Retrospective study of clinical outcomes with hydrocortisone versus indomethacin prophylaxis in preterm neonates

Retrospective study of clinical outcomes with hydrocortisone versus indomethacin prophylaxis in preterm neonates | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Retrospective study of clinical outcomes with hydrocortisone versus indomethacin prophylaxis in preterm neonates Sandra Gerges, Danielle Mara, Krishanta Maharaj, Dany Weisz, Michael Dunn, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4473323/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Indomethacin and hydrocortisone prophylaxis may improve clinical outcomes when administered to extremely preterm neonates. However, they cannot be administered together and there is limited evidence to support which therapy may be most beneficial. Study Design: A retrospective matched cohort study was conducted in neonates less than 28 weeks gestational age (GA) and birth weight less than 1000 grams who received prophylaxis with indomethacin or hydrocortisone. Multivariable logistic regression analysis was used to evaluate clinical outcomes. Results Among 177 neonates, 40 treated with prophylactic hydrocortisone were matched with 137 neonates treated with prophylactic indomethacin. Indomethacin-treated neonates had significantly lower incidence of PDA, PDA requiring surgical closure, late-onset sepsis, and higher rates of survival without oxygen supplementation at discharge. There was no difference in mortality, BPD, NEC, or IVH. Conclusion When compared to hydrocortisone, indomethacin prophylaxis was associated with more favorable outcomes. Health sciences/Medical research/Outcomes research Health sciences/Health care/Therapeutics/Drug therapy Figures Figure 1 Article Summary Among extremely preterm neonates, prophylaxis with indomethacin may be preferable for the prevention of complications of prematurity over hydrocortisone prophylaxis. What’s Known on This Subject: Indomethacin and hydrocortisone are separately used to prevent complications of prematurity but cannot be used concomitantly. Prophylaxis with indomethacin may lower the incidence of intraventricular hemorrhage and patent ductus arteriosus and hydrocortisone may reduce the risk of death or bronchopulmonary dysplasia. What This Study Adds: In extremely preterm neonates, there was no difference in mortality or BPD between prophylaxis with indomethacin compared with hydrocortisone prophylaxis. Indomethacin was associated with significantly less PDA, PDA requiring surgical closure, late-onset sepsis, and higher rates of survival without oxygen supplementation at discharge than hydrocortisone. Introduction There have been significant improvements in neonatal intensive care over the past few decades with increasing survival and a reduction in the limits of viability 1 . Lowering the gestation at which care can be provided, however, increases the risk of adverse outcomes. Some of the most severe complications, including bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), and intraventricular haemorrhage (IVH) have consequences that can persist into adulthood 1, 2, 3, 4 . Research into treatments is ongoing, and several medical interventions exist both to treat and prevent these conditions. A systematic review of 19 trials comparing indomethacin prophylaxis to placebo in preterm neonates found that indomethacin significantly reduced the incidence of PDA and severe intraventricular haemorrhage in very low or extremely low birth weight neonates 5 . Based on these results, indomethacin is widely used as prophylaxis in extremely low birth weight neonates for prevention of severe IVH and reduction in the incidence of PDA. Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in infants with up to 80% of infants born at 22–24 weeks diagnosed with BPD 6, 7 . Despite the development of new interventions and changes to clinical practice, the prevalence of BPD in babies with a birth weight of 501 grams to 1 500 grams has only decreased from 31–28% since 2005 7 . A systematic review found that prophylaxis with early hydrocortisone or dexamethasone was associated with lower rates of BPD at 36 weeks 8 . These results have led to the use of hydrocortisone prophylaxis to reduce the incidence of BPD in extremely preterm neonates. Unfortunately, infants exposed to both prophylactic