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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.)

Objectives: Persistent ductus arteriosus (PDA) delays the recovery of very preterm infants (VLGA, gestation <32 weeks). Indomethacin/ibuprofen treatment and ligation of PDA have complications. As a prostaglandin synthase inhibitor paracetamol may also promote the closure of ductus arteriosus. We studied retrospectively whether early paracetamol therapy was associated with decreased incidence of PDA without adverse events., Methods: On June 2009, we introduced intravenous paracetamol during early respiratory therapy. We included 105 VLGA infants who received paracetamol before the age of 72 h. The loading dose was 20 mg/kg followed by 7.5 mg/kg every 6 hours. The 96 VLGA infants admitted from January 2008 to May 2009 without lethal congenital disease were controls. Infants dying very early were excluded, leaving 102 paracetamol-exposed and 88 controls for analysis., Results: After the introduction of paracetamol, the incidence of PDA decreased from 30.7% to 14.7% (p = 0.008). Ibuprofen treatment was given to 15 paracetamol-treated and to 26 control infants (p = 0.013). Three paracetamol-exposed and seven control infants required surgery. There was no detectable increase in adverse events., Conclusions: Annual incidence of PDA decreased after introduction of paracetamol. Efficacy and safety in promoting the early closure of ductus arteriosus remains to be established.

Objective: To compare the effects of prophylactic indomethacin versus expectant management on short-term respiratory outcomes in extremely low-birth-weight (ELBW) infants., Methods: This was a retrospective cohort study of ELBW infants with gestational age less than 28 weeks, born at a level III neonatal intensive care unit from 2004 to 2009. Patients were grouped based on whether they received prophylactic indomethacin or expectant treatment. The key outcome was the cumulative number of days of mechanical ventilation. Other outcomes were cumulative number of days supplemental oxygen and continuous positive airway pressure (CPAP) were required; duration of hospital stay; mortality; and other morbidities such as necrotizing enterocolitis and intraventricular hemorrhage. Multivariable linear regression was performed with treatment group and seven covariates, defined a priori, as predictor variables and cumulative number of days of mechanical ventilation as the outcome., Results: There were 144 infants in the prophylaxis group and 221 infants in the expectant treatment group. At baseline, the Score for Neonatal Acute Physiology-Perinatal Extension, incidence of respiratory distress syndrome, and usage of antenatal corticosteroids were significantly higher in the prophylaxis group. The cumulative number of days of mechanical ventilation, supplemental oxygen, and CPAP were significantly higher in the prophylaxis group. On multivariable linear regression, after adjusting for confounders, use of prophylactic indomethacin (unstandardized β coefficient = 12.4; 95% confidence interval [CI]: 6.6, 18.1; p < 0.001), birth weight (β =  -0.025; 95% CI: -0.05, -0.001; p = 0.043), and gestation (β =  -4.5; 95% CI: -7.24, -1.8; p = 0.001) were the independent predictors of cumulative number of days of mechanical ventilation., Conclusion: ELBW infants who received prophylactic indomethacin had significantly longer cumulative number of days of mechanical ventilation, supplemental oxygen, and CPAP. Prophylactic indomethacin is an independent predictor of cumulative number of days of mechanical ventilation., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Most premature infants are physiologically not sufficiently mature to orally ingest all of their required water and nutrients. Therefore, premature infants rely on their caregivers to regulate their volume of water intake. Thus, the caregiver must determine the amount of water to be given each day to such infants., Objectives: To determine the effect of water intake on postnatal weight loss and the risks of dehydration, patent ductus arteriosus, necrotizing enterocolitis, bronchopulmonary dysplasia, intracranial hemorrhage, and death in premature infants., Search Methods: Randomized clinical trials (RCTs) identified in previous versions of this review were re-examined and, in each case, retained. Additional trials were sought that compared the outcomes of interest in groups of premature infants who were given different levels of water intake according to an experimental protocol. Such trials were sought in a list of trials provided by the Cochrane Neonatal Review Group, with a PubMed search and in the authors' personal files.This search was updated in 2014., Selection Criteria: Only RCTs of varying water intake in premature infants were included. The review was limited to trials that included infants whose water intake was provided mainly or entirely by intravascular infusion., Data Collection and Analysis: The standard methods of The Cochrane Collaboration were used. Study selection and data abstraction were performed independently by each review author. The adverse event rates were calculated for the restricted and liberal water intake groups for each dichotomous outcome, and the relative risk and risk difference were computed. In addition, the maximal weight loss results were recorded and the weighted mean difference was computed., Main Results: The analysis of the five studies taken together indicated that restricted water intake significantly increased postnatal weight loss and significantly reduced the risks of patent ductus arteriosus and necrotizing enterocolitis. With restricted water intake, there were trends toward increased risk of dehydration and reduced risks of bronchopulmonary dysplasia, intracranial hemorrhage, and death but these trends were not statistically significant., Authors' Conclusions: Based on this analysis, the most prudent prescription for water intake to premature infants would seem to be careful restriction of water intake so that physiological needs are met without allowing significant dehydration. This practice could be expected to decrease the risks of patent ductus arteriosus and necrotizing enterocolitis without significantly increasing the risk of adverse consequences.

