Surfactant for pulmonary haemorrhage in neonates.

BACKGROUND: In the 1960s and 1970s, pulmonary haemorrhage (PH) occurred mainly in full-term infants with pre-existing illness with an incidence of 1.3 per 1000 live births. Risk factors for PH included severity of illness, intrauterine growth restriction, patent ductus arteriosus (PDA), coagulopathy and the need for assisted ventilation. Presently, PH occurs in 3% to 5% of preterm ventilated infants with severe respiratory distress syndrome (RDS) who often have a PDA and have received surfactant. The cause of PH is thought to be due to rapid lowering of intrapulmonary pressure, which facilitates left to right shunting across a PDA and an increase in pulmonary blood flow. Retrospective case reports and one prospective uncontrolled study have shown promising results for surfactant in treating PH. OBJECTIVES: To evaluate the effect of surfactant treatment compared to placebo or no intervention on mortality and morbidities in neonates with PH. SEARCH METHODS: For this update The Cochrane Library, Issue 2, 2012; MEDLINE; EMBASE; CINAHL; Clinicaltrials.gov; Controlled-trials.com; proceedings (2000 to 2011) of the Annual Meetings of the Pediatric Academic Societies (Abstracts2View) and Web of Science were searched on 8 February 2012. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that evaluated the effect of surfactant in the treatment of PH in intubated term or preterm (< 37 weeks) neonates with PH. Infants were included up to 44 weeks' postmenstrual age. The interventions studied were intratracheal instillation of surfactant (natural or synthetic, regardless of dose) versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: If studies were identified by the literature search, the planned analyses included risk ratio, risk difference, number needed to treat to benefit or to harm for dichotomous outcomes, and mean difference for continuous outcomes, with their 95% confidence intervals. A fixed-effect model would be used for meta-analyses. The risk of bias for included trials would be assessed. Heterogeneity tests, including the I2 statistic, would be performed to assess the appropriateness of pooling the data and the results would be reported. MAIN RESULTS: No trials were identified. AUTHORS' CONCLUSIONS: No randomised or quasi-randomised trials that evaluated the effect of surfactant in PH were identified. Therefore, no conclusions from such trials can be drawn. In view of the promising results from studies with less strict study designs than a randomised controlled trial, there is reason to conduct further trials of surfactant for the treatment of PH in neonates.

Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants.

BACKGROUND: Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. OBJECTIVES: To assess the effectiveness and safety of early versus late initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight (LBW) infants. SEARCH METHODS: The standard search of the Cochrane Neonatal Review Group (CNRG) was performed in 2006 and updated in 2009. Updated search in September 2009 as follows: The Cochrane Library, MEDLINE (search via PubMed), CINAHL and EMBASE were searched from 2005 to September 2009. The searches were repeated in March 2012. The Pediatric Academic Societies' Annual meetings were searched electronically from 2000 to 2012 at Abstracts2ViewTM as were clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp). SELECTION CRITERIA: Randomised or quasi-randomised controlled trials enrolling preterm or LBW infants less than eight days of age. INTERVENTION: Early initiation of EPO (initiated at less than eight days of age) versus late initiation of EPO (initiated at eight to 28 days of age). DATA COLLECTION AND ANALYSIS: The standard methods of the CNRG were followed. Weighted treatment effects included typical risk ratio (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses and heterogeneity was evaluated using the I-squared (I2) test. MAIN RESULTS: No new trials were identified in March of 2012. Two high quality randomised double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I2 = 0% for both RR and RD] favouring early EPO was noted. Early EPO administration resulted in a non-significant reduction in the "number of transfusions per infant" compared with late EPO [typical MD - 0.32 (95% CI -0.92 to 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Early EPO led to a significant increase in the risk of retinopathy of prematurity (ROP) (all stages) [two studies, 191 infants; typical RR 1.40 (95% CI 1.05 to 1.86); typical RD 0.16 (95% CI 0.03 to 0.29); NNTH 6 (95% CI 3 to 33)]. There was high heterogeneity for this outcome (I2 = 86% for RR and 81% for RD). Both studies (191 infants) reported on ROP stage > 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71 to 3.41); typical RD 0.05 (-0.04 to 0.14)] There was no heterogeneity for this outcome (0% for both RR and RD). No other important favourable or adverse neonatal outcomes or side effects were reported. AUTHORS' CONCLUSIONS: The use of early EPO did not significantly reduce the 'Use of one or more RBC transfusions' or the 'Number of transfusions per infant" compared with late EPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern.

Early erythropoiesis-stimulating agents in preterm or low birth weight infants.

BACKGROUND: Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES: To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions: To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives: Review authors performed subgroup analyses of low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (≤ 5 mg/kg/d), and high (> 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs: To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance: To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives: To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. MAIN RESULTS: This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment. Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low. Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate. Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low. Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the ESA group (weighted mean difference (WMD) 8.22, 95% CI 6.52 to 9.92; I2 = 97% (high heterogeneity); 3 studies, 981 children). The quality of the evidence was low. The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced. Data show no significant difference in risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI -0.02 to 0.04; I2 = 0% (no heterogeneity) for RR; I2 = 34% (low heterogeneity) for RD; 8 studies, 1283 infants). Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL). AUTHORS' CONCLUSIONS: Early administration of ESAs reduces the use of red blood cell (RBC) transfusions, the volume of RBCs transfused, and donor exposure after study entry. Small reductions are likely to be of limited clinical importance. Donor exposure probably is not avoided, given that all but one study included infants who had received RBC transfusions before trial entry. This update found no significant difference in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age, which has been a topic of concern in earlier versions of this review. Early EPO treatment significantly decreased rates of IVH, PVL, and NEC. Neurodevelopmental outcomes at 18 to 22 months and later varied in published studies. Ongoing research should evaluate current clinical practices that will limit donor exposure. Promising but conflicting results related to the neuro protective effect of early EPO require further study. Very different results from the two largest published trials and high heterogeneity in the analyses indicate that we should wait for the results of two ongoing large trials before drawing firm conclusions. Administration of EPO is not currently recommended because limited benefits have been identified to date. Use of darbepoetin requires further study.

Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants.

