared with the systemic steroid group (N = 48) (RR 0.42, 95% CI 0.19 to 0.94; RD -0.31, 95% CI -0.58 to -0.05; NNTB 3, 95% CI 2 to 20).According to GRADE the quality of the evidence was moderate to low. Evidence was downgraded on the basis of design (risk of bias), consistency (heterogeneity) and precision of the estimates.Both studies received grant support and the industry provided aero chambers and metered dose inhalers of budesonide and placebo for the larger study. No conflict of interest was identified. AUTHORS' CONCLUSIONS: We found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator-dependent preterm infants. Based on this review inhaled steroids cannot be recommended over systemic steroids as a part of standard practice for ventilated preterm infants. Because they might have fewer adverse effects than systemic steroids, further randomised controlled trials of inhaled steroids are needed that address risk/benefit ratio of different delivery techniques, dosing schedules and long-term effects, with particular attention to neurodevelopmental outcome.

Early administration of inhaled corticosteroids for preventing chronic lung disease in very low birth weight preterm neonates.

BACKGROUND: Chronic lung disease (CLD) remains a common complication among preterm infants. There is increasing evidence that inflammation plays an important role in the pathogenesis of CLD. Due to their strong anti-inflammatory properties, corticosteroids are an attractive intervention strategy. However, there are growing concerns regarding short- and long-term effects of systemic corticosteroids. Theoretically, administration of inhaled corticosteroids may allow for beneficial effects on the pulmonary system with a lower risk of undesirable systemic side effects. OBJECTIVES: To determine the impact of inhaled corticosteroids administered to preterm infants with birth weight up to 1500 grams (VLBW) beginning in the first two weeks after birth for the prevention of CLD as reflected by the requirement for supplemental oxygen at 36 weeks' postmenstrual age (PMA). SEARCH METHODS: Randomised and quasi-randomised trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 12) in the Cochrane Library (searched 5 January 2016), MEDLINE (1966 to 5 January 2016), Embase (1980 to 5 January 2016), CINAHL (1982 to 5 January 2016), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web-site (1990 to May 2016). SELECTION CRITERIA: We included in this review randomised controlled trials of inhaled corticosteroid therapy initiated within the first two weeks of life in VLBW preterm infants. DATA COLLECTION AND ANALYSIS: We evaluated data regarding clinical outcomes, including: CLD at 28 days or 36 weeks' PMA; mortality; combined outcome of death or CLD at 28 days of age and at 36 weeks' PMA; the need for systemic corticosteroids; failure to extubate within 14 days; and adverse effects of corticosteroids. All data were analysed using Review Manager (RevMan) 5. Meta-analyses were performed using relative risk (RR) and risk difference (RD), along with their 95% confidence intervals (CI). If RD was significant, the number needed to treat for an additional beneficial outcome (NNTB) was calculated. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: According to GRADE the quality of the studies was moderate. Three additional trials are included in this update. The present review includes data analyses based on 10 qualifying trials that enrolled 1644 neonates. There was no significant difference in the incidence of CLD at 36 weeks' PMA in the inhaled steroid versus the placebo group (5 trials, 429 neonates) among all randomised (typical RR 0.97, 95% CI 0.62 to 1.52; typical RD -0.00, 95% CI -0.07 to 0.06). There was no heterogeneity for this outcome (typical RR I² = 11%; typical RD I² = 0%). There was a significant reduction in the incidence of CLD at 36 weeks' PMA among survivors (6 trials, 1088 neonates) (typical RR 0.76, 95% CI 0.63 to 0.93; typical RD -0.07, 95% CI -0.13 to -0.02; NNTB 14, 95% CI 8 to 50). There was a significant reduction in the combined outcome of death or CLD at 36 weeks' PMA among all randomised neonates (6 trials, 1285 neonates) (typical RR 0.86, 95% CI 0.75 to 0.99; typical RD -0.06, 95% CI -0.11 to -0.00) (P = 0.04); NNTB 17, 95% CI 9 to infinity). There was no significant heterogeneity for any of these analyses (I² = 0%). A lower rate of reintubation was noted in the inhaled steroid group compared with the control group in one study. There were no statistically significant differences in short-term complications between groups and no differences in adverse events at long-term follow-up reported. Long-term follow-up of infants enrolled in the study by Bassler 2015 is ongoing. AUTHORS' CONCLUSIONS: Based on this updated review, there is increasing evidence from the trials reviewed that early administration of inhaled steroids to VLBW neonates is effective in reducing the incidence of death or CLD at 36 weeks' PMA among either all randomised infants or among survivors. Even though there is statistical significance, the clinical relevance is of question as the upper CI limit for the outcome of death or CLD at 36 weeks' PMA is infinity. The long-term follow-up results of the Bassler 2015 study may affect the conclusions of this review. Further studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both the short- and long-term benefits and adverse effects of inhaled steroids with particular attention to neurodevelopmental outcome.

Arginine supplementation for prevention of necrotising enterocolitis in preterm infants.