The primary objective of this review is to verify if there are differences in the diagnostic and therapeutic strategies in cases of PDA employed in different NICUs that might help explain the different percentages of duct closure, surgical ligation and outcome in these vulnerable patients. The secondary objective is to document if the selection of a specific NSAID and/or the way of administration are based on factors such as costs and local availability of drugs, as well as influenced by clinical and haemodynamic parameters, potential risks, local experience and the existing literature. Data Sources were MEDLINE, EMBASE, Cochrane Library and analysis of the most important papers were performed. We examined a total of 89 trials including 15,657 neonates (with gestational ages between 22 and 35 weeks and study weights between 380 and 2500 g), due to the lack of homogeneity of case studies it was not possible to standardize for gestational age and weight. To simplify, the studies we considered were subdivided into 5 groups corresponding to 5 tables: 1- INDO-prophylaxis (15 trials); 2- IBU-prophylaxis (11 trials); 3- INDO-therapy (18 trials); 4- IBU-therapy (16 trials); 5- IBU vs INDO therapy (29 trials). Each table reports the journal, the reference, the type of study, the number of neonates enrolled, the drugs used, management after failure of the first cycle, percentage of duct closure and adverse effects. Treatment with indomethacin is prescribed prevalently in the United States and Canada. According to the data collected, prolonged treatment and administration of high doses would appear to be more effective. The early administration of indometacin has been associated with gastrointestinal bleeding, renal insufficiency, altered cerebral self-regulation and, especially when administered together with postnatal steroids, it has been correlated with isolated intestinal perforation. Ibuprofen treatment is preferred in Europe but it may be associated with nephrotoxicity and an increase in BDP and ROP, although less frequently compared to indometacin. Indometacin is associated with major nephrotoxicity, as well as with a higher incidence of NEC, intestinal perforations and a reduced cerebral blood flow. Despite this, the administration of ibuprofen does not appear to be without short- and long-term renal adverse effects.

Indomethacin is a non-steroidal anti-inflammatory drug that is a potent inhibitor of prostaglandin E(2) synthesis. After birth, the ductus arteriosus closes spontaneously within 2-4 days in term infants. The major factor closing the ductus arteriosus is the tension of oxygen, which increases significantly after birth. Prostaglandin E(2) has the opposite effect to that of oxygen; it relaxes smooth muscle and tends to inhibit the closure of the ductus arteriosus. In preterm infants with respiratory distress syndrome, the ductus arteriosus fails to close (patent ductus arteriosus [PDA]) because the concentration of prostaglandin E2 is relatively high. PDA occurs in more than 70 % of neonates weighing less than 1,500 g at birth. The aim of this article was to review the published data on the clinical pharmacology of indomethacin in preterm infants in order to provide a critical analysis of the literature and a useful tool for physicians. The bibliographic search was performed electronically using the PubMed and EMBASE databases as search engines and February 2012 was the cutoff point. A remarkable interindividual variability was observed for the half-life (t(½)), clearance (CL), and volume of distribution (V(d)) of indomethacin. Prophylactic indomethacin consists of a continuous infusion of low levels of indomethacin and may be useful in preterm infants. Extremely preterm infants are less likely to respond to indomethacin. Infants with a postnatal age of 2 months do not respond to treatment with indomethacin. Indomethacin has several adverse effects, the most common of which is renal failure. An increase in serum creatinine of ≥0.5 % mg/dL after indomethacin was observed in about 10-15 % of the patients and creatinine returns to a normal level about 1 week after cessation of therapy. Indomethacin should be administered intravenously by syringe pump for at least 30 min to minimize adverse effects on cerebral, gastrointestinal, and renal blood flow velocities. A prolonged course of indomethacin appears to reduce the risk of severe intracranial hemorrhage and renal impairment in patients with PDA. In conclusion, indomethacin is a useful drug to treat PDA.

