Intravenous immunoglobulin G therapy for neonatal hyperbilirubinemia.

BACKGROUND: Neonatal hyperbilirubinemia (NHb) results from increased total serum bilirubin and is a common reason for admission and readmission amongst newborn infants born in North America. The use of intravenous immunoglobulin (IVIG) therapy for treating NHb has been widely debated, and the current incidence of NHb and its therapies remain unknown. METHODS: Using national and provincial databases, a population-based retrospective cohort study of infants born in Ontario from April 2014 to March 2018 was conducted. RESULTS: Of the 533,084 infants born in Ontario at ≥35 weeks gestation, 29,756 (5.6%) presented with NHb. Among these infants, 80.1-88.2% received phototherapy, 1.1-2.0% received IVIG therapy and 0.1-0.2% received exchange transfusion (ET) over the study period. Although phototherapy was administered (83.0%) for NHb, its use decreased from 2014 to 2018 (88.2-80.1%) (P < 0.01). Similarly, the incidence of IVIG therapy increased from 71 to 156 infants (1.1-2.0%) (P < 0.01) and a small change in the incidence of ET (0.2-0.1%) was noted. CONCLUSION: IVIG therapy is increasingly being used in Ontario despite limited studies evaluating its use. The results of this study could inform treatment and management protocols for NHb. IMPACTS: Clinically significant neonatal hyperbilirubinemia still occurs in Ontario, with an increasing number of infants receiving Intravenous Immunoglobulin G (IVIG) therapy. IVIG continues to be used at increasing rates despite inconclusive evidence to recommend its use. This study highlights the necessity of a future prospective study to better determine the effectiveness of IVIG use in treating neonatal hyperbilirubinemia, especially given the recent shortage in IVIG supply in Ontario. The results of this study could inform treatment and management protocols for neonatal hyperbilirubinemia.

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.

Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews.

BACKGROUND: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Several non-pharmacological, pharmacological, and surgical approaches have been explored to prevent or treat a PDA. OBJECTIVES: To summarise Cochrane Neonatal evidence on interventions (pharmacological or surgical) for the prevention of PDA and related complications, and interventions for the management of asymptomatic and symptomatic PDA in preterm infants. METHODS: We searched the Cochrane Database of Systematic Reviews on 20 October 2022 for ongoing and published Cochrane Reviews on the prevention and treatment of PDA in preterm (< 37 weeks' gestation) or low birthweight (< 2500 g) infants. We included all published Cochrane Reviews assessing the following categories of interventions: pharmacological therapy using prostaglandin inhibitor drugs (indomethacin, ibuprofen, and acetaminophen), adjunctive pharmacological interventions, invasive PDA closure procedures, and non-pharmacological interventions. Two overview authors independently checked the eligibility of the reviews retrieved by the search, and extracted data from the included reviews using a predefined data extraction form. Any disagreements were resolved by discussion with a third overview author. Two overview authors independently assessed the methodological quality of the included reviews using the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews) tool. We reported the GRADE certainty of evidence as assessed by the respective review authors using summary of findings tables. MAIN RESULTS: We included 16 Cochrane Reviews, corresponding to 138 randomised clinical trials (RCT) and 11,856 preterm infants, on the prevention and treatment of PDA in preterm infants. One of the 16 reviews had no included studies, and therefore, did not contribute to the results. Six reviews reported on prophylactic interventions for the prevention of PDA and included pharmacological prophylaxis with prostaglandin inhibitor drugs, prophylactic surgical PDA ligation, and non-pharmacologic interventions (chest shielding during phototherapy and restriction of fluid intake); one review reported on the use of indomethacin for the management of asymptomatic PDA; nine reviews reported on interventions for the management of symptomatic PDA, and included pharmacotherapy with prostaglandin inhibitor drugs in various routes and dosages, surgical PDA ligation, and adjunct therapies (use of furosemide and dopamine in conjunction with indomethacin). The quality of reviews varied. Two reviews were assessed to be high quality, seven reviews were of moderate quality, five of low quality, while two reviews were deemed to be of critically low quality. For prevention of PDA, prophylactic indomethacin reduces severe intraventricular haemorrhage (IVH; relative risk (RR) 0.66, 95% confidence interval (CI) 0.53 to 0.82; 14 RCTs, 2588 infants), and the need for invasive PDA closure (RR 0.51, 95% CI 0.37 to 0.71; 8 RCTs, 1791 infants), but it does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability (RR 1.02, 95% CI 0.90 to 1.15; 3 RCTs, 1491 infants). Prophylactic ibuprofen probably marginally reduces severe IVH (RR 0.67, 95% CI 0.45 to 1.00; 7 RCTs, 925 infants; moderate-certainty evidence), and the need for invasive PDA closure (RR 0.46, 95% CI 0.22 to 0.96; 7 RCTs, 925 infants; moderate-certainty evidence). The evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH (RR 1.09, 95% CI 0.07 to 16.39; 1 RCT, 48 infants). Necrotising enterocolitis (NEC) was lower with both prophylactic surgical ligation (RR 0.25, 95% CI 0.08 to 0.83; 1 RCT, 84 infants), and fluid restriction (RR 0.43, 95% CI 0.21 to 0.87; 4 RCTs, 526 infants). For treatment of asymptomatic PDA, indomethacin appears to reduce the development of symptomatic PDA post-treatment (RR 0.36, 95% CI 0.19 to 0.68; 3 RCTs, 97 infants; quality of source review: critically low). For treatment of symptomatic PDA, all available prostaglandin inhibitor drugs appear to be more effective in closing a PDA than placebo or no treatment (indomethacin: RR 0.30, 95% CI 0.23 to 0.38; 10 RCTs, 654 infants; high-certainty evidence; ibuprofen: RR 0.62, 95% CI 0.44 to 0.86; 2 RCTs, 206 infants; moderate-certainty evidence; early administration of acetaminophen: RR 0.35, 95% CI 0.23 to 0.53; 2 RCTs, 127 infants; low-certainty evidence). Oral ibuprofen appears to be more effective in PDA closure than intravenous (IV) ibuprofen (RR 0.38, 95% CI 0.26 to 0.56; 5 RCTs, 406 infants; moderate-certainty evidence). High-dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (RR 0.37, 95% CI 0.22 to 0.61; 3 RCTs, 190 infants; moderate-certainty evidence). With respect to adverse outcomes, compared to indomethacin administration, NEC appears to be lower with ibuprofen (any route; RR 0.68, 95% CI 0.49 to 0.94; 18 RCTs, 1292 infants; moderate-certainty evidence), oral ibuprofen (RR 0.41, 95% CI 0.23 to 0.73; 7 RCTs, 249 infants; low-certainty evidence), and with acetaminophen (RR 0.42, 95% CI 0.19 to 0.96; 4 RCTs, 384 infants; low-certainty evidence). However, NEC appears to be increased with a prolonged course of indomethacin versus a shorter course (RR 1.87, 95% CI 1.07 to 3.27; 4 RCTs, 310 infants). AUTHORS' CONCLUSIONS: This overview summarised the evidence from 16 Cochrane Reviews of RCTs regarding the effects of interventions for the prevention and treatment of PDA in preterm infants. Prophylactic indomethacin reduces severe IVH, but does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability. Prophylactic ibuprofen probably marginally reduces severe IVH (moderate-certainty evidence), while the evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH. All available prostaglandin inhibitor drugs appear to be effective in symptomatic PDA closure compared to no treatment (high-certainty evidence for indomethacin; moderate-certainty evidence for ibuprofen; low-certainty evidence for early administration of acetaminophen). Oral ibuprofen appears to be more effective in PDA closure than IV ibuprofen (moderate-certainty evidence). High dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (moderate-certainty evidence). There are currently two ongoing reviews, one on fluid restriction for symptomatic PDA, and the other on invasive management of PDA in preterm infants.