BACKGROUND: Decreased concentration of nitric oxide has been proposed as one of the possible cellular mechanisms of necrotising enterocolitis (NEC). Arginine can act as a substrate for production of nitric oxide in the tissues, and arginine supplementation may help to prevent NEC. OBJECTIVES: To examine the effect of arginine supplementation (administered by any route) on the incidence of NEC in preterm neonates. To conduct subgroup analyses based on the dose of arginine and the gestational age of participants (≤ 32 weeks, > 32 weeks). 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 4), MEDLINE via PubMed (from 1966 to 12 May 2016), Embase (from 1980 to 12 May 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; from 1982 to 12 May 2016). We also searched clinical trials databases, conference proceedings and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of arginine supplementation (administered orally or parenterally for at least seven days, in addition to what an infant may be receiving from an enteral or parenteral source) compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of trials by using information obtained from study reports and through personal communication with study authors. We extracted data on relevant outcomes and estimated and reported the effect size as risk ratio (RR), risk difference (RD) and mean difference (MD), as appropriate. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. MAIN RESULTS: We identified three eligible studies that included a total of 285 neonates (140 received arginine) from three countries. We assessed the overall methodological quality of the included studies as good. We noted a statistically significant reduction in risk of development of NEC (any stage) among preterm neonates in the arginine group compared with the placebo group (RR 0.38, 95% confidence interval (CI) 0.23 to 0.64; I2 = 27%) (RD -0.19, 95% CI -0.28 to -0.10; I2 = 0%) and rated the quality of evidence as moderate. The number needed to treat for an additional beneficial outcome (NNTB) as required to prevent the development of NEC (any stage) was 6 (95% CI 4 to 10). Study results showed a statistically significant reduction in risk of development of NEC stage 1 (RR 0.37, 95% CI 0.15 to 0.90; I2 = 52%) (RD -0.07, 95% CI -0.14 to -0.01; I2 = 0%) and NEC stage 3 (RR 0.13, 95% CI 0.02 to 1.03; I2 = 0%) (RD -0.05, 95% CI -0.09 to -0.01; I2 = 89%) in the arginine group compared with the control group; the quality of evidence was moderate.Arginine supplementation was associated with a significant reduction in death related to NEC (RR 0.18, 95% CI 0.03 to 1.00; I2 = 0%) (RD -0.05, 95% CI -0.09 to -0.01; I2 = 87%). Results showed clinical heterogeneity in mortality rates. Mortality due to any cause was not significantly different between arginine and control or no treatment groups (RR 0.77, 95% CI 0.41 to 1.45; I2 = 42%) (RD -0.03, 95% CI -0.10 to 0.04; I2 = 79%). Investigators noted no significant side effects directly attributable to arginine, including hypotension or alterations in glucose homeostasis. Follow-up data from one trial revealed no statistically significant differences in adverse outcomes (cerebral palsy, cognitive delay, bilateral blindness or hearing loss requiring hearing aids) at 36 months. Limitations of the present findings include a relatively small overall sample size. AUTHORS' CONCLUSIONS: Administration of arginine to preterm infants may prevent development of NEC. Because information was provided by three small trials that included 285 participants, the data are insufficient at present to support a practice recommendation. A multi-centre randomised controlled study that is focused on the incidence of NEC, particularly at more severe stages (2 and 3), is needed.

Breastfeeding for procedural pain in infants beyond the neonatal period.

BACKGROUND: Randomised controlled trials (RCTs) show that breastfeeding newborn infants during painful procedures reduces pain. Mechanisms are considered to be multifactorial and include sucking, skin-to-skin contact, warmth, rocking, sound and smell of the mother, and possibly endogenous opiates present in the breast milk. OBJECTIVES: To determine the effect of breastfeeding on procedural pain in infants beyond the neonatal period (first 28 days of life) up to one year of age compared to no intervention, placebo, parental holding, skin-to-skin contact, expressed breast milk, formula milk, bottle feeding, sweet-tasting solutions (e.g. sucrose or glucose), distraction, or other interventions. SEARCH METHODS: We searched the following databases to 18 February 2016: the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library), MEDLINE including In-Process & Other Non-Indexed Citations (OVID), Embase (OVID), PsycINFO (OVID), and CINAHL (EBSCO); the metaRegister of Controlled Trials (mRCT), ClinicalTrials.gov (clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (apps.who.int/trialsearch/) for ongoing trials. SELECTION CRITERIA: We included RCTs and quasi-RCTs involving infants aged 28 days postnatal to 12 months and receiving breastfeeding while undergoing a painful procedure. Comparators included, but were not limited to, oral administration of water, sweet-tasting solutions, expressed breast or formula milk, no intervention, use of pacifiers, positioning, cuddling, distraction, topical anaesthetics, and skin-to-skin care. Procedures included, but were not limited to: subcutaneous or intramuscular injection, venipuncture, intravenous line insertion, heel lance, and finger lance. We applied no language restrictions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. The main outcome measures were behavioural or physiological indicators and composite pain scores, as well as other clinically important outcomes reported by the authors of included studies. We pooled data for the most comparable outcomes and where data from at least two studies could be included. We used mean difference (MD) with 95% confidence interval (CI), employing a random-effects model for continuous outcomes measured on the same scales. For continuous outcomes measured on different scales, we pooled standardised mean differences (SMDs) and associated 95% CIs. For dichotomous outcomes, we planned to pool events between groups across studies using risk ratios (RRs) and 95% CIs. However, as insufficient studies reported dichotomous outcomes, we did not pool such events. We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included 10 studies with a total of 1066 infants. All studies were conducted during early childhood immunisation. As the breastfeeding intervention cannot be blinded, we rated all studies as being at high risk of bias for blinding of participants and personnel. We assessed nine studies as being at low risk of bias for incomplete outcome data. In addition, we rated nine studies as high risk for blinding of outcome assessment. We scored risk of bias related to random sequence generation, allocation concealment, and selective reporting as unclear for the majority of the studies due to lack of information.Our primary outcome was pain. Breastfeeding reduced behavioural pain responses (cry time and pain scores) during vaccination compared to no treatment, oral water, and other interventions such as cuddling, oral glucose, topical anaesthetic, massage, and vapocoolant. Breastfeeding did not consistently reduce changes in physiological indicators, such as heart rate. We pooled data for duration of cry from six studies (n = 547 infants). Breastfeeding compared to water or no treatment resulted in a 38-second reduction in cry time (MD -38, 95% CI -50 to -26; P < 0.00001). The quality of the evidence according to GRADE for this outcome was moderate, as most infants were 6 months or younger, and outcomes may be different for infants during their 12-month immunisation. We pooled data for pain scores from five studies (n = 310 infants). Breastfeeding was associated with a 1.7-point reduction in standardised pain scores (SMD -1.7, 95% CI -2.2 to -1.3); we considered this evidence to be of moderate quality as data were primarily from infants younger than 6 months of age. We could pool heart rate data following injections for only two studies (n = 186); we considered this evidence to be of low quality due to insufficient data. There were no differences between breastfeeding and control (MD -3.6, -23 to 16).Four of the 10 studies had more than two study arms. Breastfeeding was more effective in reducing crying duration or pain scores during vaccination compared to: 25% dextrose and topical anaesthetic cream (EMLA), vapocoolant, maternal cuddling, and massage.No included studies reported adverse events. AUTHORS' CONCLUSIONS: We conclude, based on the 10 studies included in this review, that breastfeeding may help reduce pain during vaccination for infants beyond the neonatal period. Breastfeeding consistently reduced behavioural responses of cry duration and composite pain scores during and following vaccinations. However, there was no evidence that breastfeeding had an effect on physiological responses. No studies included in this review involved populations of hospitalised infants undergoing other skin-breaking procedures. Although it may be possible to extrapolate the review results to this population, further studies of efficacy, feasibility, and acceptability in this population are warranted.