Aim: The aim of this study was to explore the effects of early oral ibuprofen administration on the incidence of hemodynamically significant patent ductus arteriosus (hsPDA) and define the association between serum ibuprofen levels and ductal closure., Method: Preterm infants with a gestational age of <28 weeks and/or birth weight of <1,000 g were randomized either to the intervention (ibuprofen prophylaxis) or control group. The intervention group received oral ibuprofen 10 mg/kg within 12-24 h after birth followed by 5 mg/kg at 24 and 48 h. Serum ibuprofen levels after the treatment were analyzed in the intervention group, and the incidence of hsPDA and complication rates were compared between two groups., Results: Nineteen infants who received one course (three doses) of prophylactic ibuprofen in the intervention group and 17 infants in the control group who underwent an echocardiographic examination on the fourth day of life were analyzed. hsPDA was observed in five (26 %) infants in the intervention group and ten (58 %) infants in the control group (p = 0.09). In the intervention group two infants experienced gastrointestinal bleeding two infants had spontaneous intestinal perforation, and two infants developed acute kidney failure. Mean serum ibuprofen level was 28.7 ± 16.9 mg/L in the intervention group, and there was no correlation between ibuprofen level obtained on the fourth day and ductal closure., Conclusion: Oral ibuprofen prophylaxis reduces the rates of hsPDA even it is not statistically significant. The ductal closure rate did not correlate with serum ibuprofen levels. Due to high prevalence of adverse events observed, our data do not support the use of oral ibuprofen for prophylaxis of hsPDA.

Background: Patent ductus arteriosus (PDA) is a common life-threatening complication among premature infants. Although cyclooxygenase inhibitors are frequently used to treat PDA, as they inhibit the synthesis of prostaglandin E(2), the most potent vasodilator in the ductus arteriosus (DA), their efficacy is often limited. As thromboxane A(2) (TXA(2)) induces vascular contraction via the TXA(2) receptor (TP), we hypothesized that TP stimulation would promote DA closure., Method: To measure the inner diameter of the vessels, a rapid whole-body freezing method was used., Results: Injection of the selective TP agonists U46619 and I-BOP constricted the fetal DA at embryonic day 19 (e19) and e21 in a dose-dependent manner. Of note, U46619 also exerted a vasoconstrictive effect on two different types of postnatal PDA models: premature PDA and hypoxia-induced PDA. We also found that U46619 constricted the ex vivo DA ring to a greater extent than it constricted the ex vivo aorta. Furthermore, we found that U46619 at lower concentrations (up to 0.05 mg/g of body weight) had a minimal vasoconstrictive effect on other vessels and did not induce microthrombosis in the pulmonary capillary arteries., Conclusion: Low-dose TP stimulation constricts the DA with minimal adverse effects at least in rat neonates and our results could point to an alternative potent vasoconstrictor for PDA.

Background and Objective: Delayed cord clamping (DCC) has been advocated during preterm delivery to improve hemodynamic stability during the early neonatal period. The hemodynamic effects of DCC in premature infants after birth have not been previously examined. Our objective was to compare the hemodynamic differences between premature infants randomized to either DCC or immediate cord clamping (ICC)., Methods: This prospective study was conducted on a subset of infants who were enrolled in a randomized controlled trial to evaluate the effects of DCC versus ICC. Entry criteria included gestational ages of 24(0) to 31(6) weeks. Twins and infants of mothers with substance abuse were excluded. Serial Doppler studies were performed at 6 ± 2, 24 ± 4, 48 ± 6, and 108 ± 12 hours of life. Measurements included superior vena cava blood flow, right ventricle output, middle cerebral artery blood flow velocity (BFV), superior mesenteric artery BFV, left ventricle shortening fraction, and presence of a persistent ductus arteriosus., Results: Twenty-five infants were enrolled in the DCC group and 26 in the ICC group. Gestational age, birth weight, and male gender were similar. Admission laboratory and clinical events were also similar. DCC resulted in significantly higher superior vena cava blood flow over the study period, as well as greater right ventricle output and right ventricular stroke volumes at 48 hours. No differences were noted in middle cerebral artery BFV, mean superior mesenteric artery BFV, shortening fraction, or the incidence of a persistent ductus arteriosus., Conclusions: DCC in premature infants is associated with potentially beneficial hemodynamic changes over the first days of life.