Systemic corticosteroids for the prevention of bronchopulmonary dysplasia, a network meta-analysis.

BACKGROUND: Despite considerable improvement in outcomes for preterm infants, rates of bronchopulmonary dysplasia (BPD) remain high, affecting an estimated 33% of very low birthweight infants, with corresponding long-term respiratory and neurosensory issues. Systemic corticosteroids can address the inflammation underlying BPD, but the optimal regimen for prevention of this disease, balancing of the benefits with the potentially meaningful risks of systemic corticosteroids, continues to be a medical quandary. Numerous studies have shown that systemic corticosteroids, particularly dexamethasone and hydrocortisone, effectively treat or prevent BPD. However, concerning short and long-term side effects have been reported and the optimal approach to corticosteroid treatment remains unclear. OBJECTIVES: To determine whether differences in efficacy and safety exist between high-dose dexamethasone, moderate-dose dexamethasone, low-dose dexamethasone, hydrocortisone, and placebo in the prevention of BPD, death, the composite outcome of death or BPD, and other relevant morbidities, in preterm infants through a network meta-analysis, generating both pairwise comparisons between all treatments and rankings of the treatments. SEARCH METHODS: We searched the Cochrane Library for all systematic reviews of systemic corticosteroids for the prevention of BPD and searched for completed and ongoing studies in the following databases in January 2023: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial databases. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in preterm infants (< 37 weeks' gestation) at risk for BPD that evaluated systemic corticosteroids (high-dose [≥ 4 mg/kg cumulative dose] dexamethasone, moderate-dose [≥ 2 to < 4 mg/kg] dexamethasone, low-dose [< 2 mg/kg] dexamethasone, or hydrocortisone) versus control or another systemic corticosteroid. DATA COLLECTION AND ANALYSIS: Our main information sources were the systematic reviews, with reference to the original manuscript only for data not included in these reviews. Teams of two paired review authors independently performed data extraction, with disagreements resolved by discussion. Data were entered into Review Manager 5 and exported to R software for network meta-analysis (NMA). NMA was performed using a frequentist model with random-effects. Two separate networks were constructed, one for early (< seven days) initiation of treatment and one for late (≥ seven days) treatment initiation, to reflect the different patient populations evaluated. We assessed the certainty of evidence derived from the NMA for our primary outcomes using principles of the GRADE framework modified for application to NMA. MAIN RESULTS: We included 59 studies, involving 6441 infants, in our analyses. Only six of the included studies provided direct comparisons between any of the treatment (dexamethasone or hydrocortisone) groups, forcing network comparisons between treatments to rely heavily on indirect evidence through comparisons with placebo/no treatment groups. Thirty-one studies evaluated early corticosteroid treatment, 27 evaluated late corticosteroid treatment, and one study evaluated both early and late corticosteroid treatments. Early treatment (prior to seven days after birth): Benefits:NMA for early treatment showed only moderate-dose dexamethasone to decrease the risk of BPD at 36 weeks' postmenstrual age (PMA) compared with control (RR 0.56, 95% CI 0.39 to 0.80; moderate-certainty evidence), although the other dexamethasone dosing regimens may have similar effects compared with control (high-dose dexamethasone, RR 0.71, 95% CI 0.50 to 1.01; low-certainty evidence; low-dose dexamethasone, RR 0.83, 95% CI 0.67 to 1.03; low-certainty evidence). Other early treatment regimens may have little or no effect on the risk of death at 36 weeks' PMA. Only moderate-dose dexamethasone decreased the composite outcome of death or BPD at 36 weeks' PMA compared with control (RR 0.77, 95% CI 0.60 to 0.98; moderate-certainty evidence). HARMS: Low-dose dexamethasone increased the risk for cerebral palsy (RR 1.92, 95% CI 1.12 to 3.28; moderate-certainty evidence) compared with control. Hydrocortisone may decrease the risk of major neurosensory disability versus low-dose dexamethasone (RR 0.65, 95% CI 0.41 to 1.01; low-certainty evidence). Late treatment (at seven days or later after birth): Benefits: NMA for late treatment showed high-dose dexamethasone to decrease the risk of BPD both versus hydrocortisone (RR 0.66, 95% CI 0.51 to 0.85; low-certainty evidence) and versus control (RR 0.72, CI 0.59 to 0.87; moderate-certainty evidence). The late treatment regimens evaluated may have little or no effect on the risk of death at 36 weeks' PMA. High-dose dexamethasone decreased risk for the composite outcome of death or BPD compared with all other treatments (control, RR 0.69, 95% CI 0.59 to 0.80, high-certainty evidence; hydrocortisone, RR 0.69, 95% CI 0.58 to 0.84, low-certainty evidence; low-dose dexamethasone, RR 0.73, 95% CI 0.60 to 0.88, low-certainty evidence; moderate-dose dexamethasone, RR 0.76, 95% CI 0.62 to 0.93, low-certainty evidence). HARMS: No effect was observed for the outcomes of major neurosensory disability or cerebral palsy. The evidence for the primary outcomes was of overall low certainty, with notable deductions for imprecision and heterogeneity across the networks. AUTHORS' CONCLUSIONS: While early treatment with moderate-dose dexamethasone or late treatment with high-dose dexamethasone may lead to the best effects for survival without BPD, the certainty of the evidence is low. There is insufficient evidence to guide this therapy with regard to plausible adverse long-term outcomes. Further RCTs with direct comparisons between systemic corticosteroid treatments are needed to determine the optimal treatment approach, and these studies should be adequately powered to evaluate survival without major neurosensory disability.

