Search

Background: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of inhaled corticosteroids (budesonide, beclomethasone, or fluticasone propionate) in preventing bronchopulmonary dysplasia (BPD) for premature infants., Method: Electronic databases, including PubMed, EMBASE, Web of science, Scopus, and Cochrane library, were searched from databases inception to January 2022 for eligible randomized controlled trials. Clinical outcomes such as BPD, mortality, BPD or death, adverse events, and neurodevelopmental outcomes were assessed., Results: Overall, budesonide was significantly associated with a reduction in BPD at 36 weeks' postmenstrual age (RR 0.48; 95 % CI [0.38, 0.62]) and patent ductus arteriosus (PDA) (RR 0.75; 95 % CI [0.63, 0.89]) compared with control treatments. Early longer duration inhalation of budesonide alone was associated with a lower risk of BPD at 36 weeks' postmenstrual age and PDA compared with controls. Early shorter duration intratracheal instillation of budesonide with surfactant as vehicle was associated with a lower risk of BPD at 36 weeks' postmenstrual age and all-cause mortality compared with surfactant. There was no statistically significant difference between budesonide and control groups regarding neurodevelopmental impairment. Beclomethasone and fluticasone propionate did not show any superior or inferior effect on clinical outcomes compared to control treatments., Conclusion: These findings suggest that budesonide, especially intratracheal instillation of budesonide using surfactant as a vehicle, is a safe and effective option in preventing BPD for preterm infants. More well-design large-scale trials with long-term follow-ups are necessary to verify the present findings., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 SPLF and Elsevier Masson SAS. All rights reserved.)