Background: Decision Aids (DA) are well established in various fields of medicine. It can improve the quality of decision-making and reduce decisional conflict. In neonatal care, and due to scientific equipoise, neonatologists caring for extreme low birth weight (ELBW) infants are in need to elicit parents' preferences with regard to the use of indomethacin therapy in ELBW infants. We aimed to develop a DA that elicits parents' preferences with regard to indomethacin therapy in ELBW infants., Methods: We developed a DA for the use of the indomethacin therapy in ELBW infants according to the Ottawa Decision Support Framework. The development process involved parents, neonatologists, DA developers and decision making experts. A pilot testing with healthy volunteers was conducted through an evaluation questionnaire, a knowledge scale, and a validated decisional conflict scale., Results: The DA is a computer-based interactive tool. In the first part, the DA provides information about patent ductus arteriosus (PDA) as a disease, the different treatment options, and the benefits and downsides of using indomethacin therapy in preterm infants. In the second part, it coaches the parent in the decision making process through clarifying values and preferences. Volunteers rated 10 out of 13 items of the DA positively and showed significant improvement on both the knowledge scale (p = 0.008) and the decisional conflict scale (p = 0.008)., Conclusion: We have developed a computer based DA to assess parental preferences with regard to indomethacin therapy in preterm infants. Future research will involve measurement of parental preferences to guide and augment the clinical decisions in current neonatal practice.

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: To determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention in the prevention of PDA in preterm infants., Search Strategy: Randomized controlled trials of prophylactic ibuprofen were identified by searching in The Cochrane Library, MEDLINE, CINAHL, EMBASE and trials registries in December 2010., Selection Criteria: Randomized or quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm and/or low birth weight infants., Data Collection and Analysis: Outcomes data including presence of PDA on day three, need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, intraventricular haemorrhage (IVH), renal, pulmonary and gastrointestinal complications were extracted. Meta-analyses were performed and treatment estimates are reported as typical weighted mean difference, relative risk (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNT) or number needed to treat to harm (NNH) along with their 95% confidence intervals (CI)., Main Results: In this update, seven studies (n = 931) comparing prophylactic ibuprofen with placebo/no intervention are included. Ibuprofen decreased the incidence of PDA on day three [typical RR 0.36 (95% CI 0.29 to 0.46); typical RD -0.27 (95% CI -0.32 to -0.21); NNT 4 (95% CI 3 to 5)], decreased the need for rescue treatment with cyclo-oxygenase inhibitors and decreased the need for surgical ligation. Results from two studies administering oral ibuprofen had similar results, but showed an increased risk of gastrointestinal bleeding (NNH 4, 95% CI 2 to 17). In the control group the spontaneous closure rate was 58% by day three. Ibuprofen negatively affects renal function. No significant differences in mortality, IVH, chronic lung disease were found., Authors' Conclusions: Prophylactic use of ibuprofen decreased the incidence of PDA, decreased the need for rescue treatment with cyclo-oxygenase inhibitors and decreased the need for surgical closure. In the control group, the PDA closed spontaneously by day three in 58% of the neonates. Prophylactic treatment exposes many infants to a drug that has concerning renal and gastrointestinal side effects without conferring any important short-term benefits and is not recommended. Until long-term follow-up results are published from the trials included in this updated review, no further trials of prophylactic ibuprofen are recommended.

Unlabelled: Important short-term intermediate outcomes such as patent ductus arteriosus (PDA), severe intraventricular haemorrhage, surgical ligation of PDA and serious pulmonary haemorrhage correlate with worse neurosensory outcomes in extreme low birth weight infants. Indomethacin prophylaxis has been shown to significantly prevent such outcomes. However, this positive effect did not translate into neither prevention of bronchopulmonary dysplasia nor long-term neurosensory outcome. The indomethacin prophylaxis story is indeed a puzzling one to neonatal practitioners. We present a summary of evidence and possible explanations to the lack of appreciated long-term effect of indomethacin prophylaxis. As the trial of indomethacin prophylaxis for preterms trial is a major contributor to current evidence, a detailed critical analysis of its methodology is presented. Methodological concerns such as the use of a composite outcome, statistical power, anticipated side effects of indomethacin prophylaxis and lack of predictive validity of cognitive delay measurements are presented., Conclusion: Conclusive evidence of indomethacin prophylaxis use in extreme low birth weight infants is still lacking. Future research should put more emphasis on parental preferences, synergistic effect of indomethacin prophylaxis and fluid restriction and early targeted approach to PDA management., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