BACKGROUND: Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer adverse effects. OBJECTIVES: To determine the effectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor(s), placebo, or no intervention for closing a patent ductus arteriosus in preterm, low-birth-weight, or preterm and 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 10), MEDLINE via PubMed (1966 to 30 November 2017), Embase (1980 to 30 November 2017), and CINAHL (1982 to 30 November 2017). We searched clinical trials databases, 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 of ibuprofen for the treatment of a PDA in preterm, low birth weight, or both preterm and low-birth-weight newborn infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included 39 studies enrolling 2843 infants. Ibuprofen (IV) versus placebo: IV Ibuprofen (3 doses) reduced the failure to close a PDA compared with placebo (typical relative risk (RR); 0.62 (95% CI 0.44 to 0.86); typical risk difference (RD); -0.18 (95% CI -0.30 to -0.06); NNTB 6 (95% CI 3 to 17); I2 = 65% for RR and I2 = 0% for RD; 2 studies, 206 infants; moderate-quality the evidence). One study reported decreased failure to close a PDA after single or three doses of oral ibuprofen compared with placebo (64 infants; RR 0.26, 95% CI 0.11 to 0.62; RD -0.44, 95% CI -0.65 to -0.23; NNTB 2, 95% CI 2 to 4; I2 test not applicable). Ibuprofen (IV or oral) compared with indomethacin (IV or oral): Twenty-four studies (1590 infants) comparing ibuprofen (IV or oral) with indomethacin (IV or oral) found no significant differences in failure rates for PDA closure (typical RR 1.07, 95% CI 0.92 to 1.24; typical RD 0.02, 95% CI -0.02 to 0.06; I2 = 0% for both RR and RD; moderate-quality evidence). A reduction in NEC (necrotising enterocolitis) was noted in the ibuprofen (IV or oral) group (18 studies, 1292 infants; typical RR 0.68, 95% CI 0.49 to 0.94; typical RD -0.04, 95% CI -0.07 to -0.01; NNTB 25, 95% CI 14 to 100; I2 = 0% for both RR and RD; moderate-quality evidence). There was a statistically significant reduction in the proportion of infants with oliguria in the ibuprofen group (6 studies, 576 infants; typical RR 0.28, 95% CI 0.14 to 0.54; typical RD -0.09, 95% CI -0.14 to -0.05; NNTB 11, 95% CI 7 to 20; I2 = 24% for RR and I2 = 69% for RD; moderate-quality evidence). The serum/plasma creatinine levels 72 hours after initiation of treatment were statistically significantly lower in the ibuprofen group (11 studies, 918 infants; MD -8.12 µmol/L, 95% CI -10.81 to -5.43). For this comparison, there was high between-study heterogeneity (I2 = 83%) and low-quality evidence. Ibuprofen (oral) compared with indomethacin (IV or oral): Eight studies (272 infants) reported on failure rates for PDA closure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (IV or oral). There was no significant difference between the groups (typical RR 0.96, 95% CI 0.73 to 1.27; typical RD -0.01, 95% CI -0.12 to 0.09; I2 = 0% for both RR and RD). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (IV or oral) (7 studies, 249 infants; typical RR 0.41, 95% CI 0.23 to 0.73; typical RD -0.13, 95% CI -0.22 to -0.05; NNTB 8, 95% CI 5 to 20; I2 = 0% for both RR and RD). There was low-quality evidence for these two outcomes. There was a decreased risk of failure to close a PDA with oral ibuprofen compared with IV ibuprofen (5 studies, 406 infants; typical RR 0.38, 95% CI 0.26 to 0.56; typical RD -0.22, 95% CI -0.31 to -0.14; NNTB 5, 95% CI 3 to 7; moderate-quality evidence). There was a decreased risk of failure to close a PDA with high-dose versus standard-dose of IV ibuprofen (3 studies 190 infants; typical RR 0.37, 95% CI 0.22 to 0.61; typical RD - 0.26, 95% CI -0.38 to -0.15; NNTB 4, 95% CI 3 to 7); I2 = 4% for RR and 0% for RD); moderate-quality evidence). Early versus expectant administration of IV ibuprofen, echocardiographically-guided IV ibuprofen treatment versus standard IV ibuprofen treatment, continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, and rectal ibuprofen versus oral ibuprofen were studied in too few trials to allow for precise estimates of any clinical outcomes. AUTHORS' CONCLUSIONS: Ibuprofen is as effective as indomethacin in closing a PDA. Ibuprofen reduces the risk of NEC and transient renal insufficiency. Therefore, of these two drugs, ibuprofen appears to be the drug of choice. The effectiveness of ibuprofen versus paracetamol is assessed in a separate review. Oro-gastric administration of ibuprofen appears as effective as IV administration. To make further recommendations, studies are needed to assess the effectiveness of high-dose versus standard-dose ibuprofen, early versus expectant administration of ibuprofen, echocardiographically-guided versus standard IV ibuprofen, and continuous infusion versus intermittent boluses of ibuprofen. Studies are lacking evaluating the effect of ibuprofen on longer-term outcomes in infants with PDA.

Late erythropoiesis-stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants.

BACKGROUND: Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia. Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES: To assess the effectiveness and safety of late initiation of ESAs, between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm or 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 2018, Issue 5), MEDLINE via PubMed (1966 to 5 June 2018), Embase (1980 to 5 June 2018), and CINAHL (1982 to 5 June 2018). We searched clinical trials databases, 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 of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) or low birth weight (< 2500 grams) neonates. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin. Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%). Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported. AUTHORS' CONCLUSIONS: Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants.

BACKGROUND: In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically; or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. An association between prenatal or postnatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported. OBJECTIVES: To determine the effectiveness and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for treatment of an echocardiographically diagnosed PDA in preterm or 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 10), MEDLINE via PubMed (1966 to 6 November 2017), Embase (1980 to 6 November 2017), and CINAHL (1982 to 6 November 2017). We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials. SELECTION CRITERIA: We included RCTs in which paracetamol was compared to no intervention, placebo or other agents used for closure of PDA irrespective of dose, duration and mode of administration in preterm (≤ 34 weeks' postmenstrual age) infants. We both reviewed the search results and made a final selection of potentially eligible articles by discussion. We included studies of both prophylactic and therapeutic use of paracetamol. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence for the following outcomes when data were available: failure of ductal closure after the first course of treatment; neurodevelopmental impairment; all-cause mortality during initial hospital stay (death); gastrointestinal bleed or stools positive for occult blood; and serum levels of creatinine after treatment (µmol/L). MAIN RESULTS: We included eight studies that reported on 916 infants. One of these studies compared paracetamol to both ibuprofen and indomethacin. Five studies compared treatment of PDA with paracetamol versus ibuprofen and enrolled 559 infants. There was no significant difference between paracetamol and ibuprofen for failure of ductal closure after the first course of drug administration (typical risk ratio (RR) 0.95, 95% confidence interval (CI) 0.75 to 1.21; typical risk difference (RD) -0.02, 95% CI -0.09 to 0.09); I² = 0% for RR and RD; moderate quality of evidence. Four studies (n = 537) reported on gastrointestinal bleed which was lower in the paracetamol group versus the ibuprofen group (typical RR 0.28, 95% CI 0.12 to 0.69; typical RD -0.06, 95% CI -0.09 to -0.02); I² = 0% for RR and RD; number needed to treat for an additional beneficial outcome (NNTB) 17 (95% CI 11 to 50); moderate quality of evidence. The serum levels of creatinine were lower in the paracetamol group compared with the ibuprofen group in four studies (moderate quality of evidence), as were serum bilirubin levels following treatment in two studies (n = 290). Platelet counts and daily urine output were higher in the paracetamol group compared with the ibuprofen group. One study reported on long-term follow-up to 18 to 24 months of age following treatment with paracetamol versus ibuprofen. There were no significant differences in the neurological outcomes at 18 to 24 months (n = 61); (low quality of evidence). Two studies compared prophylactic administration of paracetamol for a PDA with placebo or no intervention in 80 infants. Paracetamol resulted in a lower rate of failure of ductal closure after 4 to 5 days of treatment compared to placebo or no intervention which was of borderline significance for typical RR 0.49 (95% CI 0.24 to 1.00; P = 0.05); but significant for typical RD -0.21 (95% CI -0.41 to -0.02); I² = 0 % for RR and RD; NNTB 5 (95% CI 2 to 50); (low quality of evidence). Two studies (n = 277) compared paracetamol with indomethacin. There was no significant difference in the failure to close a PDA (typical RR 0.96, 95% CI 0.55 to 1.65; I² = 11%; typical RD -0.01, 95% CI -0.09 to 0.08; I² = 17%) (low quality of evidence). Serum creatinine levels were significantly lower in the paracetamol group compared with the indomethacin group and platelet counts and daily urine output were significantly higher in the paracetamol group. AUTHORS' CONCLUSIONS: Moderate-quality evidence according to GRADE suggests that paracetamol is as effective as ibuprofen; low-quality evidence suggests paracetamol to be more effective than placebo or no intervention; and low-quality evidence suggests paracetamol as effective as indomethacin in closing a PDA. There was no difference in neurodevelopmental outcome in children exposed to paracetamol compared to ibuprofen; however the quality of evidence is low and comes from only one study. In view of concerns raised regarding neurodevelopmental outcomes following prenatal and postnatal exposure to paracetamol, long-term follow-up to at least 18 to 24 months' postnatal age must be incorporated in any studies of paracetamol in the newborn population. At least 19 ongoing trials have been registered. Such trials are required before any recommendations for the possible routine use of paracetamol in the newborn population can be made.