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

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

Intrapartum antibiotics for known maternal Group B streptococcal colonization.

BACKGROUND: Maternal colonization with group B streptococcus (GBS) during pregnancy increases the risk of neonatal infection by vertical transmission. Administration of intrapartum antibiotic prophylaxis (IAP) during labor has been associated with a reduction in early onset GBS disease (EOGBSD). However, treating all colonized women during labor exposes a large number of women and infants to possible adverse effects without benefit. OBJECTIVES: To assess the effect of intrapartum antibiotics for maternal Group B haemolytic streptococci (GBS) colonization on mortality from any cause, from GBS infection and from organisms other than GBS. SEARCH METHODS: We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 11 March 2014. SELECTION CRITERIA: Randomized trials assessing the impact of maternal IAP on neonatal GBS infections were included. DATA COLLECTION AND ANALYSIS: We independently assessed eligibility and quality of the studies. MAIN RESULTS: We did not identify any new trials from the updated search so the results remain unchanged as follows.We included four trials involving 852 women.Three trials (involving 500 women) evaluating the effects of IAP versus no treatment were included. The use of IAP did not significantly reduce the incidence of all cause mortality, mortality from GBS infection or from infections caused by bacteria other than GBS. The incidence of early GBS infection was reduced with IAP compared to no treatment (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.04 to 0.74, three trials, 488 infants; risk difference -0.04, 95% CI -0.07 to -0.01; number needed to treat to benefit 25, 95% CI 14 to 100, I² 0%). The incidence of LOD or sepsis from organisms other than GBS and puerperal infection was not significantly different between groups.One trial (involving 352 women) compared intrapartum ampicillin versus penicillin and reported no significant difference in neonatal or maternal outcomes.We found a high risk of bias for one or more key domains in the study methodology and execution. AUTHORS' CONCLUSIONS: Intrapartum antibiotic prophylaxis appeared to reduce EOGBSD, but this result may well be due to bias as we found a high risk of bias for one or more key domains in the study methodology and execution. There is lack of evidence from well designed and conducted trials to recommend IAP to reduce neonatal EOGBSD.Ideally the effectiveness of IAP to reduce neonatal GBS infections should be studied in adequately sized double-blind controlled trials. The opportunity to conduct such trials has likely been lost, as practice guidelines (albeit without good evidence) have been introduced in many jurisdictions.

Vaginal chlorhexidine during labour to prevent early-onset neonatal group B streptococcal infection.

BACKGROUND: Although early-onset group B ß-hemolytic streptococcus (GBS) infection is rare, it accounts for approximately 30% of neonatal infections, has a high mortality rate, and is acquired through vertical transmission from colonized mothers. Several trials have demonstrated the efficacy of intrapartum antibiotic prophylaxis (IAP) for preventing early-onset disease (EOD). Vaginal disinfection with chlorhexidine during labour has been proposed as another strategy for preventing GBS EOD in the preterm and term neonate. Chlorhexidine has been found to have no impact on antibiotic resistance, is inexpensive, and applicable to poorly equipped delivery sites. OBJECTIVES: To determine the effectiveness of vaginal disinfection with chlorhexidine during labour in women who are colonized with GBS for preventing early-onset GBS infection in preterm and term neonates. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2014) and reference lists of retrieved studies. SELECTION CRITERIA: Randomized and quasi-randomized trials comparing vaginal disinfection with chlorhexidine (vaginal wash or gel/cream) versus placebo, or no treatment. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the trials for inclusion and risk of bias, extracted the data and checked them for accuracy. MAIN RESULTS: We identified no new trials eligible for inclusion in this update. One study was moved from included to excluded studies from the previous version of the review. Four studies, including 1125 preterm and term infants, met the inclusion criteria and reported on at least one of the outcomes of interest. For the comparison chlorhexidine (vaginal wash or gel) versus placebo or no treatment, two studies (n = 987) were pooled. There was no statistically significant difference in early-onset GBS disease (sepsis and/or meningitis) comparing chlorhexidine (vaginal wash or gel/cream) versus placebo or no treatment; risk ratio (RR), 2.32 (95% confidence interval (CI) 0.34 to 15.63); I-squared (I²) = 0% or in GBS pneumonia; RR 0.35 (95% CI 0.01 to 8.6); test for heterogeneity not applicable. The outcome of colonization of the neonate with GBS was reported in three studies (n = 328); RR 0.64 (95% CI 0.40 to 1.01; there was substantial between-study heterogeneity (Chi² = 3.19; P = 0.20; I² = 37%). Maternal mild side effects (stinging or local irritation) (three trials, 1066 women) were more commonly seen in women treated with chlorhexidine (RR 8.50 (95% CI 1.60 to 45.28); there was no heterogeneity (Chi² = 0.01, df = 1 (P = 0.91); I² = 0%). No side effects were reported among the neonates.For the comparison chlorhexidine vaginal wash verus mechanical washing with placebo or no treatment (one study, n = 79), there was a significant reduction in neonatal colonization with GBS; RR 0.32 (95% CI 0.12 to 0.90). Tests for heterogeneity not applicable. There were no other significant results for this comparison.For the comparison chlorhexidine gel or cream versus placebo or no treatment, there were no statistically significant results for the outcomes reported on.The quality of the trials varied and the overall risk of bias was rated as unclear or high. The quality of the evidence using GRADE was very low for the outcomes of the comparison chlorhexidine (vaginal wash or gel/cream) versus placebo or no treatment. These outcomes included: early-onset GBS disease (sepsis and/or meningitis), GBS pneumonia, neonatal colonization with GBS, neonatal mortality due to early-onset GBS infection and adverse (mild) effects in the mother and the neonate. AUTHORS' CONCLUSIONS: The quality of the four included trials varied as did the risk of bias and the quality of the evidence using GRADE was very low. Vaginal chlorhexidine was not associated with reductions in any of the primary outcomes of early-onset GBS disease (sepsis and/or meningitis) or GBS pneumonia. Vaginal chlorhexidine may reduce GBS colonization of neonates. The intervention was associated with an increased risk of maternal mild adverse effects. The review currently does not support the use of vaginal disinfection with chlorhexidine in labour for preventing early-onset disease. Results should be interpreted with caution as the methodological quality of the studies was poor. As early-onset GBS disease is a rare condition trials with very large sample sizes are needed to assess the effectiveness of vaginal chlorhexidine to reduce its occurrence. In the era of intrapartum antibiotic prophylaxis, such trials may be difficult to justify especially in developed countries.