Background: Preterm infants are recommended for prophylactic indomethacin (PIND) to promote closure of patent ductus arteriosus (PDA) and reduce morbidity and mortality. This study investigated the predictive factors of a non-response to PIND for PDA in preterm-birth infants., Methods: Consecutive preterm-birth infants (gestational age: < 28 weeks) who received PIND between 2009 and 2019 were retrospectively enrolled. Seventy-six eligible participants were classified as PIND responders (N = 42) or non-responders (N = 34). Information on potential confounders in maternal obstetric and perinatal data were collected from medical records. Multiple logistic regression analysis was carried out to identify the prognostic factors of a PIND response in preterm-birth infants., Results: The prevalence of intrauterine infection and multiple births was significantly different between responders and non-responders to PIND (intrauterine infection: 2 [4.8%] vs. 8 [23.5%], P = 0.036; twins: 3 [7.1%] vs. 9 [ 26.5%], P = 0.029, respectively). In multivariate logistic regression analysis after adjustment for multiple births, intrauterine infection was a significant and independent predictive factor of a non-response to PIND (odds ratio [OR] 5.54, 95% confidence interval [CI] 1.05-29.2, P = 0.044). A remarkable association was also noted for multiple births with a non-response to PIND (OR 4.22, 95% CI 0.99-17.8, P = 0.050)., Conclusions: Intrauterine infection and multiple births were identified as potential risk factors of a non-response to PIND for PDA in preterm infants., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Background: Mechanical ventilation is associated with mortality/morbidities in preterm infants. Nearly a third of these infants fail extubation, and this may increase morbidities., Objective: To evaluate the association of moderate to large symptomatic patent ductus arteriosus (PDA) with failure of extubation among preterm infants., Methods: This was a retrospective study on preterm infants (birth weight <1250 g and gestational age ≥23 weeks) born between January 2009 and December 2016, who were mechanically ventilated and extubated within the first 60 days of age., Results: Three hundred and sixty infants were evaluated, of these, 26% failed, and 74% succeeded in the initial extubation attempt. On adjusted analysis, symptomatic PDA was associated with an increased risk of extubation failure., Conclusion: The presence of symptomatic patent ductus arteriosus was associated with extubation failure. Further investigations are needed to establish whether there is a causal relationship between PDA and extubation failure and whether proactive screening for presence of PDA and treatment of the same, before extubation among these infants, improves chances of successful extubation and cardiorespiratory outcomes., (© 2023 Wiley Periodicals LLC.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a frequently prescribed class of medications in the neonatal intensive care unit (NICU). We aimed to reveal acute kidney injury (AKI) epidemiology in NSAID-exposed premature infants admitted to the NICU using a standardized definition and determine the percentage of NSAID-exposed patients with adequate serum creatinine (SCr) monitoring., Methods: This retrospective study compared infants born at ≤34 weeks gestational age who received NSAID for intraventricular hemorrhage prophylaxis (prophylaxis group) or symptomatic treatment for patent ductus arteriosus (PDA; treatment group) between January and December 2014 at a tertiary NICU. All available SCr and 12-h urine output (UO) values were recorded from admission until day seven post-NSAID exposure. AKI incidence was determined using the neonatal modified Kidney Disease Improving Global Outcomes classification, defined as an increase in SCr (i.e., 1.5 fold rise from previous SCr measurement within seven days or 26.5 mmol/L increase within 48 h) or UO < 1 mL/kg/hour, excluding the first 24 h of life., Results: We identified 70 eligible subjects; 32 received prophylactic NSAIDs, and 38 received indomethacin or ibuprofen for treating symptomatic PDA. AKI incidence for the entire cohort was 23% (16/70). The prophylaxis group had a significantly lower AKI rate than the treatment group (9% vs. 34%; p = 0.014). The treatment group had a higher proportion of infants with adequate SCr monitoring during NSAID treatment than the prophylaxis group (87% vs. 13%, p < 0.001)., Conclusion: NSAID-associated AKI occurred in approximately one-quarter of premature infants overall, and the AKI incidence was higher in infants treated with NSAIDs for the symptomatic treatment of PDA than in those receiving prophylactic treatment during the first day of life. Standardized protocols for monitoring daily SCr and UO after exposure should be implemented for all neonates with NSAID exposure to improve early AKI recognition and management., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Importance: There is wide variability in the use of prophylactic cyclooxygenase inhibitor (COX-I) drugs to prevent morbidity and mortality in preterm infants. Parents of preterm infants are rarely involved in this decision-making process., Objective: To explore the health-related values and preferences of adults who were preterm infants and families of preterm infants concerning the prophylactic use of indomethacin, ibuprofen, and acetaminophen initiated within the first 24 hours after birth., Design, Setting, and Participants: This cross-sectional study used direct choice experiments conducted in 2 phases of virtual video-conferenced interviews between March 3, 2021, and February 10, 2022: (1) a pilot feasibility study and (2) a formal study of values and preferences, using a predefined convenience sample. Participants included adults born very preterm (gestational age <32 weeks) or parents of very preterm infants currently in the neonatal intensive care unit (NICU) or having graduated from the NICU in the last 5 years., Main Outcomes and Measures: Relative importance of clinical outcomes, willingness to use each of the COX-Is when presented as the only option, preference for using prophylactic hydrocortisone vs indomethacin, willingness to use any of the COX-Is when all 3 options are available, and relative importance of having family values and preferences included in decision-making., Results: Of 44 participants enrolled, 40 were included in the formal study (31 parents and 9 adults born preterm). The median gestational age of the participant or the participant's child at birth was 26.0 (IQR, 25.0-28.8) weeks. Death (median score, 100 [IQR, 100-100]) and severe intraventricular hemorrhage (IVH) (median score, 90.0 [IQR, 80.0-100]) were rated as the 2 most critical outcomes. Based on direct choice experiments, most participants were willing to consider prophylactic indomethacin (36 [90.0%]) or ibuprofen (34 [85.0%]), but not acetaminophen (4 [10.0%]) when offered as the only option. Among participants who initially chose indomethacin (n = 36), if prophylactic hydrocortisone was offered as a potential therapy with the caveat that both cannot be used simultaneously, only 12 of 36 (33.3%) preferred to remain with indomethacin. Variability in preference was noted when all 3 COX-I options were available, indomethacin (19 [47.5%]) being the most preferred option followed by ibuprofen (16 [40.0%]), while the remainder opted for no prophylaxis (5 [12.5%])., Conclusions and Relevance: The findings of this cross-sectional study of former preterm infants and parents of preterm infants suggest that there was minimal variability in how participants valued the main outcomes, with death and severe IVH being rated as the 2 most important undesirable outcomes. While indomethacin was the most preferred form of prophylaxis, variability was noted in the choice of COX-I interventions when participants were presented with the benefits and harms of each drug.