Paracetamol (acetaminophen) for prevention or treatment of pain in newborns.

BACKGROUND: Newborn infants have the ability to experience pain. Hospitalised infants are exposed to numerous painful procedures. Healthy newborns are exposed to pain if the birth process consists of assisted vaginal birth by vacuum extraction or by forceps and during blood sampling for newborn screening tests. OBJECTIVES: To determine the efficacy and safety of paracetamol for the prevention or treatment of procedural/postoperative pain or pain associated with clinical conditions in neonates. To review the effects of various doses and routes of administration (enteral, intravenous or rectal) of paracetamol for the prevention or treatment of pain in neonates. 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 (1966 to 9 May 2016), Embase (1980 to 9 May 2016), and CINAHL (1982 to 9 May 2016). We searched clinical trials' databases, Google Scholar, conference proceedings, and the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials of paracetamol for the prevention/treatment of pain in neonates (≤ 28 days of age). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the articles using pre-designed forms. We used this form to decide trial inclusion/exclusion, to extract data from eligible trials and to request additional published information from authors of the original reports. We entered and cross-checked data using RevMan 5 software. When noted, we resolved differences by mutual discussion and consensus. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included nine trials with low risk of bias, which assessed paracetamol for the treatment of pain in 728 infants. Painful procedures studied included heel lance, assisted vaginal birth, eye examination for retinopathy of prematurity assessment and postoperative care. Results of individual studies could not be combined in meta-analyses as the painful conditions, the use of paracetamol and comparison interventions and the outcome measures differed. Paracetamol compared with water, cherry elixir or EMLA cream (eutectic mixture of lidocaine and prilocaine) did not significantly reduce pain following heel lance. The Premature Infant Pain Profile score (PIPP) within three minutes following lancing was higher in the paracetamol group than in the oral glucose group (mean difference (MD) 2.21, 95% confidence interval (CI) 0.72 to 3.70; one study, 38 infants). Paracetamol did not reduce "modified facies scores" after assisted vaginal birth (one study, 119 infants). In another study (n = 123), the Échelle de Douleur et d'Inconfort du Nouveau-Né score at two hours of age was significantly higher in the group that received paracetamol suppositories than in the placebo suppositories group (MD 1.00, 95% CI 0.60 to 1.40). In that study, when infants were subjected to a heel lance at two to three days of age, Bernese Pain Scale for Neonates scores were higher in the paracetamol group than in the placebo group, and infants spent a longer time crying (MD 19 seconds, 95% CI 14 to 24). For eye examinations, no significant reduction in PIPP scores in the first or last 45 seconds of eye examination was reported, nor at five minutes after the eye examination. In one study (n = 81), the PIPP score was significantly higher in the paracetamol group than in the 24% sucrose group (MD 3.90, 95% CI 2.92 to 4.88). In one study (n = 114) the PIPP score during eye examination was significantly lower in the paracetamol group than in the water group (MD -2.70, 95% CI -3.55 to 1.85). For postoperative care following major surgery, the total amount of morphine (µg/kg) administered over 48 hours was significantly less among infants assigned to the paracetamol group than to the morphine group (MD -157 µg/kg, 95% CI -27 to -288). No adverse events were noted in any study. The quality of evidence according to GRADE was low. AUTHORS' CONCLUSIONS: The paucity and low quality of existing data do not provide sufficient evidence to establish the role of paracetamol in reducing the effects of painful procedures in neonates. Paracetamol given after assisted vaginal birth may increase the response to later painful exposures. Paracetamol may reduce the total need for morphine following major surgery, and for this aspect of paracetamol use, further research is needed.

Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.