hydrocortisone and indomethacin are at increased risk of spontaneous intestinal perforation, which can be life threatening 8 . Since these two medications should not be used concomitantly, clinicians wishing to provide prophylaxis aimed at the prevention of PDA or BPD must choose between indomethacin and hydrocortisone, with limited evidence to support their choice. Information is needed to support the selection of either indomethacin or hydrocortisone for the prevention of PDA, BPD, and other complications of prematurity. This study aims to compare the outcomes of preterm neonates given either indomethacin or hydrocortisone prophylaxis to support this clinical decision. Methods Study design: A retrospective matched cohort study was conducted among extremely preterm neonates admitted to the Neonatal Intensive Care Unit (NICU) at Sunnybrook Health Sciences Centre in Toronto, Canada. Sunnybrook NICU is a high-performing tertiary perinatal center 9 that admits approximately 150 extremely low gestational age neonates (ELGANs) annually. Eligible participants included inborn or outborn neonates weighing less than 1000 grams and born at a gestational age of ≤ 27 + 6 weeks who were admitted to the Sunnybrook NICU, born between January 1, 2018 and January 22, 2022. Study participants were included if they were prescribed prophylactic indomethacin 0.1 mg/kg intravenous (IV) daily for 3 days, or prophylactic hydrocortisone 1 mg/kg IV daily divided into two doses for 7 days, then 0.5 mg/kg IV daily for 3 days for the prevention of BPD. Participants were included on an intention to treat basis, meaning they were included in the study group if they received at least one dose of the prophylaxis regimen and allocated to the group for which they initially received treatment. Exclusion criteria included the presence of major congenital or chromosomal anomalies, or membrane rupture greater than 2 weeks before delivery. Neonates were excluded if they received a dose of indomethacin or hydrocortisone other than the dose regimen prescribed above. The study was reviewed and approved by the Sunnybrook Health Sciences Centre Research Ethics Board (REB #5250) and was performed in accordance with the Declaration of Helsinki. Matching: After inclusion and exclusion criteria were met, 419 neonates were eligible for the study. Of these, 389 received prophylactic indomethacin and 40 received prophylactic hydrocortisone. It was expected that fewer hydrocortisone-treated neonates would be eligible for the study, as studies supporting hydrocortisone prophylaxis were published more recently, and the use of hydrocortisone at Sunnybrook was a newer clinical practice. The selection of prophylactic drug, if any, occurred at the discretion of the attending neonatologist. Participants were matched by gestational age (± 7 days) and by maternal antenatal steroid use, defined as any antenatal steroid use or no antenatal steroid use, to account for this confounder. Sample size limited the number of matching parameters used. Gestational age and maternal antenatal steroid use were selected as matching criteria to maximize the number of study participants eligible for matching. Other relevant variables, such as chorioamnionitis, were not present in a high enough frequency to be used as a matching criterion but were adjusted for elsewhere in the analysis. Neonates were matched in a 4:1 ratio when feasible. Outcomes: Outcomes of this exploratory study included overall mortality, BPD, PDA, PDA requiring surgical or procedural closure, late-onset sepsis, intraventricular hemorrhage, necrotizing enterocolitis, treatment with dexamethasone for evolving BPD, survival without oxygen supplementation at discharge, and pulmonary hemorrhage. BPD was defined as the use of oxygen, invasive or non-invasive ventilatory support, and/or high flow air when the infant reaches 36 weeks postmenstrual age, or at the time of discharge to a Level 2 hospital, whichever was earlier. PDA was diagnosed on echocardiography, and PDA requiring surgical closure included those managed using transcatheter percutaneous device closure or surgical ligation. Intraventricular hemorrhage was separated into grades I through IV based on the criteria outlined by the Canadian Neonatal Network. NEC (stage 2 or higher) was defined according to the Modified Bell’s Criteria. Treatment with dexamethasone