This study was aimed to verify the efficacy and safety of ibuprofen prophylaxis of patent ductus arteriosus in very preterm infants, in order to select infants receiving higher benefits from this intervention. Two hundred neonates with gestational age (GA) < or = 28 weeks receiving ibuprofen within the first two hours of life were included. Ductus closure rate was 68%, and results were significantly dependent on GA (48.8% among neonates with GA < 26 weeks vs 73.2% among those with GA > or = 26 weeks, p < 0.01). Neonates with GA < 26 weeks showed a lower ductus closure after the primary course of therapy (20% vs 57.5%, p < 0.01), as well as higher reopening rate (16.2% vs 3.8%, p < 0.05) and need for surgical ligation (38.8% vs 5.8%, p < 0.01). During the prophylaxis period, 11 neonates (5.5%) showed pulmonary hypertension. Considering risks/benefits, we recommend prophylaxis only in infants with GA < 26 weeks.

Although the prophylactic administration of indomethacin in extremely low-birth weight infants reduces the frequency of patent ductus arteriosus and severe intraventricular hemorrhage, it does not appear to provide any long-term benefit in terms of survival without neurosensory and cognitive outcomes. Considering the increased drug-induced reduction in renal, intestinal, and cerebral blood flow, the use of prophylaxis cannot be routinely recommended in preterm neonates. However, a better understanding of the genetic background of each infant may allow for individualized prophylaxis using NSAIDs and metabolomics.

Objective: The aim of this study is to evaluate the influence of antenatal magnesium sulfate (MgSO(4)) treatment on the clinical responsiveness of the ductus arteriosus to indomethacin prophylaxis and on that of symptomatic patent ductus arteriosus (sPDA) to indomethacin treatment in premature neonates., Study Design: This is a retrospective study of 160 consecutively admitted neonates with a gestational age of <28 weeks (41 MgSO(4) exposed and 119 controls) who received indomethacin prophylaxis., Result: Incidence of early closure of the ductus arteriosus was lower in the MgSO(4)-exposed neonates than in the control group (59 vs 84%, respectively; P=0.002), whereas incidence of an sPDA was higher (46 vs 24%, respectively; P=0.006). Response to indomethacin treatment was similar between the two groups. Logistic regression analysis indicated increased risk of failure of early ductus arteriosus closure following antenatal MgSO(4) treatment (odds ratio, 4.03; P=0.002)., Conclusion: In extremely preterm neonates, antenatal MgSO(4) treatment reduces clinical responsiveness of the ductus arteriosus to indomethacin prophylaxis but not that of sPDA to indomethacin treatment.

Objective: To evaluate the efficacy and safety of ambroxol in the prevention of respiratory distress syndrome (RDS) in preterm infants., Methods: Electronic searches were performed in the Cochrane Library, PubMED, EMBASE, Chinese CBM, Chinese VIP Database, Chinese Wanfang Database and Chinese CNKI Database up to the year of 2009 for randomized controlled trials (RCT) on ambroxol for the prevention of RDS in preterm infants. The meeting articles related to the RCT were manually searched in Pediatrics and Pediatric Research. Meta analysis was performed for the results of homogeneous studies by the Cochrane Collaboration's software RevMan 5.0.17., Results: Six RCTs involving 823 preterm infants were included, and the quality assessment for the trials demonstrated 1 article as A class, 1 article as B class and 4 articles as C class. The Meta analysis showed that ambroxol administration significantly reduced the incidence of RDS (OR=0.24, 95%CI: 0.15 - 0.64, P<0.01), bronchopulmonary dysplasis (BPD, OR=0.41, 95%CI: 0.23 - 0.75, P<0.01), intraventricular hemorrhage (IVH, OR=0.39, 95%CI:0.24 - 0.64, P<0.01), patent ductus arteriosus (PDA, OR=0.33, 95%CI: 0.17 - 0.67, P<0.01) and pulmonary infection (OR=0.24, 95%CI:0.14 - 0.38, P<0.01). No adverse events related to the ambroxol treatment were reported., Conclusions: The current evidence shows that early use of ambroxol can reduce the risk of RDS, BPD, IVH, PDA and pulmonary infection in preterm infants.