Intrapartum antibiotics for known maternal Group B streptococcal colonization.

BACKGROUND: Maternal colonization with group B streptococcus (GBS) during pregnancy increases the risk of neonatal infection by vertical transmission. Administration of intrapartum antibiotic prophylaxis (IAP) during labor has been associated with a reduction in early onset GBS disease (EOGBSD). However, treating all colonized women during labor exposes a large number of women and infants to possible adverse effects without benefit. OBJECTIVES: To assess the effect of IAP for maternal GBS colonization on neonatal: 1) all cause mortality and 2) morbidity from proven and probable EOGBSD, late onset GBS disease (LOD), maternal infectious outcomes and allergic reactions to antibiotics. SEARCH METHODS: We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 10 November 2012. SELECTION CRITERIA: Randomized trials assessing the impact of maternal IAP on neonatal GBS infections were included. DATA COLLECTION AND ANALYSIS: We independently assessed eligibility and quality of the studies. MAIN RESULTS: We did not identify any new trials from the updated search so the results remain unchanged as follows.Three trials (involving 852 women) evaluating the effects of IAP versus no treatment were included. The risk of bias was high. The use of IAP did not significantly reduce the incidence of all cause mortality, mortality from GBS infection or from infections caused by bacteria other than GBS. The incidence of early GBS infection was reduced with IAP compared to no treatment (risk ratio 0.17, 95% confidence interval (CI) 0.04 to 0.74, three trials, 488 infants; risk difference -0.04, 95% CI -0.07 to -0.01; number needed to treat to benefit 25, 95% CI 14 to 100, I(2) 0%). The incidence of LOD or sepsis from organisms other than GBS and puerperal infection was not significantly different between groups.One trial (involving 352 women) compared intrapartum ampicillin versus penicillin and reported no significant difference in neonatal or maternal outcomes. AUTHORS' CONCLUSIONS: Intrapartum antibiotic prophylaxis appeared to reduce EOGBSD, but this result may well be a result of bias as we found a high risk of bias for one or more key domains in the study methodology and execution. There is lack of evidence from well designed and conducted trials to recommend IAP to reduce neonatal EOGBSD.Ideally the effectiveness of IAP to reduce neonatal GBS infections should be studied in adequately sized double-blind controlled trials. The opportunity to conduct such trials has likely been lost, as practice guidelines (albeit without good evidence) have been introduced in many jurisdictions.

Intraventricular antibiotics for bacterial meningitis in neonates.

BACKGROUND: Neonatal meningitis may be caused by bacteria, especially gram-negative bacteria, which are difficult to eradicate from the cerebrospinal fluid (CSF) using safe doses of antibiotics. In theory, intraventricular administration of antibiotics would produce higher antibiotic concentrations in the CSF than intravenous administration alone, and eliminate the bacteria more quickly. However, ventricular taps may cause harm. OBJECTIVES: To assess the effectiveness and safety of intraventricular antibiotics (with or without intravenous antibiotics) in neonates with meningitis (with or without ventriculitis) as compared to treatment with intravenous antibiotics alone. SEARCH METHODS: The Cochrane Library, Issue 2, 2007; MEDLINE; EMBASE; CINAHL and Science Citation Index were searched in June 2007. The Oxford Database of Perinatal Trials was searched in June 2004. Pediatric Research (abstracts of proceedings) were searched (1990 to April 2007) as were reference lists of identified trials and personal files. No language restrictions were applied.This search was updated in May 2011. SELECTION CRITERIA: Selection criteria for study inclusion were: randomised or quasi-randomised controlled trials in which intraventricular antibiotics with or without intravenous antibiotics were compared with intravenous antibiotics alone in neonates (< 28 days old) with meningitis. One of the following outcomes was required to be reported: mortality during initial hospitalisation; neonatal or infant mortality, or both; neurodevelopmental outcome; duration of hospitalisation; duration of culture positivity of CSF and side effects. DATA COLLECTION AND ANALYSIS: All review authors abstracted information for outcomes reported and one review author checked for discrepancies and entered data into RevMan 5.1. Risk ratio (RR), risk difference (RD), number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH), and mean difference (MD), using the fixed-effect model are reported with 95% confidence intervals (CI). MAIN RESULTS: The updated search in June 2011 did not identify any new trials. One study is included in the review. This study assessed the effect of intraventricular gentamicin in a mixed population of neonates (69%) and older infants (31%) with gram-negative meningitis and ventriculitis. Mortality was statistically significantly higher in the group that received intraventricular gentamicin in addition to intravenous antibiotics compared to the group receiving intravenous antibiotics alone (RR 3.43; 95% CI 1.09 to 10.74; RD 0.30; 95% CI 0.08 to 0.53); NNTH 3; 95% CI 2 to 13). Duration of CSF culture positivity did not differ significantly (MD -1.20 days; 95% CI -2.67 to 0.27). AUTHORS' CONCLUSIONS: In one trial that enrolled infants with gram-negative meningitis and ventriculitis, the use of intraventricular antibiotics in addition to intravenous antibiotics resulted in a three-fold increased RR for mortality compared to standard treatment with intravenous antibiotics alone. Based on this result, intraventricular antibiotics as tested in this trial should be avoided. Further trials comparing these interventions are not justified in this population.

Breastfeeding or breast milk for procedural pain in neonates.