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

BACKGROUND: The different management strategies for patent ductus arteriosus (PDA) in preterm infants are expectant management, surgery, or medical treatment with non-selective cyclo-oxygenase inhibitors. Randomized controlled trials (RCTs) have suggested that paracetamol may be an effective and safe agent for the closure of a PDA. OBJECTIVES: To determine the efficacy and safety of paracetamol as monotherapy or as part of combination therapy via any route of administration, compared with placebo, no intervention, or another prostaglandin inhibitor, for prophylaxis or treatment of an echocardiographically-diagnosed PDA in preterm or low birth weight infants. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and three trials registers on 13 October 2021, and one other database on 1 March 2022. We also checked references and contacted study authors to identify additional studies. SELECTION CRITERIA: We included RCTs and quasi-RCTs in which paracetamol (single-agent or combination therapy) was compared to no intervention, placebo, or other agents used for closure of PDA, irrespective of dose, duration, and mode of administration in preterm infants. Two independent authors reviewed the search results and made a final selection of potentially eligible articles through discussion. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of Cochrane Neonatal. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of ductal closure after the first course of treatment; all-cause mortality during initial hospital stay; and necrotizing enterocolitis (NEC). MAIN RESULTS: For this update, we included 27 studies enrolling 2278 infants. We considered the overall risk of bias in the 27 studies to vary from low to unclear. We identified 24 ongoing studies. Paracetamol versus ibuprofen  There was probably little to no difference between paracetamol and ibuprofen for failure of ductal closure after the first course (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.18; 18 studies, 1535 infants; moderate-certainty evidence). There was likely little to no difference between paracetamol and ibuprofen for all-cause mortality during hospital stay (RR 1.09, 95% CI 0.80 to 1.48; 8 studies, 734 infants; moderate-certainty evidence), and for NEC (RR 1.30, 95% CI 0.87 to 1.94; 10 studies, 1015 infants; moderate-certainty evidence). Paracetamol versus indomethacin There was little to no difference between paracetamol and indomethacin for failure of ductal closure after the first course (RR 1.02, 95% CI 0.78 to 1.33; 4 studies, 380 infants; low-certainty evidence). There was little to no difference between paracetamol and indomethacin for all-cause mortality during hospital stay (RR 0.86, 95% CI 0.39 to 1.92; 2 studies, 114 infants; low-certainty evidence). The rate of NEC may be lower in the paracetamol group (3.7%) versus the indomethacin group(9.2%) (RR 0.42, 95% CI 0.19 to 0.96; 4 studies, 384 infants; low-certainty evidence).  Prophylactic paracetamol versus placebo/no intervention Prophylactic paracetamol (17%) compared to placebo/no intervention (61%) may reduce failure of ductal closure after one course (RR 0.27, 95% CI 0.18 to 0.42; 3 studies, 240 infants; low-certainty evidence). There was little to no difference between prophylactic paracetamol and placebo/no intervention for all-cause mortality during hospital stay (RR 0.59, 95% CI 0.24 to 1.44; 3 studies, 240 infants; low-certainty evidence). No studies reported on NEC.  Early paracetamol treatment versus placebo/no intervention Early paracetamol treatment (28%) compared to placebo/no intervention (79%) may reduce failure of ductal closure after one course when used before 14 days' postnatal age (RR 0.35, 95% CI 0.23 to 0.53; 2 studies, 127 infants; low-certainty evidence). No studies reported on all-cause mortality during hospital stay or NEC.  Late paracetamol treatment versus placebo/no intervention  There was little to no difference between late paracetamol and placebo for failure of ductal closure after one course of treatment when used at or after 14 days' postnatal age (RR 0.85, 95% CI 0.72 to 1.01; 1 study, 55 infants; low-certainty evidence) or NEC (RR 1.04, 95% CI 0.07 to 15.76; 1 study, 55 infants; low-certainty evidence). No data were reported for all-cause mortality during hospital stay.  Paracetamol combined with ibuprofen versus ibuprofen combined with placebo or no intervention There was little to no difference between paracetamol plus ibuprofen compared to ibuprofen plus placebo or no intervention for failure of ductal closure after the first course (RR 0.77, 95% CI 0.43 to 1.36; 2 studies, 111 infants; low-certainty evidence). There was little to no difference between paracetamol plus ibuprofen compared to ibuprofen plus placebo or no intervention for NEC (RR 0.33, 95% CI 0.01 to 7.45; 1 study, 24 infants; low-certainty evidence). No data were reported for all-cause mortality during hospital stay.  AUTHORS' CONCLUSIONS: Moderate-certainty evidence suggests that there is probably little or no difference in effectiveness between paracetamol and ibuprofen; low-certainty evidence suggests that there is probably little or no difference in effectiveness between paracetamol and indomethacin; low-certainty evidence suggests that prophylactic paracetamol may be more effective than placebo/no intervention; low-certainty evidence suggests that early paracetamol treatment may be more effective than placebo/no intervention; low-certainty evidence suggests that there is probably little or no difference between late paracetamol treatment and placebo, and probably little or no difference in effectiveness between the combination of paracetamol plus ibuprofen versus ibuprofen alone for the closure of PDA after the first course of treatment. The majority of neonates included in these studies were of moderate preterm gestation. Thus, establishing the efficacy and safety of paracetamol for PDA treatment in extremely low birth weight (ELBW: birth weight < 1000 grams) and extremely low gestational age neonates (ELGANs < 28 weeks' gestation) requires further studies.