This study aimed to evaluate the short-term morbidities and efficacy of single-dose prophylactic intravenous ibuprofen for patent ductus arteriosus (PDA) on the first day of life in preterm infants. Data of 69 preterm infants with birth weight < 1250 g and gestational age < 30 weeks admitted to the neonatal intensive care unit were analyzed. Of these, 37 infants were assigned to the prophylactic treatment (PT) group and 32 were assigned to the nonprophylactic treatment (non-PT) group. Only the PT group administered intravenous ibuprofen (10 mg/kg) once within 6 hours after birth. Until postnatal day 7, ductal closure occurred in 11 (34.4%) infants in the non-PT group, and in 35 (94.6%) infants in the PT group, of which 30 (81.1%) infants had ductal closure on postnatal day 1. There were 2 (5.4%) infants in the PT group and 9 (28.1%) in the non-PT group who needed ibuprofen treatment due to moderate-to-large PDA after postnatal day 7. Preterm infants in the PT group were less likely to develop an intraventricular hemorrhage (≥grade 2) (adjusted odds ratio 0.007, 95% confidence interval 0.01-0.45), had a shorter duration of invasive ventilatory support and central venous catheter, and earlier postnatal age to achieve feeding of 50 and 100 mL/kg/day compared with those in the non-PT group. Single-dose prophylactic intravenous ibuprofen on the first day of life decreased the occurrence of a persistent PDA and intraventricular hemorrhage (≥grade 2), and reduced the duration of invasive ventilatory support, central venous catheter use, and hospital stay., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Evaluate maximal weight loss (MWL) and total fluid administration (TFA) association in first week after birth with outcomes among extremely preterm (EP) newborns., Study Design: We performed a retrospective analysis of the Preterm Erythropoietin Neuroprotection Trial evaluating first-week MWL, TFA, and association with in-hospital outcomes., Results: Among n = 883 included EP neonates, n = 842 survived ≥ 7 days and were included in outcome analyses. MWL between 5% to 15% was associated with decreased odds of necrotizing enterocolitis compared to MWL > 15% (OR 0.49, 95% CI 0.25-0.98). Average TFA > 150 mL/kg birthweight/day was associated with increased odds of necrotizing enterocolitis (OR 3.22, 95% CI 1.40-7.42) and patent ductus arteriosus requiring surgery (OR 2.14, 95% CI 1.10-4.15)., Conclusion: MWL between 5% to 15% is a potentially optimal window of MWL. Increasing average TFA in the first week is associated with adverse neonatal outcomes. Prospective studies evaluating MWL and TFA and relationship to outcomes in EP neonates are needed., Clinical Trial Registration: This study is a secondary analysis of pre-existing data from the PENUT Trial Registration: NCT01378273, https://clinicaltrials.gov/ct2/show/NCT01378273 ., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Acetaminophen use for pharmacological treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants is becoming more popular with emerging evidence that it is effective as well as safe alternative for other agents used to close hsPDA., Data Sources: We performed a narrative review of literature about pharmacological treatment of PDA using acetaminophen., Results: Acetaminophen was used as a prophylaxis, symptomatic, targeted, and a rescue approach., Conclusions: It appears that acetaminophen could be used in different approaches to close the hsPDA. Long-term outcomes of acetaminophen exposure early in life still lack certainty., (© 2022. Children's Hospital, Zhejiang University School of Medicine.)

Introduction: Prophylactic low-dose paracetamol administration is used to induce closure of the ductus arteriosus. Effects on the neurological outcome in preterm infants remain unknown. We compared microstructural brain development in very preterm infants with and without exposure to prophylactic paracetamol by using MR-based diffusion tensor imaging., Materials and Methods: Infants aged <32 gestational weeks born between October 2014 and December 2018 received prophylactic paracetamol (10 mg/kg intravenously every 8 h until echocardiography after at least 72 h) and form the paracetamol group; infants born between February 2011 and September 2014 form the control group. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) at term-equivalent age were measured in 14 defined cerebral regions and compared between the groups., Results: Included in the study were 340 infants, of whom 217 received prophylactic paracetamol, and 123 formed the control group. The paracetamol group showed significantly higher FA values and lower ADC values in the splenium of the corpus callosum, as well as higher FA values in the pons bilaterally, the left middle cerebellar peduncle, the right occipital white matter, and the right posterior limb of the internal capsule (p ≤ 0.02)., Conclusion: The perceived safety of prenatal paracetamol exposure has been questioned in recent years. We found no impairment on microstructural maturation processes in the brain of preterm infants at term-equivalent age following early paracetamol administration. The clinical relevance of these imaging findings has to be determined in long-term follow-up studies on neurodevelopmental outcome., (© 2022 S. Karger AG, Basel.)