BACKGROUND: Physiological changes brought about by pain may contribute to the development of morbidity in neonates. Clinical studies have shown reduction in changes in physiological parameters and pain score measurements following pre-emptive analgesic administration in situations where the neonate is experiencing pain or stress. Non-pharmacological measures (such as holding, swaddling and breastfeeding) and pharmacological measures (such as acetaminophen, sucrose and opioids) have been used for this purpose. OBJECTIVES: The primary objective was to evaluate the effectiveness of breastfeeding or supplemental breast milk in reducing procedural pain in neonates. The secondary objective was to conduct subgroup analyses based on the type of control intervention, gestational age and the amount of supplemental breast milk given. SEARCH METHODS: We performed a literature search using the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 10), MEDLINE (1966 to February 2011), EMBASE (1980 to February 2011), CINAHL (1982 to February 2011), abstracts from the annual meetings of the Society for Pediatric Research (1994 to 2011), and major paediatric pain conference proceedings. We did not apply any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs of breastfeeding or supplemental breast milk versus no treatment/other measures in neonates were eligible for inclusion in this review. The study must have reported on either physiologic markers of pain or validated pain scores. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of the trials using the information provided in the studies and by personal communication with the authors. We extracted data on relevant outcomes, estimated the effect size and reported this as a risk ratio (RR), risk difference (RD) and weighted mean difference (MD) as appropriate. MAIN RESULTS: Of twenty eligible studies, ten evaluated breastfeeding and ten evaluated supplemental breast milk. Sixteen studies analysed used heel lance and four used venepuncture as procedure. We noted marked heterogeneity in control intervention and pain assessment measures among the studies. Neonates in the breastfeeding group had statistically a significantly lower increase in heart rate, reduced proportion of crying time and reduced duration of first cry and total crying time compared to positioning (swaddled and placed in a crib), holding by mother, placebo, pacifier use, no intervention or oral sucrose group, or both.Premature Infant Pain Profile (PIPP) scores were significantly lower in the breastfeeding group compared to positioning, placebo or oral sucrose group, or both. However, there was no statistically significant difference in PIPP scores when compared to no intervention. Douleur Aigue Nouveau-ne scores (DAN) were significantly lower in the breastfeeding group compared to the placebo group and the group held in mother's arms, but not when compared to the glucose group. Neonatal Infant Pain Scale (NIPS) was significantly lower in the breastfeeding group compared to the no intervention group, but there was no difference when compared to the oral sucrose group. The Neonatal Facial Coding System (NFCS) was significantly lower in the breastfeeding group when compared to oral glucose, pacifier use, holding by mother and no intervention, but no difference was found when compared to formula feeding.Supplemental breast milk yielded variable results. Neonates in the supplemental breast milk group had a significantly lower increase in heart rate, a reduction in duration of crying and a lower NFCS compared to the placebo group. Neonates in the supplemental breast milk group had a significantly higher increase in heart rate changes when compared to the sucrose group. Sucrose (in any concentration, i.e. 12.5%, 20%, 25%) was found to reduce the duration of cry when compared to breast milk, as did glycine, pacifier use, rocking, or no intervention. Breast milk was found not to be effective in reducing validated and non-validated pain scores such as NIPS, NFCS, and DAN; only being significantly better when compared to placebo (water) or massage. We did not identify any study that has evaluated safety/effectiveness of repeated administration of breastfeeding or supplemental breast milk for pain relief. AUTHORS' CONCLUSIONS: If available, breastfeeding or breast milk should be used to alleviate procedural pain in neonates undergoing a single painful procedure rather than placebo, positioning or no intervention. Administration of glucose/sucrose had similar effectiveness as breastfeeding for reducing pain. The effectiveness of breast milk for painful procedure should be studied in the preterm population, as there are currently a limited number of studies in the literature that have assessed it's effectiveness in this population.

Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates.

BACKGROUND: Chronic lung disease remains a common complication among preterm infants. There is increasing evidence that inflammation plays an important role in the pathogenesis of CLD. Due to their strong anti-inflammatory properties, corticosteroids are an attractive intervention strategy. However, there are growing concerns regarding short and long-term effects of systemic corticosteroids. Theoretically, administration of inhaled corticosteroids may allow for beneficial effects on the pulmonary system with a lower risk of undesirable systemic side effects. OBJECTIVES: To determine the impact of inhaled corticosteroids administered to ventilated very low birth weight preterm neonates in the first two weeks of life for the prevention of chronic lung disease (CLD). SEARCH METHODS: Randomised and quasi-randomised trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1966 to July 2007), EMBASE (1980 to July 2007), CINAHL (1982 to July 2007), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web-site (1990 to April 2007).This search was updated in 2011. SELECTION CRITERIA: Randomised controlled trials of inhaled corticosteroid therapy initiated within the first two weeks of life in ventilated preterm infants with birth weight <1500 grams were included in this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including chronic lung disease at 28 days or 36 weeks postmenstrual age (PMA), mortality, combined outcome of death or CLD at 28 days of age and at 36 weeks PMA, the need for systemic corticosteroids, failure to extubate within 14 days and adverse effects of corticosteroids were evaluated. All data were analysed using RevMan 4.2.10. When possible, meta-analysis was performed using relative risk (RR), risk difference (RD), along with their 95% confidence intervals (CI). If RD was significant, the number needed to treat (NNT) was calculated. MAIN RESULTS: One ongoing trial was identified for inclusion in this update. Eleven trials assessing the impact of inhaled corticosteroid for the prevention of CLD were identified. Four trials were excluded. The present review includes data analyses based on seven qualifying trials. There was no statistically significant effect of inhaled steroids on CLD either at 28 days [typical RR 1.05 (95% CI 0.84 to 1.32); typical RD 0.02 (95% CO -0.07 to 0.11)] or at 36 weeks PMA [typical RR 0.97 (95% CI 0.62 to 1.52); typical RD 0.00 (95% CI -0.07, 0.06)], when analysed either for all randomised infants or among survivors. No statistically significant differences were noted for mortality or for the combined outcome of mortality and CLD either at 28 days of age or at 36 weeks PMA. There were no statistically significant differences in adverse events between groups. AUTHORS' CONCLUSIONS: Based on this updated review, there is no evidence from the trials reviewed that early administration (in the first two weeks of life) of inhaled steroids to ventilated preterm neonates was effective in reducing the incidence of CLD. Currently, use of inhaled steroids in this population cannot be recommended. Studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both the short-term and long-term benefits and adverse effects of inhaled steroids with particular attention to neurodevelopmental outcome.

Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants.

BACKGROUND: Chronic lung disease (CLD) remains a serious and common problem among very low birth weight (VLBW) infants despite the use of antenatal steroids and postnatal surfactant therapy to decrease the incidence and severity of respiratory distress syndrome. Due to their anti-inflammatory properties, corticosteroids have been widely used to treat or prevent CLD. However, the use of systemic steroids has been associated with serious short and long-term adverse effects. Administration of corticosteroids topically through the respiratory tract might result in beneficial effects on the pulmonary system with fewer undesirable systemic side effects. OBJECTIVES: To determine the effect of inhaled versus systemic corticosteroids administered to ventilator dependent preterm neonates with birth weight < 1500 g or gestational age < 32 weeks after two weeks of life for the treatment of evolving CLD. SEARCH METHODS: Randomised and quasi-randomised trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1966 to June 2007), EMBASE (1980 to June 2007), CINAHL (1982 to June 2007), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web site (1990 to April 2007). This search was updated in June 2011 and included additional searches of Clinicaltrials.gov, Controlled-trials.com and Web of Science. SELECTION CRITERIA: Randomised or quasi-randomised trials comparing inhaled versus systemic corticosteroid therapy (irrespective of the dose and duration of therapy) starting after the first two weeks of life in ventilator dependent VLBW infants. DATA COLLECTION AND ANALYSIS: Data were extracted regarding clinical outcomes and were analysed using Review Manager. When appropriate, meta-analysis was performed using relative risk (RR), risk difference (RD), and weighted mean difference (WMD) along with their 95% confidence intervals (CI). If RD was statistically significant, the number needed to benefit (NNTB) or the number needed to harm (NNTH) was calculated. MAIN RESULTS: Five trials comparing inhaled versus systemic corticosteroids in the treatment of CLD were identified. Two trials were excluded as both included non-ventilator dependent patients and three trials qualified for inclusion in this review. No new trials were identified in the 2011 update.Halliday et al (Halliday 2001) randomised infants at < 72 hours (n = 292), while Rozycki et al (Rozycki 2003) and Suchomski et al (Suchomski 2002) randomised at 12 to 21 days. The data from the two trials of Rozycki et al and Suchmoski et al are combined using meta-analytic techniques. The data from the trial by Halliday et al are reported separately, as outcomes were measured over different time periods from the age at randomisation.In none of the trials was there a statistically significant difference between the groups in the incidence of CLD at 36 weeks PMA among all randomised infants. The estimates for the trial by Halliday et al (Halliday 2001) were RR 1.10 (95% CI 0.82 to 1.47), RD 0.03 (95% CI -0.08 to 0.15).For the trials by Rozycki et al (Rozycki 2003) and Suchomski et al (Suchomski 2002) the typical RR was 1.02 (95% CI 0.83 to 1.25) and the typical RD 0.01 (95% CI -0.11 to 0.14); (number of infants = 139 ). There were no statistically significant differences between the groups in either trial for oxygen dependency at 28 days of age, death by 28 days or 36 weeks PMA, the combined outcome of death by or CLD at 28 days or 36 weeks PMA, duration of intubation, duration of oxygen dependence, or adverse effects. Information on the long-term neurodevelopmental outcomes was not available. AUTHORS' CONCLUSIONS: This review found no evidence that inhaled corticosteroids confer net advantages over systemic corticosteroids in the management of ventilator dependent preterm infants. Neither inhaled steroids nor systemic steroids can be recommended as standard treatment for ventilated preterm infants. There was no evidence of difference in effectiveness or side-effect profiles for inhaled versus systemic steroids. A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing side-effects. To resolve this issue, studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. The long-term effects of inhaled steroids, with particular attention to neurodevelopmental outcome, should be addressed in future studies.

Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates.

BACKGROUND: Chronic lung disease (CLD) remains an important cause of mortality and morbidity in preterm infants and inflammation plays an important role in its pathogenesis. The use of inhaled corticosteroids may modulate the inflammatory process without concomitant high systemic steroid concentrations and less risk of adverse effects. OBJECTIVES: To determine the effect of inhaled versus systemic corticosteroids started within the first two weeks of life on preventing CLD in ventilated very low birth weight (VLBW) infants. SEARCH METHODS: Randomised and quasi-randomised trials were identified by searching The Cochrane Library, MEDLINE , EMBASE , CINAHL, reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web site in June 2007.This search was updated in June 2011 and included additional searches of Clinicaltrials.gov, Controlled-trials.com and Web of Science. SELECTION CRITERIA: Randomised or quasi-randomised clinical trials comparing inhaled versus systemic corticosteroid therapy (regardless of the dose and duration of therapy) started in the first two weeks of life in VLBW infants receiving assisted ventilation. DATA COLLECTION AND ANALYSIS: Outcomes including CLD at 28 days or 36 weeks postmenstrual age (PMA), mortality, the combined outcome of death or CLD at 28 days or 36 weeks PMA, other pulmonary outcomes and adverse effects were evaluated. All data were analysed using RevMan 5.1. Meta-analyses were performed using relative risk (RR), risk difference (RD), and mean difference (MD) with their 95% confidence intervals (CI). If RD was significant, the numbers needed to benefit (NNTB) or to harm (NNTH) were calculated. MAIN RESULTS: No new trials were identified in this update. Two trials qualified for inclusion in this review. The incidence of CLD at 36 weeks PMA was increased (of borderline statistical significance) in the inhaled steroid group [RR 1.45 (95% CI 0.99 to 2.11); RD 0.11 (95% CI 0.00 to 0.21), p = 0.05, one trial, n = 278]. The incidence of CLD at 36 weeks PMA among all survivors [RR 1.34 (95% CI 0.94 to 1.90); RD 0.11 (95% CI -0.02 to 0.24), one trial, n = 206], oxygen dependency at 28 days (two trials, n = 294), death by 28 days (two trials, n = 294) or 36 weeks PMA (two trials, n = 294) and the combined outcome of death or CLD by 28 days (two trials, n = 294) or 36 weeks PMA (one trial, n = 278) did not differ significantly between the groups. The duration of mechanical ventilation was significantly longer in the inhaled steroid group as compared to the systemic steroid group [typical MD 4 days (95% CI 0.2 to 8); two trials, n = 294] as was the duration of supplemental oxygen [typical MD 11 days (95% CI 2 to 20); two trials, n = 294]. The incidence of hyperglycaemia was significantly lower in the group receiving inhaled steroids [RR 0.52 (95% CI 0.39 to 0.71); RD -0.25 (95% CI -0.37 to -0.14); one trial, n = 278; NNTB 4 (95% CI 3 to 7) to avoid one infant experiencing hyperglycaemia]. The rate of patent ductus arteriosus was increased in the group receiving inhaled steroids [RR 1.64 (95% CI 1.23 to 2.17); RD 0.21 (95% CI 0.10 to 0.33); one trial, n = 278; NNTH 5 (95% CI 3 to 10)]. No information was available on long-term neurodevelopmental outcomes. AUTHORS' CONCLUSIONS: This review found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator dependent preterm infants. Neither inhaled steroids nor systemic steroids can be recommended as a part of standard practice for ventilated preterm infants. Because they might have fewer adverse effects than systemic steroids, further randomised controlled trials of inhaled steroids are needed that address risk/benefit ratio of different delivery techniques, dosing schedules and long-term effects, with particular attention to neurodevelopmental outcome.