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.

Different unfractionated heparin doses for preventing arterial thrombosis in children undergoing cardiac catheterization.

BACKGROUND: The role of cardiac catheterization in pediatrics has progressed significantly over the last two decades, evolving from a primary diagnostic tool to a primary treatment modality in children with congenital heart disease. Vascular complications, particularly arterial thrombosis, are among the most common unwanted post-cardiac catheterization events. In 1974, unfractionated heparin proved to be superior to placebo in decreasing the incidence of arterial thrombosis in pediatric patients. However, the optimal dose of unfractionated heparin to be utilized in this setting remains a matter of controversy. This is an update of the review first published in 2014. OBJECTIVES: To evaluate the use of low-dose (< 100 units/kg) versus high-dose (≥ 100 units/kg) unfractionated heparin administered as an intravenous bolus at the time of initiation of cardiac catheterization (that is, immediately after arterial puncture), with or without subsequent heparin maintenance doses, for the prevention of post-procedural arterial thrombosis in children. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 15 October 2019. We planned to undertake reference checking of identified trials to identify additional studies. No language restrictions were applied. SELECTION CRITERIA: We included randomized or quasi-randomized trials that compared low dose to high dose unfractionated heparin administered prior to cardiac catheterization. We selected studies conducted in children aged 0 to 18 years. DATA COLLECTION AND ANALYSIS: The first screening of potentially eligible studies was conducted by one of the authors (MLA). The second screening, risk of bias assessment and data extraction were independently conducted by two authors (MLA, LRB). Outcomes (thrombotic events, bleeding complications, other complications) were treated as dichotomous variables. The effect measures used were risk ratio (RR), risk difference (RD) and number needed to treat (NNT), with 95% confidence intervals (CI). We assessed the certainty of evidence for each outcome using the GRADE approach. MAIN RESULTS: We identified no new studies for inclusion in this review. In total, two studies with a total of 492 participants were included. We had concerns about risk of bias for one of the two studies. The certainty of the evidence for our key outcomes was downgraded to moderate due to risk of bias concerns and imprecision. The confidence interval for the risk of arterial thrombotic events was compatible with benefits of either high or low unfractionated heparin dose regimens (RR low-dose versus high-dose 1.06, 95% CI 0.58 to 1.92). Only one of the studies reported the frequency of bleeding events and found no clear difference in the incidence of major or minor bleeding events between arms (RR low-dose versus high-dose 2.96, 95% CI 0.12 to 71.34 for major bleeding events; RR low-dose versus high-dose 1.38, 95% CI 0.46 to 4.13 for minor bleeding). This study also reported on the incidence of deep vein thrombosis when comparing the high versus low dose of heparin and reported a non-significant difference (RR low-dose versus high-dose 0.34, 95% CI 0.01 to 8.28). The other study lacked information about bleeding. Additional side effects of heparin other than bleeding events were not reported in either of the studies. AUTHORS' CONCLUSIONS: Due to the limitations of the current evidence, small number of included studies, and lack of details reported in one study, we are unable to determine the effects of different dosing regimens of unfractionated heparin for the prevention of vascular thrombosis during cardiac catheterization in children. Further adequately powered, randomized clinical trials are needed.

Review of guidelines and recommendations from 17 countries highlights the challenges that clinicians face caring for neonates born to mothers with COVID-19.