for evolving BPD included neonates who had difficulty weaning from the ventilator who were treated with dexamethasone. Survival without oxygen supplementation at discharge included infants who survived and did not require respiratory support at the time of discharge. Pulmonary hemorrhage was defined as blood present in an endotracheal aspirate. Data collection: Participant health information was extracted from Sunnybrook Health Sciences Centre electronic health record systems. Clinically relevant maternal history was collected regarding the pregnancy and delivery of the study participant. Pharmacy records for all NICU-admitted patients were screened for study eligibility for patients born during the pre-specified study period. Statistical analysis: Descriptive statistics were used to summarize the baseline characteristics of the study population, including maternal, antenatal and perinatal characteristics, illness severity and intensive care support in the first 24 hours of life. Continuous variables were presented as mean and standard deviation, or median and interquartile range, for parametric and skewed data, respectively. Categorical data were presented as count and percent. Differences in baseline characteristics were evaluated using the Student t-test or Wilcoxon rank-sum test for continuous variables (as appropriate) or chi-square test for categorical variables. Multivariable logistic regressions with generalized estimating equations were used to evaluate the association of prophylactic treatment with all outcomes, adjusting for chorioamnionitis and birth weight z-score, and accounting for clustering due to multiple gestation. Results A total of 2 349 patient charts were screened, of which 1 920 did not meet inclusion criteria. Ten patients met exclusion criteria; nine were excluded for premature rupture of membranes greater than 2 weeks before delivery, and one neonate was excluded for the presence of congenital anomalies (Fig. 1 ). Among 177 neonates included in the study, 40 received hydrocortisone (mean GA 24.5 ± 1.0 weeks, mean birth weight 650 ± 126 grams) and were matched with 137 neonates who received prophylactic indomethacin (mean GA 24.7 ± 1.0 weeks, mean birth weight 684 ± 133 grams). Of the 40 neonates in the hydrocortisone group, 31 were matched with indomethacin-treated neonates at a ratio of 4:1, 4 were matched in a 2:1 ratio, and 5 were matched in a 1:1 ratio. No eligible neonates included in the hydrocortisone group were unmatched. Baseline infant characteristics were similar between the indomethacin group and the hydrocortisone group, with the exception of positive blood cultures at birth, which was higher in the hydrocortisone group (15.0% vs 5.11%, p = 0.04) (Table 1 ). Maternal characteristics of pregnancy were also similar among the two study groups (Table 1 ). Neonatal illness severity and intensive care support required in the first 24 hours was also characterized and were similar with the exception of a higher SNAP II score in the hydrocortisone group compared to the indomethacin group (27.8 vs 21, p = 0.02) (Table 1 ). Table 1 Baseline infant and maternal characteristics. Indomethacin (N = 137) Hydrocortisone (N = 40) P-value Infant characteristics Gestational age (weeks), mean (SD) 24.70 (1.01) 24.51 (0.98) 0.31 Birth weight (grams), mean (SD) 683.53 (132.80) 650.00 (126.18) 0.16 Z-score, mean (SD) -0.13 (0.83) -0.26 (0.88) 0.41 Male sex, N (%) 83 (60.58) 23 (57.50) 0.73 Inborn, N (%) 111 (81.02) 32 (80.00) 0.89 Twins, N (%) 20 (14.60) 6 (15.00) 0.95 Triplets, N (%) 4 (2.92) 0 (0.00) 0.40 IUGR: birth weight < 10th centile, N (%) 8 (5.84) 4 (10.00) 0.46 IUGR: birth weight < 3rd centile, N (%) 5 (3.65) 3 (7.50) 0.42 APGAR score at 1 minute of life, mean (SD) 4.55 (2.42) 3.85 (2.36) 0.11 APGAR score at 5 minutes of life, mean (SD) 6.74 (2.18) 6.23 (2.33) 0.21 Positive blood culture at birth, N (%) 7 (5.11) 6 (15.00) 0.04 Maternal characteristics Maternal age (years), mean (SD) 31.74 (5.02) 31. 