Association of Weight Changes by Three Days after Birth and Mortality and/or Severe Neurological Injury in Preterm Infants < 29 Weeks Gestational Age: A Multicenter Cohort Study.

OBJECTIVE: This study aimed to determine the range of weight loss, at 3 days postnatal age, associated with the lowest risk of mortality/short-term morbidity in preterm infants <29 weeks gestational age (GA). STUDY DESIGN: This multicenter retrospective cohort study employed data from the Canadian Neonatal Network database. The primary outcome was a composite of mortality and/or severe neurological injury. Multivariable quadratic and linear regression models which adjusted for potential confounders were built. RESULTS: A total of 9275 preterm infants (median GA 26, IQR 25, 28 weeks) were included. The optimal weight change range at day three, after adjustment for potential confounders for the primary outcomes, was -15 to -8.9%. CONCLUSIONS: There is a 'U'-shaped relationship between weight change from birth to day three and mortality and/or severe neurological injury. Interventional studies, which target weight loss within the range found in this study and evaluate the impact on neonatal outcomes, are needed to corroborate our findings.

Venepuncture versus heel lance for blood sampling in term neonates.

BACKGROUND: Heel lance has been the conventional method of blood sampling in neonates for screening tests. Neonates undergoing heel lance experience pain which cannot be completely alleviated. OBJECTIVES: To determine whether venepuncture or heel lance is less painful and more effective for blood sampling in term neonates. SEARCH STRATEGY: Randomized or quasi-randomised controlled trials comparing pain response to venepuncture versus heel lance were identified by searching the Cochrane Central Regsiter of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, CINAHL, and clinical trials registries in May 2011. SELECTION CRITERIA: Trials comparing pain response to venepuncture versus heel lance with or with out the use of a sweet tasting solution as a co-intervention in term neonates. DATA COLLECTION AND ANALYSIS: Outcomes included pain response to venepuncture versus heel lance with or without the use of a sweet tasting solution using validated pain measures, the need of repeat sampling and cry characteristics. Analyses included typical relative risk (RR), risk difference (RD), number needed to treat (NNT), weighted mean difference (WMD) and standardized mean difference (SMD) with their 95% confidence intervals (CI). Between study heterogeneity was reported including the I squared (I(2)) test. MAIN RESULTS: Six studies (n = 478) of variable quality were included. A composite outcome of Infant Pain Scale (NIPS), Neonatal Facial Action Coding System (NFCS) and/or Premature Infant Pain Profile (PIPP) score was reported in 288 infants, who did not receive a sweet tasting solution. Meta-analysis showed a significant reduction in the venepuncture versus the heel lance group (SMD -0.76, 95% CI -1.00 to -0.52; I(2) = 0%). When a sweet tasting solution was provided the SMD remained significant favouring the venepuncture group (SMD - 0.38, 95% CI -0.69 to -0.07). The typical RD for requiring more than one skin puncture for venepuncture versus heel lance (reported in 4 studies; n = 254) was -0.34 (95% CI -0.43 to -0.25; I(2) = 97%). The NNT to avoid one repeat skin puncture was 3 (95% CI 2 to 4). Cry characteristics favoured the venepuncture group but the differences were reduced by the provision of sweet tasting solutions prior to either procedure. AUTHORS' CONCLUSIONS: Venepuncture, when performed by a skilled phlebotomist, appears to be the method of choice for blood sampling in term neonates. The use of a sweet tasting solution further reduces the pain.Further well designed randomised controlled trials should be conducted in settings where several individuals perform the procedures.

Propofol for procedural sedation/anaesthesia in neonates.

BACKGROUND: Elective medical or surgical procedures are commonplace for neonates admitted to NICU. Agents such as opioids are commonly used for achieving sedation/analgesia/anaesthesia for such procedures; however, these agents are associated with adverse effects. Propofol is used widely in paediatric and adult populations for this purpose. The efficacy and safety of the use of propofol in neonates has not been defined. OBJECTIVES: To determine the efficacy and safety of propofol treatment compared to placebo or no treatment or alternate active agents in neonates undergoing sedation or anaesthesia for procedures. To conduct subgroup analyses according to method of propofol administration (bolus or continuous infusion), type of active control agent (neuromuscular blocking agents with or without the use of sedative, analgesics or anxiolytics), type of procedure (endotracheal intubation, eye examination, other procedure), and gestational age (preterm and term). SEARCH STRATEGY: We searched MEDLINE (1950 to September 30, 2010), EMBASE (1980 to September 30, 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 2) for eligible studies without language restriction. We searched reference lists of identified articles and abstracts submitted to Pediatric Academic Societies (2002 to 2009), and international trials registries for eligible articles. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials of propofol versus placebo, no treatment or other sedative/anaesthetic/analgesic agents in isolation or combination used in neonates for procedures. DATA COLLECTION AND ANALYSIS: We collected and analysed data in accordance with the standard methods of the Cochrane Neonatal Review Group. MAIN RESULTS: One open-label randomised controlled trial of 63 neonates was eligible for inclusion. Thirty-three neonates in the propofol group were compared to 30 infants in the morphine-atropine-suxamethonium group. There was no statistically significant difference in the number of infants who required multiple intubation attempts (39% in the propofol group versus 57% in the morphine-atropine-suxamethonium group; RR 1.40, 95% CI 0.85 to 2.29). Times required to prepare medication, to complete the procedure and for recovery to previous clinical status were shorter in the propofol group. No difference in clinically significant side effects was observed; however, the number of events was small. AUTHORS' CONCLUSIONS: No practice recommendation can be made based on the available evidence regarding the use of propofol in neonates. Further research is needed on the pharmacokinetics of propofol in neonates and once a relatively safe dose is identified, randomised controlled trials assessing the safety and efficacy of propofol are needed.