AIM: This review examined how applicable national and regional clinical practice guidelines and recommendations for managing neonates born to mothers with COVID-19 mothers were to the evolving pandemic. METHODS: A systematic search and review identified 20 guidelines and recommendations that had been published by May 25, 2020. We analysed documents from 17 countries: Australia, Brazil, Canada, China, France, India, Italy, Japan, Saudi Arabia, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, the UK and the United States. RESULTS: The documents were based on expert consensus with limited evidence and were of variable, low methodological rigour. Most did not provide recommendations for delivery methods or managing symptomatic infants. None provided recommendations for post-discharge assimilation of potentially infected infants into the community. The majority encouraged keeping mothers and infants together, subject to infection control measures, but one-third recommended separation. Although breastfeeding or using breastmilk was widely encouraged, two countries specifically prohibited this. CONCLUSION: The guidelines and recommendations for managing infants affected by COVID-19 were of low, variable quality and may be unsustainable. It is important that transmission risks are not increased when new information is incorporated into clinical recommendations. Practice guidelines should emphasise the extent of uncertainty and clearly define gaps in the evidence.

Interventions for preventing osteoradionecrosis of the jaws in adults receiving head and neck radiotherapy.

BACKGROUND: Osteoradionecrosis (ORN) of the jaws is among the most serious oral complications of head and neck cancer radiotherapy, arising from radiation-induced fibro-atrophic tissue injury, manifested by necrosis of osseous tissues and failure to heal, often secondary to operative interventions in the oral cavity. It is associated with considerable morbidity and has important quality of life ramifications. Since ORN is very difficult to treat effectively, preventive measures to limit the onset of this disease are needed; however, the effects of various preventive interventions has not been adequately quantified. OBJECTIVES: To assess the effects of interventions for preventing ORN of the jaws in adult patients with head and neck cancer undergoing curative or adjuvant (i.e. non-palliative) radiotherapy. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 5 November 2019), the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 10) in the Cochrane Library (searched 5 November 2019), MEDLINE Ovid (1946 to 5 November 2019), Embase Ovid (1980 to 5 November 2019), Allied and Complementary Medicine (AMED) Ovid (1985 to 5 November 2019), Scopus (1966 to 5 November 2019), Proquest Dissertations and Theses International (1861 to 5 November 2019) and Web of Science Conference Proceedings (1990 to 5 November 2019). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) or quasi-RCTs of adult patients 18 years or older with head and neck cancer who had undergone curative or adjuvant radiotherapy to the head and neck, who had received an intervention to prevent the onset of ORN. Eligible patients were those subjected to pre- or post-irradiation dental evaluation. Management of these patients was to be with interventions independent of their cancer therapy, including but not limited to local, systemic, or behavioural interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials from search results, assessed risk of bias, and extracted relevant data for inclusion in the review. Authors of included studies were contacted to request missing data. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Four studies were identified that met pre-determined eligibility criteria, evaluating a total of 342 adults. From the four studies, all assessed as at high risk of bias, three broad interventions were identified that may potentially reduce the risk of ORN development: one study showed no reduction in ORN when using platelet-rich plasma placed in the extraction sockets of prophylactically removed healthy mandibular molar teeth prior to radiotherapy (odds ratio (OR) 3.32, 95% confidence interval (CI) 0.58 to 19.09; one trial, 44 participants; very low-certainty evidence). Another study involved comparing fluoride gel and high-content fluoride toothpaste (1350 parts per million (ppm)) in prevention of post-radiation caries, and found no difference between their use as no cases of ORN were reported (one trial, 220 participants; very low-certainty evidence). The other two studies involved the use of perioperative hyperbaric oxygen (HBO) therapy and antibiotics. One study showed that treatment with HBO caused a reduction in the development of ORN in comparison to patients treated with antibiotics following dental extractions (risk ratio (RR) 0.18, 95% CI 0.43 to 0.76; one trial, 74 participants; very low-certainty evidence). Another study found no difference between combined HBO and antibiotics compared to antibiotics alone prior to dental implant placement (RR 3.00, 95% CI 0.14 to 65.16; one trial, 26 participants; very low-certainty evidence). Adverse effects of the different interventions were not reported clearly or were not important. AUTHORS' CONCLUSIONS: Given the suboptimal reporting and inadequate sample sizes of the included studies, evidence regarding the interventions evaluated by the trials included in this review is uncertain. More well-designed RCTs with larger samples are required to make conclusive statements regarding the efficacy of these interventions.

Management and Neonatal Outcomes of Pregnancies with Fetal/Neonatal Alloimmune Thrombocytopenia: A Single-Center Retrospective Cohort Study.

BACKGROUND: There is no consensus regarding the optimal antenatal treatment of fetal/neonatal alloimmune thrombocytopenia (F/NAIT). We aimed to review the fetal blood sampling (FBS)-related risk, fetal response to maternal intravenous immunoglobulin (IVIG), and cesarean section (CS) rate in pregnancies with a history of F/NAIT. METHODS: Maternal demographics, alloantibodies, pregnancy management, fetal and neonatal outcomes, and index case characteristics were collected. Responders (R) and non-responders (NR) were defined as women treated with IVIG in whom fetal platelets (PLTs) were normal or low (< 50 × 109/L). RESULTS: An FBS-related risk occurred in 1.6% (2/119) of procedures. Maternal characteristics did not differ between responders (n = 21) and non-responders (n = 21). HPA-1a antibody was detected in all non-responders and in 72% of responders (p < 0.01). The index case had a significantly lower PLT count at birth in non-responders versus responders (median PLT count: R = 20 × 109/L [IQR 8-43] vs. NR = 9 × 109/L [IQR 4-18], p < 0.02). No differences were found in IVIG treatment duration or dosage. PLTs at birth were significantly lower in non-responders compared to responders. No intracranial hemorrhages occurred. CSs were performed for obstetric indications only in all but two cases. CONCLUSION: Maternal IVIG can elicit different fetal responses. The lack of prognostic factors to predict responders or non-responders suggests that there remains a role for FBS in F/NAIT in experienced hands.