Three independent risk factors (immature gestation, absence of antenatal glucocorticoid exposure, and presence of the rs2817399(A) allele of the gene TFAP2B) are associated with patent ductus arteriosus (PDAs) that fail to close during prostaglandin inhibition. We hypothesized that these three factors may affect a common set of genes that increase the risk of persistent PDA after birth. We studied baboon ductus from term, preterm, and glucocorticoid-treated preterm fetuses and found that both immature gestation and absence of antenatal glucocorticoid exposure decreased RNA expression of calcium- and potassium-channel genes involved in oxygen-induced constriction, and phosphodiesterase genes (that modulate cAMP/cGMP signaling). Ductus obtained from second trimester human pregnancies were genotyped for TFAP2B polymorphisms. When present, the rs2817399(A) allele also was associated with decreased expression of calcium- and potassium-channel genes. In contrast, alleles of two other TFAP2B polymorphisms, rs2817419(G) and rs2635727(T), which are not related to the incidence of PDA after birth, had no effect on RNA expression. In conclusion, three calcium- and potassium-channel genes (CACNA1G/ alpha1G, CACNB 2/CaL-beta2, and KCNA2/ Kv1.2) were similarly affected by each of the PDA risk factors. We speculate that these channels may play a significant role in closing the preterm ductus during prostaglandin inhibition and may be potential targets for future pharmacologic manipulations.

The ductus arteriosus (DA) is a small vessel with major functional importance for the integrity of the fetal circulation. Technical advances in prenatal diagnostics facilitate appropriate echocardiographic estimation of the ductal flow and its abnormalities. Despite the emerging knowledge of its embryological background and developmental processes during advancing gestation we still have to face unresolved questions regarding the identification and optimal surveillance of fetuses at risk of premature closure of the ductus. Prenatal administration of tocolytics such as indomethacin should be monitored by close Doppler sonographic scans to follow the ductal circulation. Understanding the transcriptional regulation of normal DA development, maturation, and closure of the arterial duct as well as the hemodynamic changes during pregnancy and after delivery may provide additional targets for rational drug design to either close or open the DA, both antenatally and postnatally.

Background: Persistent patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. Prostaglandin synthetase inhibitors such as indomethacin promote PDA closure but also have potential side effects. The effect of the prophylactic use of indomethacin, where infants who may not have gone on to develop a symptomatic PDA would be exposed to indomethacin, warrants particular scrutiny., Objectives: To determine the effect of prophylactic indomethacin on mortality and morbidity in preterm infants., Search Strategy: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 5, 2010), MEDLINE, EMBASE and CINAHL (until April 2010), conference proceedings, and previous reviews., Selection Criteria: Randomised or quasi-randomised controlled trials that compared prophylactic indomethacin versus placebo or no drug in preterm infants., Data Collection and Analysis: The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two review authors., Main Results: Nineteen eligible trials in which 2872 infants participated were identified. Most participants were very low birth weight, but the largest single trial restricted participation to extremely low birth weight infants (N = 1202). The trials were generally of good quality.The incidence of symptomatic PDA [typical relative risk (RR) 0.44, 95% confidence interval (CI) 0.38 to 0.50] and PDA surgical ligation (typical RR 0.51, 95% CI 0.37,0.71) was significantly lower in treated infants. Prophylactic indomethacin also significantly reduced the incidence of severe intraventricular haemorrhage (typical RR 0.66, 95% CI 0.53 to 0.82). Meta-analyses found no evidence of an effect on mortality (typical RR 0.96, 95% CI 0.81 to 1.12) or on a composite of death or severe neurodevelopmental disability assessed at 18 to 36 months old (typical RR 1.02, 95% CI 0.90, 1.15)., Authors' Conclusions: Prophylactic indomethacin has short-term benefits for preterm infants including a reduction in the incidence of symptomatic PDA, PDA surgical ligation, and severe intraventricular haemorrhage. However, there is no evidence of effect on mortality or neurodevelopment.