Intrapartum antibiotics for known maternal Group B streptococcal colonization.

BACKGROUND: Maternal colonization with group B streptococcus (GBS) during pregnancy increases the risk of neonatal infection by vertical transmission. Administration of intrapartum antibiotic prophylaxis (IAP) during labor has been associated with a reduction in early onset GBS disease (EOGBSD). However, treating all colonized women during labor exposes a large number of women and infants to possible adverse effects without benefit. OBJECTIVES: To assess the effect of IAP for maternal GBS colonization on neonatal: 1) all cause mortality and 2) morbidity from proven and probable EOGBSD, late onset GBS disease (LOD), maternal infectious outcomes and allergic reactions to antibiotics. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2009). SELECTION CRITERIA: Randomized trials assessing the impact of maternal IAP on neonatal GBS infections were included. DATA COLLECTION AND ANALYSIS: We independently assessed eligibility and quality of the studies. MAIN RESULTS: Three trials (involving 852 women) evaluating the effects of IAP versus no treatment were included. The risk of bias was high. The use of IAP did not significantly reduce the incidence of all cause mortality, mortality from GBS infection or from infections caused by bacteria other than GBS. The incidence of early GBS infection was reduced with IAP compared to no treatment (risk ratio 0.17, 95% confidence interval (CI) 0.04 to 0.74, three trials, 488 infants; risk difference -0.04, 95% CI -0.07 to -0.01; number needed to treat to benefit 25, 95% CI 14 to 100, I(2) 0%). The incidence of LOD or sepsis from organisms other than GBS and puerperal infection was not significantly different between groups.One trial (involving 352 women) compared intrapartum ampicillin versus penicillin and reported no significant difference in neonatal or maternal outcomes. AUTHORS' CONCLUSIONS: Intrapartum antibiotic prophylaxis appeared to reduce EOGBSD, but this result may well be a result of bias as we found a high risk of bias for one or more key domains in the study methodology and execution. There is lack of evidence from well designed and conducted trials to recommend IAP to reduce neonatal EOGBSD.Ideally the effectiveness of IAP to reduce neonatal GBS infections should be studied in adequately sized double-blind controlled trials. The opportunity to conduct such trials has likely been lost, as practice guidelines (albeit without good evidence) have been introduced in many jurisdictions.

Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters.

BACKGROUND: Complications associated with peripherally placed percutaneous central venous catheters (PCVC) in neonates include mechanical complications (catheter thrombosis, occlusion or dislodgement) and infection. Strategies to prevent catheter thrombosis and occlusion include the use of heparin. However, heparin is known to be associated with complications such as bleeding and thrombocytopenia. PRIMARY OBJECTIVE: To assess the effectiveness of heparin for prevention of catheter related thrombosis. SECONDARY OBJECTIVES: To assess the effectiveness of heparin on catheter occlusion, duration of catheter patency, catheter related sepsis and complications associated with the use of heparin. SEARCH STRATEGY: A literature search of MEDLINE, EMBASE, CINAHL from their inception to December 2007, The Cochrane Library (Issue 4, 2007) and abstracts from the annual meetings of the Pediatric Academic Societies was performed without language restrictions. SELECTION CRITERIA: Randomized or quasi-randomized clinical trials of neonates where heparin infusion was compared to placebo or no treatment for prevention of any of the complications related to peripherally placed PCVC were included. DATA COLLECTION AND ANALYSIS: The methodological quality of included trials was assessed using criteria for masking of randomization, masking of intervention, completeness of follow-up and masking of outcome measurement. Data on relevant outcomes were extracted and the effect size was estimated by calculating relative risk (RR), risk difference (RD) and associated 95% confidence intervals (CI). MAIN RESULTS: Three randomized trials were identified. Two trials of adequate methodology met the eligibility criteria. These studies included 267 neonates. There was reduced risk of catheter occlusion (typical RR 0.28, 95% CI 0.15, 0.53, NNT 5, 95% CI 3, 8). There was no statistically significant difference in the duration of catheter patency when analyzed as continuous data; however, in one study survival analyses identified benefit with heparin (adjusted hazard ratio 0.55, 95% CI 0.36, 83); (Shah 2007). This could be due to higher incidence of elective removal of catheters in neonates at the completion of therapy in the heparin group (63% vs. 42%; p = 0.002) (Shah 2007). There was no statistically significant differences in the risk of thrombosis (typical RR 0.93, 95% CI 0.58, 1.51), catheter related sepsis (typical RR 1.96, 95% CI 0.50, 7.60), or extension of intraventricular hemorrhage (typical RR 0.87, 95% CI 0.25, 3.03) between the two groups. IMPLICATIONS FOR PRACTICE: Prophylactic use of heparin for peripherally placed PCVC allows a greater number of infants to complete their intended use (complete therapy) by reducing occlusion. Evidence from this systematic review support the prophylactic use of heparin for PCVC in neonates at a dose of 0.5 IU/kg/hr. IMPLICATIONS FOR RESEARCH: None of these studies was powered to evaluate a lower incidence rate of adverse events. If this therapy is adopted in routine practice, monitoring of side effects is indicated.