Background: Prophylactic indomethacin (3 doses) decreases patent ductus arteriosus (PDA) and intraventricular hemorrhage (IVH) in preterm infants. The study aim was to determine whether single-dose indomethacin (SD-INDO) decreases PDA, IVH, and improves motor function., Methods: A retrospective cohort (2007-2014) compared infants born < 29 weeks who did (n = 299) or did not (n = 85) receive SD-INDO and estimated outcomes association with ordinal logistic regression, adjusting for multiple variables using propensity scores., Results: Infants who received SD-INDO were more premature (p < 0.001) but had lower odds of PDA (OR 0.26 [0.15, 0.44], p < 0.005), PDA receiving treatment (OR 0.12 [0.03, 0.47], p < 0.005), death (OR 0.41 [0.20, 0.86], p = 0.02), and CP severity (OR 0.33 [0.12, 0.89], p = 0.03). There was less IVH (OR 0.58 [0.36, 0.94], p = 0.03) when adjusted for gestational age., Conclusions: SD-INDO is associated with decreased PDA and CP severity and improved survival.

Background: To determine the rate of patent ductus arteriosus after prophylactic low-dose paracetamol administration, the impact on outcome parameters, possible treatment side-effects and the influence on pain perception., Methods: We report retrospective single-centre outcome data of premature infants ≤ 32 weeks of gestation (n = 476). The intervention group received intravenous paracetamol, the control group obtained no preventive therapy. Ductal closure rate and outcome parameters were compared between the two groups. Adverse effects were determined by laboratory parameters. For the assessment of pain the Bernese Pain Scale for Neonates was used., Results: The rate of patent ductus arteriosus was significantly lower in the paracetamol-treated group compared to the control group (13.6% vs. 38.2%, p < 0.001). With regard to secondary outcome parameters, severe and moderate bronchopulmonary dysplasia (2.7% vs. 7.4%, p = 0.023), severe retinopathy of prematurity (0% vs. 4.4%, p = 0.002) and late onset sepsis (2.7% vs. 8.3%, p = 0.009) were significantly less frequent in the paracetamol group. Except for a 1.5-fold increased risk for hyperbilirubinemia (86.0% vs. 77.6%, p = 0.035) in the paracetamol group following treatment, no significant differences in laboratory parameters were found. Relating to pain, the administration of Glucose 33% was significantly more often necessary in the control group compared to the paracetamol-treated group (mean 13.48 vs. 8.71, p < 0.001), just as the need for additional treatment with systemic analgesics, which was more frequent in the control group (mean 0.72 vs. 0.57, p = 0.361)., Conclusion: In our study we were able to show a significantly lower rate of patent ductus arteriosus after prophylactic paracetamol administration without serious adverse effect, but a beneficial influence of this regime on the patient's pain perception., (Copyright © 2019. Published by Elsevier B.V.)

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., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Aim: To answer the clinical question: 'In preterm infants, does fluid restriction, as opposed to liberal fluid prescription, reduce the risk of important morbidities (namely, intraventricular haemorrhage, necrotising enterocolitis, bronchopulmonary dysplasia and patent ductus arteriosus) and mortality?', Methods: Literature searches were conducted of Medline, Embase and Cochrane Library. Results were limited to human clinical trials on infants and those published in English. The reference lists of relevant articles were screened for further articles. Studies that examined measures which inform diagnostic criteria of morbidities of interest (such as echocardiographic changes) but did not go further to confirm or exclude presence of said morbidities in study populations were excluded., Results: A total of 110 articles were found and screened by title and abstract. The final analysis included five randomised controlled trials and five case control studies. Among the randomised controlled trials, there is some suggestion (though not unanimous) that liberal fluid regimens are associated with an increased risk of patent ductus arteriosus, necrotising enterocolitis and mortality. Case control studies focused on patent ductus arteriosus and bronchopulmonary dysplasia or chronic lung disease, with all but one study suggesting an increased risk of these complications with liberal fluid regimens., Conclusion: Further investigation is needed to clarify the optimal fluid regimen for preterm infants to ensure adequate hydration and nutrition without contributing to serious complications., (© 2019 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

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.