48 (4.92) 0.76 No antenatal steroids, N (%) 17 (12.41) 9 (22.50) 0.14 Antenatal steroids: 1 dose, N (%) 37 (27.01) 9 (22.50) 0.62 Antenatal steroids: 2 doses, N (%) 82 (59.85) 21 (52.50) 0.59 Diagnosis of chorioamnionitis, N (%) 15 (10.95) 9 (22.50) 0.08 Delivery by Cesarean section, N (%) 76 (55.47) 28 (70.00) 0.29 Rupture of membranes > 24 hours before delivery, N (%) 30 (21.90) 10 (25.00) 0.68 Illness severity and intensive care support in the first 24 hours SNAP II score, mean (SD) or *median (IQR) *21 (13.00) 27.82 (14.66) 0.02 Respiratory severity score at 6 hours of life, median (IQR) *6.72 (2.47) *6.83 (4.40) 0.58 Antibiotic exposure in the first 24 hours of life, N (%) 125 (91.24) 35 (87.50) 0.83 Required vasopressors in the first 24 hours of life, N (%) 28 (20.44) 15 (37.50) 0.05 IUGR = intrauterine growth restriction Overall mortality was not different among neonates who received indomethacin prophylaxis compared with those who received hydrocortisone prophylaxis (20.4% vs 20.0%; aOR 1.07; 95% CI 0.94–1.21; p = 0.30). Neonates treated with indomethacin had a lower incidence of PDA (49.5% vs 93.8%; aOR 0.59; 95% CI 0.48–0.73; p < 0.0001), and PDA requiring surgical or procedural closure (4.6% vs 21.9%, OR 0.59; 95% CI 0.39–0.90, p = 0.01) compared with hydrocortisone (Table 2 ). The incidence of late-onset sepsis was lower in the indomethacin group compared with the hydrocortisone group (35.8% vs 59.4% aOR 0.82, 95% CI 0.70–0.97, p = 0.02). Survival without oxygen supplementation at discharge was significantly higher in the indomethacin group compared to the hydrocortisone group (77% vs 50% aOR 2.44, 95% CI 1.16–5.26, p = 0.02). There was no difference in the incidence of BPD, IVH, NEC, pulmonary hemorrhage, spontaneous intestinal perforation, survival without morbidity, or the number of neonates treated with dexamethasone for evolving BPD among the indomethacin-treated neonates compared with the hydrocortisone-treated neonates. Table 2 Clinical outcomes of indomethacin versus hydrocortisone prophylaxis in neonates with a birth weight less than 1000 grams and gestational age less than or equal to 27 + 6 weeks. Outcome Indomethacin, N (%) Hydrocortisone, N (%) Adjusted Odds Ratio or *Odds Ratio (95% Confidence Interval) P-value Overall mortality 28 (20.4) 8 ( 20 ) 1.07 (0.94–1.21) 0.30 Patent ductus arteriosus 54 (49.5) 30 (93.8) 0.59 (0.48–0.73) < 0.0001 PDA requiring surgical management 5 (4.6) 7 (21.9) *0.59 (0.39–0.90) 0.01 Bronchopulmonary dysplasia (Mild, moderate, and severe) 44 (40.4) 17 (53.1) 0.69 (0.33–1.44) 0.33 Late onset sepsis 39 (35.8) 19 (59.4) 0.82 (0.70–0.97) 0.02 Intraventricular hemorrhage 39 (35.8) 15 (46.9) 0.97 (0.82–1.15) 0.74 Necrotizing enterocolitis 20 (18.3) 9 (28.1) 0.93 (0.83–1.04) 0.12 Survival without oxygen supplementation at discharge 82 (77.1) 16 (50.0) 2.44 (1.16–5.26) 0.02 Treated with dexamethasone for evolving BPD 43 (39.4) 16 (0.5) 0.92 (0.79–1.08) 0.30 Pulmonary hemorrhage 10 (9.2) 5 (15.6) *0.95 (0.84–1.06) 0.33 Spontaneous intestinal perforation 13 (11.9) 4 (12.5) *1.00 (0.93–1.07) 0.92 Survival without morbidity 37 (27.0) 8 (20.0) 1.45 (0.64–3.44) 0.40 Discussion In this retrospective cohort study of extremely preterm neonates treated with either prophylactic indomethacin or prophylactic hydrocortisone, there was no difference in mortality, though indomethacin prophylaxis was associated with reduced incidence of PDA, PDA requiring surgical or procedural closure, late-onset sepsis, and improved survival without home oxygen. A modest benefit to survival has been shown with indomethacin prophylaxis in a recent network meta-analysis which included 19 randomized-controlled trials comparing indomethacin prophylaxis to placebo or no therapy, including a total of 2877 neonates 10 . Our study may not demonstrate this survival benefit due to the small sample size or because of a difference in comparison group. The indomethacin group was diagnosed with less PDA and PDA requiring surgical or procedural closure in this study, which is consistent with the recent data although there was no difference in rates of IVH 10 . There were few outcome events of IVH in the overall study population so there was likely not enough power to detect any potential differences in rates of IVH. We also found a lack of benefit of hydrocortisone for the prevention of BPD, which differed from the results of the PREMILOC trial. We compared hydrocortisone to indomethacin whereas in the PREMILOC trial hydrocortisone was being compared to placebo which may partially account for this difference 8 . The mean gestational age was also lower in our study by about 2 weeks compared to the PREMILOC trial (study population mean GA 24.5 weeks compared to 26.4 weeks