BACKGROUND: Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal, and cerebral side effects. Ibuprofen has less effect on blood flow velocity to important organs. OBJECTIVES: Primary objectives To determine the effectiveness and safety of ibuprofen compared to placebo/no intervention, or other cyclo-oxygenase inhibitor drugs in the prevention of PDA in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10), MEDLINE via PubMed (1966 to 17 October 2018), Embase (1980 to 17 October 2018), and CINAHL; 1982 to 17 October 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted outcomes data including presence of PDA on day three or four of life (after 72 hours of treatment), need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, cerebral, renal, pulmonary, and gastrointestinal complications. We performed meta-analyses and reported treatment estimates as typical mean difference (MD), risk ratio (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNTB) or to harm (NNTH), along with their 95% confidence intervals (CI). We assessed between-study heterogeneity by the I-squared test (I²). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: In this updated analysis, we included nine trials (N = 1070 infants) comparing prophylactic ibuprofen (IV or oral) with placebo/no intervention or indomethacin. Ibuprofen (IV or oral) probably decreases the risk of PDA on day 3 or 4 (typical RR 0.39, 95% CI 0.31 to 0.48; typical RD -0.26, 95% CI -0.31 to -0.21; NNTB 4, 95% CI 3 to 5; 9 trials; N = 1029) (moderate-quality evidence). In the control group, the spontaneous closure rate was 58% by day 3 to 4 of age. In addition, ibuprofen probably decreases the need for rescue treatment with cyclo-oxygenase inhibitors (typical RR 0.17, 95% CI 0.11 to 0.26; typical RD -0.27, 95% CI -0.32 to -0.22; NNTB 4; 95% CI 3 to 5),and the need for surgical ductal ligation (typical RR 0.46, 95% CI 0.22 to 0.96; typical RD -0.03, 95% CI -0.05 to -0.00; NNTB 33, 95% CI 20 to infinity; 7 trials; N = 925) (moderate-quality evidence). There was a possible decrease in the risk of grade 3 or 4 intraventricular haemorrhage (IVH) in infants receiving prophylactic ibuprofen (typical RR 0.67, 95% CI 0.45 to 1.00; I² = 34%; typical RD -0.04, 95% CI -0.08 to- 0.00; I² = 60%; 7 trials; N = 925) (moderate-quality evidence). High quality evidence showed increased risk for oliguria (typical RR 1.45, 95% CI 1.04 to 2.02; typical RD 0.06, 95% CI 0.01 to 0.11; NNTH 17, 95% CI 9 to 100; 4 trials; N = 747). Low quality results from four studies (N = 202) showed that administering oral ibuprofen may decrease the risk of PDA (typical RR 0.47, 95% CI 0.30 to 0.74) and may increase risk of gastrointestinal bleeding (NNTH 7, 95% CI 4 to 25). No evidence of a difference was identified for mortality, any intraventricular haemorrhage (IVH), or chronic lung disease. AUTHORS' CONCLUSIONS: This review shows that prophylactic use of ibuprofen, compared to placebo or no intervention, probably decreases the incidence of patent ductus arteriosus, the need for rescue treatment with cyclo-oxygenase inhibitors, and for surgical ductal closure. Adverse effects associated with ibuprofen (IV or oral) included increased risks for oliguria, increase in serum creatinine levels, and increased risk of gastrointestinal haemorrhage. There was a reduced risk for intraventricular haemorrhage (grade III - IV) but no evidence of a difference in mortality, chronic lung disease, necrotising enterocolitis, or time to reach full feeds. In the control group, the patent ductus arteriosus had closed spontaneously by day 3 or 4 in 58% of neonates. Prophylactic treatment exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short-term benefits. Current evidence does not support the use of ibuprofen for prevention of patent ductus arteriosus. Until long-term follow-up results of the trials included in this review have been published, no further trials of prophylactic ibuprofen are recommended. A new approach to patent ductus arteriosus management is an early targeted treatment based on echocardiographic criteria within the first 72 hours of life, that have a high sensitivity for diagnosing a patent ductus arteriosus that is unlikely to close spontaneously. Such trials are currently ongoing in many parts of the world. Results of such trials will be included in updates of our "Ibuprofen for treatment of PDA" review.

Sound reduction management in the neonatal intensive care unit for preterm or very low birth weight infants.

BACKGROUND: Infants in the neonatal intensive care unit (NICU) are subjected to stress, including sound of high intensity. The sound environment in the NICU is louder than most home or office environments and contains disturbing noises of short duration and at irregular intervals. There are competing auditory signals that frequently challenge preterm infants, staff and parents. The sound levels in NICUs often exceed the maximum acceptable level of 45 decibels (dB), recommended by the American Academy of Pediatrics. Hearing impairment is diagnosed in 2% to 10% of preterm infants versus 0.1% of the general paediatric population. Noise may cause apnoea, hypoxaemia, alternation in oxygen saturation, and increased oxygen consumption secondary to elevated heart and respiratory rates and may, therefore, decrease the amount of calories available for growth. Elevated levels of speech are needed to overcome the noisy environment in the NICU, thereby increasing the negative impacts on staff, newborns, and their families. High noise levels are associated with an increased rate of errors and accidents, leading to decreased performance among staff. The aim of interventions included in this review is to reduce sound levels to 45 dB or less. This can be achieved by lowering the sound levels in an entire unit, treating the infant in a section of a NICU, in a 'private' room, or in incubators in which the sound levels are controlled, or reducing the sound levels that reaches the individual infant by using earmuffs or earplugs. By lowering the sound levels that reach the neonate, the resulting stress on the cardiovascular, respiratory, neurological, and endocrine systems can be diminished, thereby promoting growth and reducing adverse neonatal outcomes. OBJECTIVES: Primary objective To determine the effects of sound reduction on growth and long-term neurodevelopmental outcomes of neonates. Secondary objectives 1. To evaluate the effects of sound reduction on short-term medical outcomes (bronchopulmonary dysplasia, intraventricular haemorrhage, periventricular leukomalacia, retinopathy of prematurity). 2. To evaluate the effects of sound reduction on sleep patterns at three months of age. 3. To evaluate the effects of sound reduction on staff performance. 4. To evaluate the effects of sound reduction in the neonatal intensive care unit (NICU) on parents' satisfaction with the care. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings, clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp), Pediatric Academic Societies Annual meetings 2000 to 2014 (Abstracts2ViewTM), reference lists of identified trials, and reviews to November 2014. SELECTION CRITERIA: Preterm infants (< 32 weeks' postmenstrual age (PMA) or < 1500 g birth weight) cared for in the resuscitation area, during transport, or once admitted to a NICU or a stepdown unit. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses according to the Cochrane Neonatal Review Group. MAIN RESULTS: One small, high quality study assessing the effects of silicone earplugs versus no earplugs qualified for inclusion. The original inclusion criteria in our protocol stipulated an age of < 48 hours at the time of initiating sound reduction. We made a deviation from our protocol and included this study in which some infants would have been > 48 hours old. There was no significant difference in weight at 34 weeks postmenstrual age (PMA): mean difference (MD) 111 g (95% confidence interval (CI) -151 to 374 g) (n = 23). There was no significant difference in weight at 18 to 22 months corrected age between the groups: MD 0.31 kg, 95% CI -1.53 to 2.16 kg (n = 14). There was a significant difference in Mental Developmental Index (Bayley II) favouring the silicone earplugs group at 18 to 22 months corrected age: MD 14.00, 95% CI 3.13 to 24.87 (n = 12), but not for Psychomotor Development Index (Bayley II) at 18 to 22 months corrected age: MD -2.16, 95% CI -18.44 to 14.12 (n =12). AUTHORS' CONCLUSIONS: To date, only 34 infants have been enrolled in a randomised controlled trial (RCT) testing the effectiveness of reducing sound levels that reach the infants' ears in the NICU. Based on the small sample size of this single trial, we cannot make any recommendations for clinical practice. Larger, well designed, conducted and reported trials are needed.

Intravenous immunoglobulin for suspected or proven infection in neonates.