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.

Sildenafil for pulmonary hypertension in neonates.

BACKGROUND: Persistent pulmonary hypertension in the neonate (PPHN) is associated with high mortality. Currently, the therapeutic mainstay for PPHN consists of assisted ventilation and administration of inhaled nitric oxide (iNO). However, nitric oxide is costly, and its use may not be appropriate in resource-poor settings. Approximately 30% of patients fail to respond to iNO. High concentrations of phosphodiesterases in the pulmonary vasculature have led to the use of phosphodiesterase inhibitors such as sildenafil or milrinone. OBJECTIVES: To assess the efficacy and safety of sildenafil for treatment of pulmonary hypertension in neonates. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 3), MEDLINE via PubMed (1966 to 18 April 2017), Embase (1980 to 18 April 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 18 April 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials of sildenafil compared with placebo or other pulmonary vasodilators, irrespective of dose, route, and duration of administration, in neonates with pulmonary hypertension, if investigators reported any of the prespecified outcomes. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of trials regarding how bias was minimised at study entry, during study intervention, and at outcomes measurement. We extracted data on relevant outcomes; we estimated the effect size and reported it as risk ratio (RR), risk difference (RD), or mean difference (MD), as appropriate. We applied the I2 test of heterogeneity and used GRADE to assess the quality of evidence. MAIN RESULTS: For this update, we identified two additional studies, for a total of five eligible trials that enrolled 166 infants. The methodological quality of these studies ranged from low to high risk of bias. Three studies were performed in resource-limited settings, where iNO and high-frequency ventilation were not available at the time of the study. One study compared sildenafil versus active controls, and another study evaluated sildenafil as adjuvant therapy to iNO. When comparing sildenafil with placebo, investigators noted significant reduction in mortality in the sildenafil alone group (three studies, 77 participants; typical RR 0.20, 95% confidence interval (CI) 0.07 to 0.56; I2 = 0% - none; typical RR -0.36, 95% CI -0.53 to -0.18; number needed to treat for an additional beneficial outcome 3, 95% CI 2 to 6; I2 = 39% - low). Trials reported no significant differences in mortality upon comparison of the sildenafil group versus the active control group (one study, 65 participants; typical RR 0.55, 95% CI 0.05 to 5.75), or when iNO was administered to both groups (one study, 24 participants; typical RR 1.27, 95% CI 0.26 to 6.28). Physiological parameters of oxygenation (oxygenation index, partial pressure of oxygen in arterial blood (PaO2)) suggested steady improvement after the first dose of sildenafil. None of the included trials identified any clinically important side effects. We rated the quality of evidence as low to very low owing to imprecision related to small sample size and unclear methodological features. AUTHORS' CONCLUSIONS: Sildenafil used for treatment of pulmonary hypertension has potential for reducing mortality and improving oxygenation in neonates, especially in resource-limited settings where iNO is not available. However, large-scale randomised trials comparing sildenafil versus active controls (other pulmonary vasodilators) and providing follow-up for survivors are needed to assess the comparative effectiveness and long-term safety of sildenafil versus other pulmonary vasodilators.

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.

Antibiotics for neonates born through meconium-stained amniotic fluid.

BACKGROUND: Approximately 1 in 10 pregnancies is affected by meconium passage at delivery, which can result in meconium aspiration syndrome (MAS). MAS can cause respiratory complications and, very rarely, death. Antibiotics have been prescribed for neonates exposed to meconium in amniotic fluid, with the intention of preventing infection due to potential bacterial contaminants. OBJECTIVES: We conducted this review to assess the efficacy and safety of antibiotics for:1. prevention of infection, morbidity, and mortality among infants born through meconium-stained amniotic fluid (MSAF) who are asymptomatic at birth; and2. prevention of infection, morbidity, and mortality among infants born through MSAF who have signs and symptoms compatible with meconium aspiration syndrome (MAS). SEARCH METHODS: We performed a literature search using the following databases: MEDLINE (1966 to July 2016); Embase (1980 to July 2016); the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to July 2016); and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 7) in the Cochrane Library. We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that compared antibiotics administered via any route versus placebo or no treatment for prevention of infection among neonates exposed to MSAF, or who developed MAS. We excluded cohort, case control, and any other non-randomised studies and applied no language restrictions. We included studies of term and preterm infants, and we included studies examining use of any antibacterial antibiotics. We included studies that reported on any outcomes of interest. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of included trials by reviewing information provided in study reports and obtained by personal communication with study authors. We extracted data on relevant outcomes, estimated effect size, and reported values as risk ratios (RRs), risk differences (RDs), and mean differences (MDs), as appropriate. We conducted subgroup analyses for treatment of MAS and for prophylaxis (asymptomatic neonates exposed to meconium). MAIN RESULTS: Four randomised controlled studies including a total of 695 participants were eligible for inclusion. Three studies evaluated neonates with MAS, and one study assessed asymptomatic neonates exposed to meconium in amniotic fluid. These studies exhibited varying degrees of methodological rigour: Two studies were at low risk of bias, and two were at unclear risk. We graded evidence derived from these studies as low quality. We downgraded overall evidence owing to the large number of participants lost to follow-up in one trial, the small sample sizes of all trials, and unclear methodological details provided for two trials.The primary outcome was risk of early- and late-onset neonatal sepsis. Antibiotics did not decrease the risk of sepsis in neonates with a diagnosis of MAS (RR 1.54, 95% confidence interval (CI) 0.27 to 8.96; RD 0.00, 95% CI -0.02 to 0.03; 445 participants, three studies; I² = 0%) nor in asymptomatic neonates exposed to meconium in amniotic fluid (RR 0.76, 95% CI 0.25 to 2.34; RD -0.01, 95% CI -0.07 to 0.04; 250 participants, one study; I² = 0%). Results show no significant differences in mortality or duration of stay in hospital between groups given antibiotics and control groups of symptomatic and asymptomatic neonates. One study in asymptomatic neonates reported a significant reduction in duration of mechanical ventilation for the control group compared with the antibiotic group (MD 0.26, 95% CI 0.15 to 0.37; 250 participants, one study; I² = 0%). AUTHORS' CONCLUSIONS: Upon review of available evidence, we found no differences in infection rates following antibiotic treatment among neonates born through meconium-stained fluid and those with meconium aspiration syndrome. The overall quality of evidence is low owing to the small number of included studies. Well-controlled studies of adequate power are needed.