Background: Systemic corticosteroids as the frontline treatment of respiratory distress syndrome (RDS) in preterm infants are associated with adverse effects on growth and neurodevelopmental outcome, but the pulmonary administration of steroids may help prevent the development of bronchopulmonary dysplasia (BPD) without these side effects., Objectives: To evaluate the efficacy and safety of pulmonary application of corticosteroids in preterm infants with RDS., Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, the WHO's International Clinical Trials Registry and grey literature were searched with no restriction on date and language of publication from inception to May 2016. Using a random-effect model, we pooled data from randomised controlled trials (RCTs) comparing inhaled or endotracheal corticosteroids with the standard of care, placebo or no other intervention in preterm infants with RDS., Results: We identified 873 potential citations and included 12 unique RCTs. Pulmonary corticosteroid therapy was associated with a significant reduction in the composite outcome of BPD or death (relative risk (RR) 0.85, 95% CI 0.76 to 0.96). Pulmonary application of corticosteroids significantly reduced the incidence of patent ductus arteriosus (PDA) (RR 0.82, 95% CI 0.74 to 0.92) and pneumonia (RR 0.57, 95% CI 0.35 to 0.92). There was no evidence of a significant difference regarding the risk of neurodevelopmental impairment or other side effects., Conclusions: Pulmonary administration of corticosteroids reduces the incidence of BPD or death, pneumonia, PDA without causing any major side effects in preterm infants with RDS., Competing Interests: Competing interests: MD’s salary is supported by GW’tJ’s Establishment Grant from the University of Manitoba and the Children’s Hospital Research Foundation of Manitoba. RZ is the recipient of a Canadian Institutes of Health Research (CIHR) New Investigator salary award., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: We examined data from a contemporary cohort of extreme prematurity (EP) infants admitted to an all-referral Children's Hospital neonatal intensive care unit (NICU) to determine whether prophylactic indomethacin (PI) may continue to benefit these patients., Study Design: An observational study utilizing the small baby ICU data registry that was queried for all EP infants admitted between 2005 and 2014 with documentation of PI use (671 total EP infants; 141 (21%) did not receive PI (control); 530 (79%) received PI (PI). This cohort of EP infants was born at outside hospitals and transferred to our level IV NICU with a mean age on admission of 13 days, well after the PI would have been administered., Results: No difference existed between the control and PI groups in gestational age, birth weight, severity of illness, other in-hospital outcomes or developmental delay. PI infants had a significantly lower mortality rate (P=0.0004), lower relative risk (RR) for mortality 0.52 (95% confidence interval (CI) 0.37 to 0.73, P=0.0001) and lower RR of developing the combined outcome of death or bronchopulmonary dysplasia (RR 0.91, 95% CI 0.85 to 0.98, P=0.012) when compared with the control group. Notably, there was no significant effect of PI on incidence of severe intraventricular hemorrhage or patent ductus arteriosus ligation., Conclusion: PI administration was associated with improved survival in EP infants referred to a level IV Children's Hospital NICU.