BACKGROUND: Neonates are at higher risk of infection due to immuno-incompetence. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks' gestation, and endogenous synthesis begins several months after birth. Administration of intravenous immunoglobulin (IVIG) provides immunoglobulin G (IgG) that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody-dependent cytotoxicity and improve neutrophilic chemo-luminescence. Theoretically, infectious morbidity and mortality could be reduced by the administration of IVIG. OBJECTIVES: To assess the effects of IVIG on mortality and morbidity caused by suspected or proven infection at study entry in neonates. To assess in a subgroup analysis the effects of IgM-enriched IVIG on mortality from suspected infection. SEARCH METHODS: For this update, MEDLINE, EMBASE, The Cochrane Library, CINAHL, trial registries, Web of Science, reference lists of identified studies, meta-analyses and personal files were searched in 2013. No language restrictions were applied. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials involving newborn infants (< 28 days old); IVIG for treatment of suspected or proven bacterial or fungal infection compared with placebo or no intervention; and where one of the following outcomes was reported, mortality, length of hospital stay or psychomotor development at follow-up. DATA COLLECTION AND ANALYSIS: Statistical analyses included typical risk ratio (RR), risk difference (RD), weighted mean difference (WMD), number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH), all with 95% confidence intervals (CIs), and the I2 statistic to examine for statistical heterogeneity. MAIN RESULTS: The updated search identified one published study that was previously ongoing. A total of 9 studies evaluating 3973 infants were included in this review. Mortality during hospital stay in infants with clinically suspected infection was not significantly different after IVIG treatment (9 studies (n = 2527); typical RR 0.95, 95% CI 0.80 to 1.13; typical RD -0.01, 95% CI - 0.04 to 0.02; I2 = 23% for RR and 29% for RD). Death or major disability at 2 years corrected age was not significantly different in infants with suspected infection after IVIG treatment (1 study (n = 1985); RR 0.98, 95% CI 0.88 to 1.09; RD -0.01, 95% CI -0.05 to 0.03). Mortality during hospital stay was not significantly different after IVIG treatment in infants with proven infection at trial entry (1 trial (n = 1446); RR 0.95, 95% CI 0.74 to 1.21; RD -0.01, 95% CI -0.04 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with proven infection at trial entry (1 trial (n = 1393); RR 1.03, 95% CI 0.91 to 1.18; RD 0.01, 95% CI -0.04 to 0.06). Mortality during hospital stay in infants with clinically suspected or proven infection at trial entry was not significantly different after IVIG treatment (1 study (n = 3493); RR 1.00, 95% CI 0.86 to 1.16; RD 0.00, 95% CI - 0.02 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with suspected or proven infection at trial entry (1 study (n = 3493); RR 1.00, 95% CI 0.92 to 1.09; RD -0.00, 95% CI -0.03 to 0.03). Length of hospital stay was not reduced for infants with suspected or proven infection at trial entry (1 study (n = 3493); mean difference (MD) 0.00 days, 95% CI -0.61 to 0.61). No significant difference in mortality during hospital stay after administration of IgM-enriched IVIG for suspected infection at trial entry was reported in 4 studies (n = 266) (typical RR 0.68, 95% CI 0.39 to 1.20; RD -0.06, 95% CI -0.14 to 0.02; I2 = 17% for RR and 53% for RD). AUTHORS' CONCLUSIONS: The undisputable results of the INIS trial, which enrolled 3493 infants, and our meta-analyses (n = 3973) showed no reduction in mortality during hospital stay, or death or major disability at two years of age in infants with suspected or proven infection. Although based on a small sample size (n = 266), this update provides additional evidence that IgM-enriched IVIG does not significantly reduce mortality during hospital stay in infants with suspected infection. Routine administration of IVIG or IgM-enriched IVIG to prevent mortality in infants with suspected or proven neonatal infection is not recommended. No further research is recommended.

Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants.

BACKGROUND: Nosocomial infections continue to be a significant cause of morbidity and mortality among preterm and/or low birth weight (LBW) infants. Preterm infants are deficient in immunoglobulin G (IgG); therefore, administration of intravenous immunoglobulin (IVIG) may have the potential of preventing or altering the course of nosocomial infections. OBJECTIVES: To use systematic review/meta-analytical techniques to determine whether IVIG administration (compared with placebo or no intervention) to preterm (< 37 weeks' postmenstrual age (PMA) at birth) or LBW (< 2500 g birth weight) infants or both is effective/safe in preventing nosocomial infection. SEARCH METHODS: For this update, MEDLINE, EMBASE, CINAHL, The Cochrane Library, Controlled Trials, ClinicalTrials.gov and PAS Abstracts2view were searched in May 2013. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) in which a group of participants to whom IVIG was given was compared with a control group that received a placebo or no intervention for preterm (< 37 weeks' gestational age) and/or LBW (< 2500 g) infants. Studies that were primarily designed to assess the effect of IVIG on humoral immune markers were excluded, as were studies in which the follow-up period was one week or less. DATA COLLECTION AND ANALYSIS: Data collection and analysis was performed in accordance with the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: Nineteen studies enrolling approximately 5000 preterm and/or LBW infants met inclusion criteria. No new trials were identified in May 2013. When all studies were combined, a significant reduction in sepsis was noted (typical risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74 to 0.98; typical risk difference (RD) -0.03, 95% CI 0.00 to -0.05; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 20 to infinity), and moderate between-study heterogeneity was reported (I2 54% for RR, 55% for RD). A significant reduction of one or more episodes was found for any serious infection when all studies were combined (typical RR 0.82, 95% CI 0.74 to 0.92; typical RD -0.04, 95% CI -0.02 to -0.06; NNTB 25, 95% CI 17 to 50), and moderate between-study heterogeneity was observed (I2 50% for RR, 62% for RD). No statistically significant differences in mortality from all causes were noted (typical RR 0.89, 95% CI 0.75 to 1.05; typical RD -0.01, 95% CI -0.03 to 0.01), and no heterogeneity for RR (I2 = 21%) or low heterogeneity for RD was documented (I2 = 28%). No statistically significant difference was seen in mortality from infection; in incidence of necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) or intraventricular haemorrhage (IVH) or in length of hospital stay. No major adverse effects of IVIG were reported in any of these studies. AUTHORS' CONCLUSIONS: IVIG administration results in a 3% reduction in sepsis and a 4% reduction in one or more episodes of any serious infection but is not associated with reductions in other clinically important outcomes, including mortality. Prophylactic use of IVIG is not associated with any short-term serious side effects. The decision to use prophylactic IVIG will depend on the costs and the values assigned to the clinical outcomes. There is no justification for conducting additional RCTs to test the efficacy of previously studied IVIG preparations in reducing nosocomial infections in preterm and/or LBW infants.

Inositol in preterm infants at risk for or having respiratory distress syndrome.