Trends and Outcomes of Patent Ductus Arteriosus Treatment in Very Preterm Infants in Canada.

Objective To assess trends in patent ductus arteriosus (PDA) management and examine concurrent changes in neonatal mortality and morbidities. Methods This retrospective observational study examined infants born at 23 to 32 weeks' gestational age with PDA and admitted to a neonatal unit during 2006 to 2012. Multivariable logistic regression assessed trends in yearly PDA treatment rates and compared a composite outcome of mortality or any severe morbidity (bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, or necrotizing enterocolitis) between and within time periods and PDA treatments. Results Study subjects included 5,824 preterm neonates with clinical/echocardiographic PDA diagnosis. During 2006 to 2012, conservative management increased (14-38%), whereas pharmacotherapy-only (58-49%), surgical ligation-only (7.1-2.5%), and both pharmacotherapy and surgical ligation (21-10%) decreased (p-values <0.01). From 2006 to 2008 and 2009 to 2012, the composite outcome decreased for infants managed conservatively (AOR = 0.70, 95% CI 0.52-0.92), with no changes detected for pharmacotherapy and/or ligation. Lower composite outcome after conservative management versus pharmacotherapy-only during 2009 to 2012 (AOR = 0.61, 95% CI 0.51-0.74), but not during 2006 to 2008 reflect significant effect modification by time period. Conclusion In Canada, during 2006 to 2012, conservative PDA management increased while pharmacotherapy and/or surgical ligation decreased. Lower composite outcome was detected during later years after increases in conservative management; however, bias due to unmeasured confounders remains possible.

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.

Xylitol for preventing acute otitis media in children up to 12 years of age.

BACKGROUND: Acute otitis media (AOM) is the most common bacterial infection among young children in the United States. There are limitations and concerns over its treatment with antibiotics and surgery and so effective preventative measures are attractive. A potential preventative measure is xylitol, a natural sugar substitute that reduces the risk of dental decay. Xylitol can reduce the adherence of Streptococcus pneumoniae (S pneumoniae) and Haemophilus influenzae (H influenzae) to nasopharyngeal cells in vitro. This is an update of a review first published in 2011. OBJECTIVES: To assess the efficacy and safety of xylitol to prevent AOM in children aged up to 12 years. SEARCH METHODS: We searched CENTRAL (to Issue 12, 2015), MEDLINE (1950 to January 2016), Embase (1974 to January 2016), CINAHL (1981 to January 2016), LILACS (1982 to January 2016), Web of Science (2011 to January 2016) and International Pharmaceutical Abstracts (2000 to January 2016). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs of children aged 12 years or younger where xylitol supplementation was compared with placebo or no treatment to prevent AOM. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials from search results, assessed and rated study quality and extracted relevant data for inclusion in the review. We contacted trial authors to request missing data. We noted data on any adverse events of xylitol. We extracted data on relevant outcomes and estimated the effect size by calculating risk ratio (RR), risk difference (RD) and associated 95% confidence intervals (CI). MAIN RESULTS: We identified five clinical trials that involved 3405 children for inclusion. For this 2016 update, we identified one new trial for inclusion. This trial was systematically reviewed but due to several sources of heterogeneity, was not included in the meta-analysis. The remaining four trials were of adequate methodological quality. In three RCTs that involved a total of 1826 healthy Finnish children attending daycare, there is moderate quality evidence that xylitol (in any form) can reduce the risk of AOM from 30% to around 22% compared with the control group (RR 0.75, 95% CI 0.65 to 0.88). Among the reasons for dropouts, there were no significant differences in abdominal discomfort and rash between the xylitol and the control groups. Xylitol was not effective in reducing AOM among healthy children during a respiratory infection (RR 1.13, 95% CI 0.83 to 1.53; moderate quality evidence) or among otitis-prone healthy children (RR 0.90, 95% CI 0.67 to 1.21; low-quality evidence). AUTHORS' CONCLUSIONS: There is moderate quality evidence showing that the prophylactic administration of xylitol among healthy children attending daycare centres can reduce the occurrence of AOM. There is inconclusive evidence with regard to the efficacy of xylitol in preventing AOM among children with respiratory infection, or among otitis-prone children. The meta-analysis was limited because data came from a small number of studies, and most were from the same research group.