Background: In extremely premature infants, the presence of a left-to-right shunt through a patent ductus arteriosus (PDA) increases the risks of pulmonary hemorrhage, intraventricular hemorrhage, necrotizing enterocolitis, renal failure, and chronic lung disease. Conservative management induces spontaneous ductus closure in <20% of extremely premature infants (infants born at <25 weeks of gestation). The aim of the present study was to determine the efficacy and safety of prophylactic indomethacin (INDO) administration for PDA closure in extremely premature infants born between 23 and 24 weeks of gestation., Methods: A historical case-control study of 30 infants born between 23 and 24 weeks of gestation was carried out. In the prophylactic INDO group, a 12 h-long, 0.01 mg/kg per h dose of INDO was administered within 6 h of life. During the historical control period, only infants with symptomatic PDA were treated with INDO for 1 h. The incidence of symptomatic PDA, mortality and early neonatal morbidity was compared between the two groups on Fisher's exact test and Mann-Whitney rank-sum test., Results: None of the infants in the prophylactic INDO group had symptomatic PDA, while 11 of the 15 infants in the control group showed symptomatic PDA (P < 0.001). There were no significant differences between the mortality rates and the early neonatal morbidities in the two groups., Conclusions: Prophylactic INDO administration to extremely premature infants born between 23 and 24 weeks of gestation decreased the incidence of symptomatic PDA without increasing the incidence of adverse effects.

Background: Preterm birth causes infant morbidity and mortality. A single course of antenatal corticosteroids (ACS) should be considered routine for preterm delivery. Benefits of therapy before 34 weeks' gestation have been established for infants born between 24 h and 7 days after treatment. It is still unclear whether multiple courses (MC) of ACS should be performed in women at risk of preterm delivery 7 days or more after initial treatment., Objectives: To determine the risks and benefits of MC of ACS., Methods: Search and selection for human randomized controlled trials were conducted in PubMed and The Cochrane Central Register of Controlled Trials. Statistical analysis was performed using the Review Manager 4.3 software., Main Results: MC of ACS were associated with a statistically decrease in the occurrence of respiratory distress syndrome, patent ductus arteriosus, use of surfactant, ventilation support, and any maternal side effects. This treatment was also associated with a significant reduction in birth weight and head circumference., Conclusions: MC of ACS in women at risk of preterm birth do not offer significant benefits concerning the composite neonatal morbidity. Data on long-term safety are still insufficient. Further evaluations, most by follow-up studies, are required to study the long-term effects.

Background: Prostaglandin E(2) (PGE(2)) plays a major role both in maintaining patency of the fetal ductus arteriosus and in closure of the ductus arteriosus after birth. The rate-limiting step in PGE(2) signal termination is PGE(2) uptake by the transporter PGT., Methods and Results: To determine the role of PGT in ductus arteriosus closure, we used a gene-targeting strategy to produce mice in which PGT exon 1 was flanked by loxP sites. Successful targeting was obtained because neither mice hypomorphic at the PGT allele (PGT Neo/Neo) nor global PGT knockout mice (PGT(-/-)) exhibited PGT protein expression; moreover, embryonic fibroblasts isolated from targeted mice failed to exhibit carrier-mediated PGE(2) uptake. Although born in a normal mendelian ratio, no PGT(-/-) mice survived past postnatal day 1, and no PGT Neo/Neo mice survived past postnatal day 2. Necropsy revealed patent ductus arteriosus with normal intimal thickening but dilated cardiac chambers. Both PGT Neo/Neo and PGT(-/-) mice could be rescued through the postnatal period by giving the mother indomethacin before birth. Rescued mice grew normally and had no abnormalities by gross and microscopic postmortem analyses. In accordance with the known role of PGT in metabolizing PGE(2), rescued adult PGT(-/-) mice had lower plasma PGE(2) metabolite levels and higher urinary PGE(2) excretion rates than wild-type mice., Conclusions: PGT plays a critical role in closure of the ductus arteriosus after birth by ensuring a reduction in local and/or circulating PGE(2) concentrations.