in PREMILOC). The benefit of hydrocortisone prophylaxis may be to facilitate earlier extubation and thus prevent dependence on mechanical ventilation to prevent the development of BPD. This may not be feasible among the extremely low gestational age population, which comprised the majority of our study population. The baseline rates of BPD at our study center are also relatively low 11 , so pharmacological interventions may not result in a detectable difference. It is unlikely that this result was affected by the baseline characteristics of the neonates. All infant, maternal, and resuscitation characteristics were similar, apart from positive blood cultures at birth and the SNAP-II score, a calculated score used as a predictor of neonatal mortality. The hydrocortisone group did have a statistically significantly higher score than the indomethacin group (27.8 versus 21), however this is not likely to be a clinically significant difference, since the difference between the groups was quite small, and both groups had a mean score below the SNAP-II score of 44 that is validated to predict neonatal mortality 13 . A higher proportion of neonates who received hydrocortisone were found to have positive blood cultures at birth compared to neonates who received indomethacin, although the absolute number was small in both groups (6 versus 7). There was no difference in the number of neonates requiring treatment for BPD with dexamethasone 14 . One potential benefit of hydrocortisone prophylaxis is that it may reduce neonatal exposure to higher doses of steroids, which can negatively impact neurodevelopmental outcomes 15,16 . It was noted in our study that some infants who received hydrocortisone prophylaxis went on to receive multiple courses of dexamethasone. If hydrocortisone-treated neonates still require dexamethasone, this may significantly reduce the perceived benefit of hydrocortisone and increase the overall cumulative steroid dose that these infants receive, ultimately leading to a higher probability of poor neurodevelopmental outcomes 16 . In the analysis of secondary outcomes of the PREMILOC study, early low-dose hydrocortisone was not associated with a statistically significant difference in full scale intelligence quotient (IQ) at 5 years of age, although some individual neurocognitive outcomes were significantly better in the hydrocortisone treated group. 17 On analysis of the outcome at 2 years of infants treated with dexamethasone there was no substantial difference in cerebral palsy or major disability between the dexamethasone and control groups. 18 There is however no definitive data on the neurodevelopmental outcomes of preterm infants exposed to both early low dose hydrocortisone followed by dexamethasone. We noted a lower incidence of PDA and PDA requiring surgical closure with indomethacin compared to hydrocortisone prophylaxis. These results are similar to the results from other studies 21 . Although a lower incidence of PDA may not be of clinical value if the PDAs were not hemodynamically significant and managed conservatively, the difference in PDA requiring surgical closure is quite significant 19 . One potential reason for a higher incidence of PDA requiring surgical closure with hydrocortisone is the potential delay in medical management of the PDA due to concerns of intestinal perforation. While hydrocortisone itself could cause intestinal perforation, an interaction between the steroid and cyclooxygenase inhibitors has been strongly implicated as a significant contributor for this effect. 20 As a result, medical management may have only commenced at the end of the ten-day course of hydrocortisone even in the presence of a hemodynamically significant PDA. This may also explain the higher incidence of survival without oxygen supplementation at discharge in the indomethacin group. In this study we also found a significantly higher incidence of late-onset sepsis with hydrocortisone compared with indomethacin. This is consistent with results from the PREMILOC trial, where neonates born at 24–25 weeks gestational age treated with hydrocortisone were found to have a higher rate of late onset sepsis 21 . This may be caused by the immunosuppressive effects of corticosteroids. 