BACKGROUND: Inositol is an essential nutrient required by human cells in culture for growth and survival. Inositol promotes maturation of several components of surfactant and may play a critical role in fetal and early neonatal life. A drop in inositol levels in infants with respiratory distress syndrome (RDS) can be a sign that their illness will be severe. OBJECTIVES: To assess the effectiveness and safety of supplementary inositol in preterm infants with or without respiratory distress syndrome (RDS) in reducing adverse neonatal outcomes including: death (neonatal and infant deaths), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC) and sepsis. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 11), MEDLINE via PubMed (1966 to 5 November 2018), Embase (1980 to 5 November 2018), and CINAHL (1982 to 5 November 2018). We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials. SELECTION CRITERIA: We included all randomised controlled trials of inositol supplementation of preterm infants compared with a control group that received a placebo or no intervention. Outcomes included neonatal death, infant death, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC) and sepsis. DATA COLLECTION AND ANALYSIS: The three review authors independently abstracted data on neonatal outcomes and resolved any disagreements through discussion and consensus. Outcomes were reported as typical risk ratio (RR), risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: Six published randomised controlled trials were identified, with a total of 1177 infants. Study quality varied for the comparison 'Inositol supplementation to preterm infants (repeat doses in any amount and any duration of treatment) versus control' and interim analyses had occurred in several trials for the outcomes of interest. In this comparison, neonatal death was found to be significantly reduced (typical RR 0.53, 95% CI 0.31 to 0.91; typical RD -0.09, 95% CI -0.16 to -0.01; NNTB 11, 95% CI 6 to 100; 3 trials, 355 neonates). Infant deaths were not reduced (typical RR 0.89, 95% CI 0.71 to 1.13; typical RD -0.02, 95% CI -0.07 to 0.02; 5 trials, 1115 infants) (low-quality evidence). ROP stage 2 or higher or stage 3 or higher was not significantly reduced (typical RR 0.89, 95% CI 0.75 to 1.06; typical RD -0.04, 95% CI -0.10 to 0.02; 3 trials, 810 infants) (moderate-quality evidence). There were no significant findings for ROP (any stage), NEC (suspected or proven), sepsis, IVH grade greater than II (moderate-quality evidence). For the comparison 'Inositol supplementation IV initially followed by enteral administration (repeat doses of 80 mg/kg/day) in preterm infants born at less than 30 weeks' postmenstrual age (PMA) compared to placebo for preterm infants at risk for or having respiratory distress syndrome' the results from two studies of high quality were included (N = 760 neonates). Recruitment to the larger study (N = 638) was terminated because of a higher rate of deaths in the inositol group. We did not downgrade the quality of the study. The meta-analyses of the outcomes of 'Type 1 ROP or death before determination of ROP outcome using the adjudicated ROP outcome', 'Type 1 ROP including adjudicated ROP outcome', 'All-cause mortality (outcome collected through first event: death, hospital discharge, hospital transfer, or 120 days after birth)' and 'Severe IVH (grade 3 or 4)' did not show significant findings (moderate-quality evidence). There were no significant findings for the outcomes 'BPD or death by it prior to 37 weeks' postmenstrual age (outcomes collected through first event: death, hospital discharge, hospital transfer, or 120 days after birth)', 'Late onset sepsis (> 72 hours of age)', and 'Suspected or proven NEC' (high-quality evidence). AUTHORS' CONCLUSIONS: Based on the evidence from randomised controlled trials to date, inositol supplementation does not result in important reductions in the rates of infant deaths, ROP stage 3 or higher, type 1 ROP, IVH grades 3 or 4, BPD, NEC, or sepsis. These conclusions are based mainly on two recent randomised controlled trials in neonates less than 30 weeks' postmenstrual age (N = 760), the most vulnerable population. Currently inositol supplementation should not be routinely instituted as part of the nutritional management of preterm infants with or without RDS. It is important that infants who have been enrolled in the trials included in this review are followed to assess any effects of inositol supplementation on long-term outcomes in childhood. We do not recommend any additional trials in neonates.

Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.

BACKGROUND: Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal, and cerebral side effects. Ibuprofen has less effect on blood flow velocity to important organs. OBJECTIVES: Primary objectivesTo determine the effectiveness and safety of ibuprofen compared to placebo/no intervention, or other cyclo-oxygenase inhibitor drugs in the prevention of PDA in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10), MEDLINE via PubMed (1966 to 17 October 2018), Embase (1980 to 17 October 2018), and CINAHL; 1982 to 17 October 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted outcomes data including presence of PDA on day three or four of life (after 72 hours of treatment), need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, cerebral, renal, pulmonary, and gastrointestinal complications. We performed meta-analyses and reported treatment estimates as typical mean difference (MD), risk ratio (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNTB) or to harm (NNTH), along with their 95% confidence intervals (CI). We assessed between-study heterogeneity by the I-squared test (I²). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: In this updated analysis, we included nine trials (N = 1070 infants) comparing prophylactic ibuprofen (IV or oral) with placebo/no intervention or indomethacin. Ibuprofen (IV or oral) probably decreases the risk of PDA on day 3 or 4 (typical RR 0.39, 95% CI 0.31 to 0.48; typical RD -0.26, 95% CI -0.31 to -0.21; NNTB 4, 95% CI 3 to 5; 9 trials; N = 1029) (moderate-quality evidence). In the control group, the spontaneous closure rate was 58% by day 3 to 4 of age. In addition, ibuprofen probably decreases the need for rescue treatment with cyclo-oxygenase inhibitors (typical RR 0.17, 95% CI 0.11 to 0.26; typical RD -0.27, 95% CI -0.32 to -0.22; NNTB 4; 95% CI 3 to 5),and the need for surgical ductal ligation (typical RR 0.46, 95% CI 0.22 to 0.96; typical RD -0.03, 95% CI -0.05 to -0.00; NNTB 33, 95% CI 20 to infinity; 7 trials; N = 925) (moderate-quality evidence). There was a possible decrease in the risk of grade 3 or 4 intraventricular haemorrhage (IVH) in infants receiving prophylactic ibuprofen (typical RR 0.67, 95% CI 0.45 to 1.00; I² = 34%; typical RD -0.04, 95% CI -0.08 to- 0.00; I² = 60%; 7 trials; N = 925) (moderate-quality evidence). High quality evidence showed increased risk for oliguria (typical RR 1.45, 95% CI 1.04 to 2.02; typical RD 0.06, 95% CI 0.01 to 0.11; NNTH 17, 95% CI 9 to 100; 4 trials; N = 747). Low quality results from four studies (N = 202) showed that administering oral ibuprofen may decrease the risk of PDA (typical RR 0.47, 95% CI 0.30 to 0.74) and may increase risk of gastrointestinal bleeding (NNTH 7, 95% CI 4 to 25). No evidence of a difference was identified for mortality, any intraventricular haemorrhage (IVH), or chronic lung disease. AUTHORS' CONCLUSIONS: This review shows that prophylactic use of ibuprofen, compared to placebo or no intervention, probably decreases the incidence of patent ductus arteriosus, the need for rescue treatment with cyclo-oxygenase inhibitors, and for surgical ductal closure. Adverse effects associated with ibuprofen (IV or oral) included increased risks for oliguria, increase in serum creatinine levels, and increased risk of gastrointestinal haemorrhage. There was a reduced risk for intraventricular haemorrhage (grade III - IV) but no evidence of a difference in mortality, chronic lung disease, necrotising enterocolitis, or time to reach full feeds. In the control group, the patent ductus arteriosus had closed spontaneously by day 3 or 4 in 58% of neonates. Prophylactic treatment exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short-term benefits. Current evidence does not support the use of ibuprofen for prevention of patent ductus arteriosus. Until long-term follow-up results of the trials included in this review have been published, no further trials of prophylactic ibuprofen are recommended.A new approach to patent ductus arteriosus management is an early targeted treatment based on echocardiographic criteria within the first 72 hours of life, that have a high sensitivity for diagnosing a patent ductus arteriosus that is unlikely to close spontaneously. Such trials are currently ongoing in many parts of the world. Results of such trials will be included in updates of our "Ibuprofen for treatment of PDA" review.