Furosemide increases prostaglandin production and may be associated with patent ductus arteriosus (PDA). We aimed to clarify the in vivo ductus-dilating effects of furosemide in neonatal rats. Near-term rat pups delivered by a cesarean section were housed at 33 degrees C. After a rapid whole-body freezing, the DA diameter was measured using a microscope and a micrometer. Pregnant rats (gestational day 21) were s.c. injected with furosemide 4 h before delivery, and the neonatal DA was examined 0, 15, 30, 60, and 120 min after birth. Furosemide was also s.c. injected into 60-min-old rats and the DA diameter was examined 30, 60, and 120 min later. The control rats showed a rapid postnatal DA constriction (diameter: 0.80 and 0.08 mm at 0 and 60 min after birth, respectively). Prenatally administered furosemide delayed postnatal DA closure (0.36 mm at 60 min after birth). Furosemide injection in 60-min-old rats dilated the constricted DA at 60 min (0.25 versus 0.02 mm in the controls). Indomethacin inhibited furosemide-induced DA dilatation. Furosemide delays DA closure and dilates the constricted DA in neonatal rats. If furosemide has similar effects in human preterm neonates, caution may be warranted in its use in the treatment of infants with PDA.

Background: Ethamsylate decreases blood loss in certain clinical situations such as menorrhagia and following some surgical procedures. This potential to reduce bleeding has led to the hypothesis that it may have a role to play in reducing intraventricular haemorrhage in preterm infants., Objectives: To determine if ethamsylate, when compared to placebo or no treatment, reduces morbidity and/or mortality in preterm infants., Search Strategy: We searched the Cochrane Neonatal Group Trials Register (24 August 2009), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2009, Issue 2), MEDLINE and EMBASE (January 1966 to July 2009) and the Oxford Database of Perinatal Trials., Selection Criteria: Randomised controlled trials or quasi-randomised trials comparing ethamsylate with placebo or no treatment. The initial search for trials enrolling infants born less than 32 weeks gestation was subsequently expanded to include trials enrolling preterm infants < 35 weeks gestation or < 2000 grams birth weight. Studies were included if they reported on outcomes of all children until death or discharge home. Data from reports of neurodevelopmental follow-up were only included if at least 80% of participants were followed up., Data Collection and Analysis: Both review authors independently assessed trial quality and extracted data. We calculated relative risk (RR) and risk difference (RD) together with 95% confidence intervals (CI) and used a fixed-effect model for meta-analysis., Main Results: Eight studies were identified but only seven trials enrolling 1410 preterm infants were located. There was no significant difference detected in neonatal mortality or neurodevelopmental outcome at two years between infants treated with ethamsylate and controls. Infants treated with ethamsylate had significantly less intraventricular haemorrhage than controls at < 31 weeks (typical RR 0.63, 95% CI 0.47 to 0.86) and < 35 weeks gestation (typical RR 0.77, 0.65 to 0.92). There was also a significant reduction in grade 3 and 4 intraventricular haemorrhage when all infants < 35 weeks gestation (typical RR 0.67, 95% CI 0.49 to 0.94) were analysed as a single group, but not for the group of infants < 32 weeks alone. There was a reduction in symptomatic patent ductus arteriosus at < 31 weeks gestation (typical RR 0.32, 95% CI 0.12 to 0.87). There were no adverse effects of ethamsylate identified from this systematic review., Authors' Conclusions: Preterm infants treated with ethamsylate showed no reductions in mortality or neurodevelopmental impairment despite the reduction in any grade of intraventricular haemorrhage seen in infants < 35 weeks gestation.

Objective: To reexamine data from a randomized controlled trial of prophylactic ductus ligation to determine whether ligation contributes directly to the development of bronchopulmonary dysplasia (BPD) in extremely low birth weight infants., Study Design: The control group underwent ligation only if they had development of a symptomatic patent ductus arteriosus (PDA). The Prophylactic Ligation group underwent ligation within 24 hours of birth regardless of the presence or absence of symptoms of a PDA. We hypothesized that the incidence of BPD would be higher in the prophylactic ligation group because more ligations were performed than in the control group., Results: Prophylactic ligation significantly increased the incidence of BPD (defined as a supplemental oxygen requirement at 36 weeks postmenstrual age) and the incidence of mechanical ventilation at 36 weeks. The groups were statistically similar in gestation, sex, race, fluid administration, intraventricular hemorrhage, pulmonary air leaks, and survival to 36 weeks. The lower incidence of BPD in the control group occurred despite the fact that the incidence of necrotizing enterocolitis (a known risk factor for BPD) was significantly elevated in the control group. Only infants who had previously undergone a PDA ligation had development of BPD in the control group., Conclusion: Prophylactic ligation, while eliminating the PDA, increases the risk for BPD.