Objective  This study aims to perform a meta-analysis of randomized studies to evaluate if chest shielding during phototherapy is associated with decreased incidence of patent ductus arteriosus (PDA) in premature infants. Design/Methods  We used published guidelines for the meta-analysis of clinical trials. The search strategy included electronic searches of CINAHL, CENTRAL Cochrane Library, MEDLINE, PubMed, and abstracts presented at the Pediatric Academic Societies. Inclusion criteria were randomized controlled trials (RCTs), quasi-RCTs or cluster RCTs published in English and involving chest shielding during phototherapy in premature infants with PDA as an outcome. Exclusion criteria involved case reports, case series, and multiple publications from the same author. Heterogeneity testing using Q statistics was performed to evaluate the variance between studies. Results  Two RCTs met study criteria. There was heterogeneity (I 2 : 55.4%) between the two trials. Meta-analysis of RCTs using the random effect model demonstrated that chest shielding during phototherapy was associated with decreased incidence of PDA (odds ratio: 0.47, 95% confidence interval: 0.23-0.96). There was no publication bias on Eggers test. Heterogeneity was seen in gestational age, gender, prophylactic use of postnatal indomethacin, duration of phototherapy, and assessment of PDA. Conclusion  Chest shielding during phototherapy may be associated with decreased incidence of PDA among premature infants., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: Indomethacin prophylaxis (IP) reduces the risk of intraventricular haemorrhage (IVH) and patent ductus arteriosus (PDA) in preterm infants. However, the optimal time to administer IP has not been determined. We hypothesised that IP at ≤6 h is associated with a lower incidence of IVH or death than if administered at >6-24 h of age., Methods: We performed a retrospective cohort study of extremely low birth weight infants (≤1000 g birth weight) treated in the neonatal intensive care units in the Neonatal Research Network from 2003 to 2010 and who received IP in the first 24 h of age. Infants were dichotomised based upon receipt of IP at ≤6 or >6-24 h of age. The primary outcomes were IVH alone and IVH or death. Secondary outcomes were PDA alone and PDA or death. We used multivariable analyses to determine associations between the age of IP and the study outcomes expressed as an OR and 95% CI., Results: IP was given at ≤6 h to 2340 infants and at >6-24 h to 1915 infants. Infants given IP at ≤6 h had more antenatal steroid exposure, more inborn and less cardiopulmonary resuscitation (p<0.01). After multivariable analyses, age of IP receipt was not associated with IVH, and IVH or death but PDA receiving treatment/ligation or death was lower among IP at ≤6 h compared with IP at >6-24 h (OR 0.83, 95% CI 0.71 to 0.98)., Conclusions: IP at ≤6 h of age is not associated with less IVH or death, but is associated with less PDA receiving treatment/ligation or death., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

This is a retrospective analysis of a multicentre randomised controlled trial (RCT) where we concluded that CeasIng Cpap At standerD criteriA (CICADA) in premature babies (PBs) <30 weeks gestational age (GA) was the significantly better method of ceasing CPAP. To identify factors that may influence the number of attempts to cease CPAP, we reviewed the records of 50 PBs from the RCT who used the CICADA method. PBs were grouped according to number of attempts to cease CPAP (fast group ≤2 attempts and slow group >2 attempts to cease CPAP). There were 26 (fast group) and 24 (slow group) PBs included in the analysis. Results showed significant differences in mean GA (27.8 ± 0.3 vs 26.9 ± 0.3 [weeks ± SE], p = 0.03) and birth weight ([Bwt]; 1080 ± 48.8 vs 899 ± 45.8 [grams ± SE], p = 0.01) between groups. Significantly fewer PBs in the fast group had a patent ductus arteriosus (PDA) compared to the slow group (5/26 (19.2%) vs 13/24 (54.2 %), p = 0.02). Bwt was a significant negative predictor of CPAP duration (r = -0.497, p = 0.03) and CPAP ceasing attempts (r = -0.290, p = 0.04)., Conclusion: PBs with a higher GA and Bwt without a PDA ceased CPAP earlier using the CICADA method. Bwt was better than GA for predicting CPAP duration and attempts to cease CPAP., What Is Known: Our previous studies showed that CeasIng Cpap At standarD criteriA (CICADA) significantly reduces CPAP time, oxygen requirements and caffeine use. Some PBs however using the CICADA method required >2 attempts to cease CPAP ('slow CICADA' group)., What Is New: PBs in the 'fast CICADA' group (<3 attempts to cease CPAP) (a) have longer gestational age and higher birth weight, (b) shorter mechanical ventilation and (c) lower incidence of patent ductus arteriosus. Attempts to cease CPAP decreased by 0.5 times per 1 week increase in GA and 0.3 times per 100-g increase in birth weight for PBs <30 weeks gestation.