Late erythropoiesis-stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants.

BACKGROUND: Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia. Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES: To assess the effectiveness and safety of late initiation of ESAs, between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm or 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 2018, Issue 5), MEDLINE via PubMed (1966 to 5 June 2018), Embase (1980 to 5 June 2018), and CINAHL (1982 to 5 June 2018). We searched clinical trials databases, 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 of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) or low birth weight (< 2500 grams) neonates. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin.Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported. AUTHORS' CONCLUSIONS: Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants.

BACKGROUND: Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer adverse effects. OBJECTIVES: To determine the effectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor(s), placebo, or no intervention for closing a patent ductus arteriosus in preterm, low-birth-weight, or preterm and 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 10), MEDLINE via PubMed (1966 to 30 November 2017), Embase (1980 to 30 November 2017), and CINAHL (1982 to 30 November 2017). We searched clinical trials databases, 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 of ibuprofen for the treatment of a PDA in preterm, low birth weight, or both preterm and low-birth-weight newborn infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included 39 studies enrolling 2843 infants.Ibuprofen (IV) versus placebo: IV Ibuprofen (3 doses) reduced the failure to close a PDA compared with placebo (typical relative risk (RR); 0.62 (95% CI 0.44 to 0.86); typical risk difference (RD); -0.18 (95% CI -0.30 to -0.06); NNTB 6 (95% CI 3 to 17); I2 = 65% for RR and I2 = 0% for RD; 2 studies, 206 infants; moderate-quality the evidence). One study reported decreased failure to close a PDA after single or three doses of oral ibuprofen compared with placebo (64 infants; RR 0.26, 95% CI 0.11 to 0.62; RD -0.44, 95% CI -0.65 to -0.23; NNTB 2, 95% CI 2 to 4; I2 test not applicable).Ibuprofen (IV or oral) compared with indomethacin (IV or oral): Twenty-four studies (1590 infants) comparing ibuprofen (IV or oral) with indomethacin (IV or oral) found no significant differences in failure rates for PDA closure (typical RR 1.07, 95% CI 0.92 to 1.24; typical RD 0.02, 95% CI -0.02 to 0.06; I2 = 0% for both RR and RD; moderate-quality evidence). A reduction in NEC (necrotising enterocolitis) was noted in the ibuprofen (IV or oral) group (18 studies, 1292 infants; typical RR 0.68, 95% CI 0.49 to 0.94; typical RD -0.04, 95% CI -0.07 to -0.01; NNTB 25, 95% CI 14 to 100; I2 = 0% for both RR and RD; moderate-quality evidence). There was a statistically significant reduction in the proportion of infants with oliguria in the ibuprofen group (6 studies, 576 infants; typical RR 0.28, 95% CI 0.14 to 0.54; typical RD -0.09, 95% CI -0.14 to -0.05; NNTB 11, 95% CI 7 to 20; I2 = 24% for RR and I2 = 69% for RD; moderate-quality evidence). The serum/plasma creatinine levels 72 hours after initiation of treatment were statistically significantly lower in the ibuprofen group (11 studies, 918 infants; MD -8.12 µmol/L, 95% CI -10.81 to -5.43). For this comparison, there was high between-study heterogeneity (I2 = 83%) and low-quality evidence.Ibuprofen (oral) compared with indomethacin (IV or oral): Eight studies (272 infants) reported on failure rates for PDA closure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (IV or oral). There was no significant difference between the groups (typical RR 0.96, 95% CI 0.73 to 1.27; typical RD -0.01, 95% CI -0.12 to 0.09; I2 = 0% for both RR and RD). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (IV or oral) (7 studies, 249 infants; typical RR 0.41, 95% CI 0.23 to 0.73; typical RD -0.13, 95% CI -0.22 to -0.05; NNTB 8, 95% CI 5 to 20; I2 = 0% for both RR and RD). There was low-quality evidence for these two outcomes. There was a decreased risk of failure to close a PDA with oral ibuprofen compared with IV ibuprofen (5 studies, 406 infants; typical RR 0.38, 95% CI 0.26 to 0.56; typical RD -0.22, 95% CI -0.31 to -0.14; NNTB 5, 95% CI 3 to 7; moderate-quality evidence). There was a decreased risk of failure to close a PDA with high-dose versus standard-dose of IV ibuprofen (3 studies 190 infants; typical RR 0.37, 95% CI 0.22 to 0.61; typical RD - 0.26, 95% CI -0.38 to -0.15; NNTB 4, 95% CI 3 to 7); I2 = 4% for RR and 0% for RD); moderate-quality evidence).Early versus expectant administration of IV ibuprofen, echocardiographically-guided IV ibuprofen treatment versus standard IV ibuprofen treatment, continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, and rectal ibuprofen versus oral ibuprofen were studied in too few trials to allow for precise estimates of any clinical outcomes. AUTHORS' CONCLUSIONS: Ibuprofen is as effective as indomethacin in closing a PDA. Ibuprofen reduces the risk of NEC and transient renal insufficiency. Therefore, of these two drugs, ibuprofen appears to be the drug of choice. The effectiveness of ibuprofen versus paracetamol is assessed in a separate review. Oro-gastric administration of ibuprofen appears as effective as IV administration. To make further recommendations, studies are needed to assess the effectiveness of high-dose versus standard-dose ibuprofen, early versus expectant administration of ibuprofen, echocardiographically-guided versus standard IV ibuprofen, and continuous infusion versus intermittent boluses of ibuprofen. Studies are lacking evaluating the effect of ibuprofen on longer-term outcomes in infants with PDA.

Neurobehavioral Outcomes 11 Years After Neonatal Caffeine Therapy for Apnea of Prematurity.