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

BACKGROUND: Newborn infants have the ability to experience pain. Newborns treated in neonatal intensive care units 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: Primary objectiveTo determine the efficacy and safety of paracetamol for the prevention or treatment of procedural/postoperative pain or pain associated with clinical conditions in neonates. Secondary objectiveTo 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. We designed the main comparisons according to intention of use, that is, paracetamol for prevention or treatment of pain. We included separate comparisons based on the painful intervention/procedure/condition (heel lance, insertion of nasogastric tube, insertion of intravenous catheter, lumbar puncture, assisted vaginal birth, postoperative pain, birth trauma, congenital anomalies such as myelomeningocoele and open cutaneous lesions) and the mode of administration of paracetamol. Within these comparisons, we planned to assess in subgroups (when possible) effects based on postmenstrual age (PMA) at the birth of randomly assigned infants (< 28 weeks, 28 weeks to 31 + 6 weeks, 32 weeks to 36 + 6 weeks and ≥ 37 weeks) or based on birth weight (or current weight) categories (≤ 1000 grams, 1001 to 1500 grams, 1501 to 2500 grams and ≥ 2501 grams) SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (October 2014), MEDLINE (1966 to October 2014), EMBASE (1980 to October 2014) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to October 2014). We applied no language restrictions.We conducted electronic searches of abstracts from meetings of the Pediatric Academic Societies (2000 to 2014) and the Perinatal Society of Australia and New Zealand (2010 to 2014).We searched clinical trial registries for ongoing trials and the Web of Science for articles quoting identified randomised controlled trials. We searched the first 200 hits on Google Scholar(TM) to identify grey literature. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials of paracetamol for the prevention or treatment of pain in neonates (≤ 30 days of age). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the full-text articles using a specifically designed form. 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 5.3.3 software. When noted, we resolved differences by mutual discussion and consensus. MAIN RESULTS: We included eight trials with low risk of bias, which assessed paracetamol use for the treatment of pain in 614 infants. Painful interventions studied included heel lance, assisted vaginal birth, eye examination for ascertainment of retinopathy of prematurity (ROP) and postoperative care following major surgery. 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 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). For postoperative care following major thoracic or abdominal surgery, the total amount of morphine (µg/kg) administered over 48 hours was significantly less among infants randomly assigned to the paracetamol group than in those randomly assigned to the morphine group (MD -157 µg/kg, 95% CI -27 to -288). No adverse events were noted in any study. AUTHORS' CONCLUSIONS: Paracetamol does not significantly reduce pain associated with heel lance or eye examinations. Paracetamol given after assisted vaginal birth may increase the response to later painful exposures. Paracetamol should not be used for painful procedures given its lack of efficacy and its potential for adverse effects. Paracetamol may reduce the total need for morphine following major surgery, and for this aspect of paracetamol use, further research is needed.

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. Concerns have been raised that in neonatal mice paracetamol may cause adverse effects on the developing brain, and an association between prenatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported. OBJECTIVES: To determine the efficacy 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 closure of a PDA in preterm or low-birth-weight infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), MEDLINE, EMBASE and CINAHL. We searched abstracts from the meetings of the Pediatric Academic Societies and the Perinatal Society of Australia and New Zealand. We searched clinicaltrials.gov; controlled-trials.com; anzctr.org.au; World Health Organization International Clinical Trials Registry Platform at who.int/ictrp for ongoing trials and the Web of Science for articles quoting identified randomised controlled trials. We searched the first 200 hits on Google Scholar(TM) to identify grey literature. All searches were conducted in December 2013. A repeat search of MEDLINE in August 2014 did not identify any new trials. SELECTION CRITERIA: We identified two randomised controlled trials (RCTs) that compared oral paracetamol to oral ibuprofen for the treatment of an echocardiographically diagnosed PDA in infants born preterm (≤ 34 weeks postmenstrual age (PMA)). DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: Two unmasked studies of treatment of PDA that enrolled 250 infants were included. The sequence of randomisation and the allocation to treatment groups were concealed in both studies. In one study the cardiologist assessing PDA closure was blinded to group allocation of the infant. In the other study it was not stated if that was the case or not. The quality of the trials, using GRADE, was low for the primary outcome of PDA closure and moderate for all other important outcomes. There was no significant difference between treatment with oral paracetamol versus oral ibuprofen for failure of ductal closure after the first course of drug administration (typical relative risk (RR) 0.90, 95% confidence interval (CI) 0.67 to 1.22; typical risk difference (RD) -0.04, 95% CI -0.16 to 0.08; I(2) = 0 % for RR and 23% for RD).There were no significant differences between the paracetamol and the ibuprofen groups in the secondary outcomes except for 'duration for need of supplemental oxygen' (mean difference -12 days, 95% CI -23 days to -2 days; 1 study, n = 90) and for hyperbilirubinaemia (RR 0.57, 95% CI 0.34 to 0.97; RD -0.15, 95% CI -0.29 to -0.01; number needed to treat to benefit (NNTB) 7, 95% CI 3 to 100 in favour of paracetamol; 1 study, n = 160). AUTHORS' CONCLUSIONS: Although a limited number of infants with a PDA have been studied in randomised trials of low to moderate quality according to GRADE, oral paracetamol appears to be as effective in closing a PDA as oral ibuprofen. In view of a recent report in mice of adverse effects on the developing brain from paracetamol, and another report of an association between prenatal paracetamol and the development of autism or autism spectrum disorder in childhood, 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. Such trials are required before any recommendations for the use of paracetamol in the newborn population can be made.