Background: The management of a patent ductus arteriosus in preterm infants continues to be debated among neonatologists due to the absence of concrete evidence that precisely weighs the long term outcomes of active, early intervention against a conservative approach. In the majority of institutions, parents are encouraged to play an active role in the complex, decision -making processes with regard to the care of their infants. The objective of this study is to elicit maternal preferences for indomethacin prophylaxis versus treatment of a patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants, utilizing a decision aid instrument (DAI)., Methods: Healthy and high risk pregnant women at 23-28 weeks gestation, and mothers of admitted ELBW infants were enrolled. A computer based, validated DAI was utilized during interviews. The DAI first provides information about prematurity and concurrent morbidities with comprehensive facts of the pros and cons about prophylactic versus treatment options. It subsequently coaches participants how to select values and preferences based on their decisions. A 17-item questionnaire assessed and valued each short and long term morbidity of extreme prematurity and preferred choice for PDA management., Results: Two hundred ninety nine subjects were enrolled; 75% were healthy women at 23-28 weeks gestation, 19% were high risk and 6% recently delivered an ELBW infant. Eighty-two percent preferred a prophylactic indomethacin strategy versus symptomatic treatment for the management of PDA. Across a spectrum of potential morbidities, the occurrence of severe intraventricular hemorrhage was viewed by mothers as the most un-wanted outcome irrespective of the two proposed options., Conclusions: In contrast to neonatal practitioners, mothers who used this particular DAI strongly endorsed prophylactic indomethacin versus a treatment intervention for the management of PDA in preterm infants.

Importance: Advantages of caffeine for apnea of prematurity have prompted clinicians to use it prophylactically even before apnea., Objective: To determine the effect of early initiation of caffeine therapy on neonatal outcomes in very preterm infants born in Canada., Design, Setting, and Participants: A retrospective cohort study was conducted. Patients included preterm neonates born at less than 31 weeks' gestation admitted to 29 participating Canadian Neonatal Network neonatal intensive care units between January 1, 2010, and December 31, 2012., Exposures: Neonates who received caffeine were divided into 2 groups based on the following timing of caffeine initiation: within the first 2 days after birth (early) and on or after the third day following birth (late)., Main Outcome and Measure: A composite of death or bronchopulmonary dysplasia., Results: Of 5517 eligible neonates, 5101 (92.5%) received caffeine (early: 3806 [74.6%]; late: 1295 [25.4%]). There was no difference in weight or gestational age at birth between the groups. Neonates in the early group had decreased odds of a composite outcome of death or bronchopulmonary dysplasia (adjusted odds ratio [AOR], 0.81; 95% CI, 0.67-0.98) and patent ductus arteriosus (AOR, 0.74; 95% CI, 0.62-0.89). There was no difference between the groups in mortality (AOR, 0.98; 95% CI, 0.70-1.37), necrotizing enterocolitis (AOR, 0.88; 95% CI, 0.65-1.20), severe neurological injury (AOR, 0.80; 95% CI, 0.63-1.01), or severe retinopathy of prematurity (AOR, 0.78; 95% CI, 0.56-1.10)., Conclusions and Relevance: In very preterm neonates, early (prophylactic) caffeine use was associated with a reduction in the rates of death or bronchopulmonary dysplasia and patent ductus arteriosus. No adverse impact on any other outcomes was observed.

Aims: At birth, dynamic changes occur in serum components and haemodynamics, such as closure of the ductus arteriosus (DA). A previous study demonstrated that, in full-term human neonates, serum osmolality decreased transiently after birth, but recovered over the next few days. However, the significance of this transient decrease in osmolality has never been addressed. The objective of the present study was to examine the role of changes in serum osmolality after birth in DA closure., Methods and Results: We found that rats exhibited a similar transient hypoosmolality after birth. Hypotonic stimulation induced constriction of DA rings and increased Ca(2+) transient in DA smooth muscle cells, but not in the aorta. The hypoosmotic sensor transient receptor potential melastatin 3 (TRPM3) was highly expressed in the rat DA, and TRPM3 silencing abolished the Ca(2+) response to hypoosmolality. Pregnenolone sulfate stimulation of TRPM3 induced rat DA constriction ex vivo and in vivo. Furthermore, hypertonic fluid injection impaired rat DA closure. In humans, neonatal serum hypoosmolality was observed in relatively mature preterm infants (≥28 weeks). In extremely preterm infants (<28 weeks), however, this hypoosmolality was absent. Instead, a rapid increase in osmolality occurred thereafter. Such an increase was greater, in particular, among patent DA (PDA) patients., Conclusions: A transient decrease in serum osmolality may promote DA closure during the first few days of life. Adjusting serum osmolality to proper levels might help to prevent the onset of PDA, improving the therapeutic outcome in extremely preterm infants., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)