BACKGROUND AND OBJECTIVES: Caffeine is effective in the treatment of apnea of prematurity. Although caffeine therapy has a benefit on gross motor skills in school-aged children, effects on neurobehavioral outcomes are not fully understood. We aimed to investigate effects of neonatal caffeine therapy in very low birth weight (500-1250 g) infants on neurobehavioral outcomes in 11-year-old participants of the Caffeine for Apnea of Prematurity trial. METHODS: Thirteen academic hospitals in Canada, Australia, Great Britain, and Sweden participated in this part of the 11-year follow-up of the double-blind, randomized, placebo-controlled trial. Measures of general intelligence, attention, executive function, visuomotor integration and perception, and behavior were obtained in up to 870 children. The effects of caffeine therapy were assessed by using regression models. RESULTS: Neurobehavioral outcomes were generally similar for both the caffeine and placebo group. The caffeine group performed better than the placebo group in fine motor coordination (mean difference [MD] = 2.9; 95% confidence interval [CI]: 0.7 to 5.1; P = .01), visuomotor integration (MD = 1.8; 95% CI: 0.0 to 3.7; P < .05), visual perception (MD = 2.0; 95% CI: 0.3 to 3.8; P = .02), and visuospatial organization (MD = 1.2; 95% CI: 0.4 to 2.0; P = .003). CONCLUSIONS: Neonatal caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine, which highlights the long-term safety of caffeine therapy for apnea of prematurity in very low birth weight neonates.

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants.

BACKGROUND: In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically; or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. An association between prenatal or postnatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported. OBJECTIVES: To determine the effectiveness and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for treatment of an echocardiographically diagnosed PDA in preterm or 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 10), MEDLINE via PubMed (1966 to 6 November 2017), Embase (1980 to 6 November 2017), and CINAHL (1982 to 6 November 2017). We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials. SELECTION CRITERIA: We included RCTs in which paracetamol was compared to no intervention, placebo or other agents used for closure of PDA irrespective of dose, duration and mode of administration in preterm (≤ 34 weeks' postmenstrual age) infants. We both reviewed the search results and made a final selection of potentially eligible articles by discussion. We included studies of both prophylactic and therapeutic use of paracetamol. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence for the following outcomes when data were available: failure of ductal closure after the first course of treatment; neurodevelopmental impairment; all-cause mortality during initial hospital stay (death); gastrointestinal bleed or stools positive for occult blood; and serum levels of creatinine after treatment (µmol/L). MAIN RESULTS: We included eight studies that reported on 916 infants. One of these studies compared paracetamol to both ibuprofen and indomethacin. Five studies compared treatment of PDA with paracetamol versus ibuprofen and enrolled 559 infants. There was no significant difference between paracetamol and ibuprofen for failure of ductal closure after the first course of drug administration (typical risk ratio (RR) 0.95, 95% confidence interval (CI) 0.75 to 1.21; typical risk difference (RD) -0.02, 95% CI -0.09 to 0.09); I² = 0% for RR and RD; moderate quality of evidence. Four studies (n = 537) reported on gastrointestinal bleed which was lower in the paracetamol group versus the ibuprofen group (typical RR 0.28, 95% CI 0.12 to 0.69; typical RD -0.06, 95% CI -0.09 to -0.02); I² = 0% for RR and RD; number needed to treat for an additional beneficial outcome (NNTB) 17 (95% CI 11 to 50); moderate quality of evidence. The serum levels of creatinine were lower in the paracetamol group compared with the ibuprofen group in four studies (moderate quality of evidence), as were serum bilirubin levels following treatment in two studies (n = 290). Platelet counts and daily urine output were higher in the paracetamol group compared with the ibuprofen group. One study reported on long-term follow-up to 18 to 24 months of age following treatment with paracetamol versus ibuprofen. There were no significant differences in the neurological outcomes at 18 to 24 months (n = 61); (low quality of evidence).Two studies compared prophylactic administration of paracetamol for a PDA with placebo or no intervention in 80 infants. Paracetamol resulted in a lower rate of failure of ductal closure after 4 to 5 days of treatment compared to placebo or no intervention which was of borderline significance for typical RR 0.49 (95% CI 0.24 to 1.00; P = 0.05); but significant for typical RD -0.21 (95% CI -0.41 to -0.02); I² = 0 % for RR and RD; NNTB 5 (95% CI 2 to 50); (low quality of evidence).Two studies (n = 277) compared paracetamol with indomethacin. There was no significant difference in the failure to close a PDA (typical RR 0.96, 95% CI 0.55 to 1.65; I² = 11%; typical RD -0.01, 95% CI -0.09 to 0.08; I² = 17%) (low quality of evidence). Serum creatinine levels were significantly lower in the paracetamol group compared with the indomethacin group and platelet counts and daily urine output were significantly higher in the paracetamol group. AUTHORS' CONCLUSIONS: Moderate-quality evidence according to GRADE suggests that paracetamol is as effective as ibuprofen; low-quality evidence suggests paracetamol to be more effective than placebo or no intervention; and low-quality evidence suggests paracetamol as effective as indomethacin in closing a PDA. There was no difference in neurodevelopmental outcome in children exposed to paracetamol compared to ibuprofen; however the quality of evidence is low and comes from only one study. In view of concerns raised regarding neurodevelopmental outcomes following prenatal and postnatal exposure to paracetamol, long-term follow-up to at least 18 to 24 months' postnatal age must be incorporated in any studies of paracetamol in the newborn population. At least 19 ongoing trials have been registered. Such trials are required before any recommendations for the possible routine use of paracetamol in the newborn population can be made.

Early erythropoiesis-stimulating agents in preterm or low birth weight infants.

BACKGROUND: Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES: To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions:To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives:Review authors performed subgroup analyses of low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (≤ 5 mg/kg/d), and high (> 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs:To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance:To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives:To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. MAIN RESULTS: This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment.Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low.Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate.Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low.Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the ESA group (weighted mean difference (WMD) 8.22, 95% CI 6.52 to 9.92; I2 = 97% (high heterogeneity); 3 studies, 981 children). The quality of the evidence was low.The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced. Data show no significant difference in risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI -0.02 to 0.04; I2 = 0% (no heterogeneity) for RR; I2 = 34% (low heterogeneity) for RD; 8 studies, 1283 infants). Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL). AUTHORS' CONCLUSIONS: Early administration of ESAs reduces the use of red blood cell (RBC) transfusions, the volume of RBCs transfused, and donor exposure after study entry. Small reductions are likely to be of limited clinical importance. Donor exposure probably is not avoided, given that all but one study included infants who had received RBC transfusions before trial entry. This update found no significant difference in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age, which has been a topic of concern in earlier versions of this review. Early EPO treatment significantly decreased rates of IVH, PVL, and NEC. Neurodevelopmental outcomes at 18 to 22 months and later varied in published studies. Ongoing research should evaluate current clinical practices that will limit donor exposure. Promising but conflicting results related to the neuro protective effect of early EPO require further study. Very different results from the two largest published trials and high heterogeneity in the analyses indicate that we should wait for the results of two ongoing large trials before drawing firm conclusions. Administration of EPO is not currently recommended because limited benefits have been identified to date. Use of darepoetin requires further study.