22 There are a number of strengths of the study worth highlighting. Firstly, the samples were matched by gestational age and antenatal steroids, two characteristics that can greatly impact clinical outcomes. When possible, results were also adjusted by the birth weight z-score and the presence of maternal chorioamnionitis during the analysis process (Table 2 ). Furthermore, results from our study were consistent with previous studies. For example, the lower incidence of PDA with indomethacin is consistent with results from the TIPP trial, and the higher rate of sepsis with hydrocortisone aligns with findings from the PREMILOC trial, giving us further confidence in our results. There are some limitations to the study that are important to discuss. This study, as with many studies in neonatology, is limited by a small sample size which could lead to underpowered results. This is particularly important when considering the lack of difference in overall mortality in this study, as well as less common adverse outcomes such as IVH or NEC. We conducted a single-centre study which creates challenging follow-up for patients who are transferred to an outlying hospital. Sunnybrook is a tertiary care perinatal centre so neonates requiring surgery are transferred to a quaternary centre. Clinical outcome data were not available for all study participants, leading some study participants to be excluded from certain analyses. Finally, since there is limited evidence available and no standardized protocol at Sunnybrook for the selection of a prophylactic drug regimen, there is a risk of selection bias since the choice of medication was left up to the discretion of the attending physician, and though the matching and adjusting process minimizes this risk and baseline characteristics were similar, the risk is still present. Conclusion This retrospective study compared clinical outcomes in extremely preterm neonates treated with hydrocortisone versus indomethacin prophylaxis. There was no difference in mortality or BPD between prophylaxis with indomethacin compared with hydrocortisone. Indomethacin prophylaxis was associated with significantly less PDA, PDA requiring surgical or procedural closure, late-onset sepsis, and higher rates of survival without oxygen supplementation at discharge than hydrocortisone prophylaxis. Based on the results of this study, indomethacin may be preferred over hydrocortisone to prevent common complications of prematurity in extremely preterm neonates. Abbreviations BPD bronchopulmonary dysplasia ELGANs extremely low gestational age neonates GA gestational age IUGR intrauterine growth restriction IV intravenous IVH intraventricular haemorrhage NEC necrotizing enterocolitis NICU neonatal intensive care unit PDA patent ductus arteriosus Declarations Conflict of Interest (includes financial disclosures): The authors declare no competing conflicts of interest or financial interests. Author Contributions: Funding/Support: None Role of Funder/Sponsor (if any): N/A Clinical Trial Registration (if any): N/A References Glass HC, Costarino AT, Stayer SA, Brett CM, Cladis F, Davis PJ. Outcomes for extremely premature infants. Anesth Analg. 2015;120(6):1337–51. doi: 10.1213/ANE.0000000000000705 . PMID: 25988638; PMCID: PMC4438860. Skidmore MD, Rivers A, Hack M. 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Epub 2019 May 29. PMID: 31144162; PMCID: PMC6647381. Schmidt B, Roberts RS, Fanaroff A, Davis P, Kirpalani H, Nwaesei C, et al. TIPP Investigators. Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP). J Pediatr . 2006;148(6):730–734. doi: 10.1016/j.jpeds.2006.01.047 . PMID: 16769377. Shaffer ML, Baud O, Lacaze-Masmonteil T, Peltoniemi OM, Bonsante F, Watterberg KL. Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis. J Pediatr. 2019;207:136–142.e5. doi: 10.1016/j.jpeds.2018.10.004 . Epub 2018 Nov 8. PMID: 30416014. Additional Declarations There is NO conflict of interest to disclose. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4473323","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":308157584,"identity":"a1529fde-2eb0-435b-ab1f-1c64b5125835","order_by":0,"name":"Sandra Gerges","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFklEQVRIiWNgGAWjYJACCQSzAkyygQgDIrWcIVkLYxsRWuTbzx68XVHDYNcvffziw5/z6hK3S/eYPa6osDFmYD/8AJsWgzN5yZZnjjEkz+zLKTbm3XY4ceecM+aGZ86kmTHwpGG1yYAhx0yygY0h2eAMT5o047YDiRtuAEUa2w7bAB2MVYt8/xugln8MyfZneNJ//pxTh6yF/QNWz0AUMNgZ8LAfY+BtYIZrMWOQ4MHusBtvjC0b+yQSJM7wMEvzHDtsvOFGWrlhw5k0YzaenALsDssxvNnwzcaev4f94ccfNXWyG24kb3vYUGFj2M9+fANWh0GARGIDA9wZHBAGGx71IGDPwMD+AMqGM0bBKBgFo2AUgAEAhzpf+K0BuowAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-2147-0269","institution":"Sunnybrook Health Sciences Centre","correspondingAuthor":true,"prefix":"","firstName":"Sandra","middleName":"","lastName":"Gerges","suffix":""},{"id":308157585,"identity":"00a28012-14cf-40ab-a17a-129645b41611","order_by":1,"name":"Danielle Mara","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Danielle","middleName":"","lastName":"Mara","suffix":""},{"id":308157586,"identity":"fb78d917-b386-4b82-8432-5f6adf439bd7","order_by":2,"name":"Krishanta Maharaj","email":"","orcid":"","institution":"Sunnybrook Health Sciences Centre","correspondingAuthor":false,"prefix":"","firstName":"Krishanta","middleName":"","lastName":"Maharaj","suffix":""},{"id":308157587,"identity":"6f751090-c30a-47e7-a0e0-1e70dabf76f5","order_by":3,"name":"Dany Weisz","email":"","orcid":"https://orcid.org/0000-0002-7335-8674","institution":"Sunnybrook Health Sciences Centre","correspondingAuthor":false,"prefix":"","firstName":"Dany","middleName":"","lastName":"Weisz","suffix":""},{"id":308157588,"identity":"7ac3b74a-3d6d-49d9-90a0-a9d8d842ac9c","order_by":4,"name":"Michael Dunn","email":"","orcid":"https://orcid.org/0000-0002-3908-4147","institution":"Sunnybrook Health Sciences Centre, Toronto, Ontario","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Dunn","suffix":""},{"id":308157589,"identity":"971e7e0a-3668-41cf-a4c3-a2a16e4cb0e6","order_by":5,"name":"Alex Kiss","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Alex","middleName":"","lastName":"Kiss","suffix":""}],"badges":[],"createdAt":"2024-05-24 15:21:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4473323/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4473323/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58245690,"identity":"fd05e558-f4fb-44ec-8c93-25bfaf99e401","added_by":"auto","created_at":"2024-06-13 02:23:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38653,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT diagram\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4473323/v1/fc17e30f2702ab51c9be87d4.png"},{"id":58349588,"identity":"8414e4fb-0df7-4de8-bc30-327c9f8934ea","added_by":"auto","created_at":"2024-06-14 08:40:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":547370,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4473323/v1/cd7d9301-db94-4333-aa87-688470f84f12.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Retrospective study of clinical outcomes with hydrocortisone versus indomethacin prophylaxis in preterm neonates","fulltext":[{"header":"Article Summary","content":"\u003cp\u003eAmong extremely preterm neonates, prophylaxis with indomethacin may be preferable for the prevention of complications of prematurity over hydrocortisone prophylaxis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat\u0026rsquo;s Known on This Subject:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIndomethacin and hydrocortisone are separately used to prevent complications of prematurity but cannot be used concomitantly. Prophylaxis with indomethacin may lower the incidence of intraventricular hemorrhage and patent ductus arteriosus and hydrocortisone may reduce the risk of death or bronchopulmonary dysplasia.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat This Study Adds:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn extremely preterm neonates, there was no difference in mortality or BPD between prophylaxis with indomethacin compared with hydrocortisone prophylaxis. Indomethacin was associated with significantly less PDA, PDA requiring surgical closure, late-onset sepsis, and higher rates of survival without oxygen supplementation at discharge than hydrocortisone.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eThere have been significant improvements in neonatal intensive care over the past few decades with increasing survival and a reduction in the limits of viability\u003csup\u003e1\u003c/sup\u003e. Lowering the gestation at which care can be provided, however, increases the risk of adverse outcomes. Some of the most severe complications, including bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), and intraventricular haemorrhage (IVH) have consequences that can persist into adulthood\u003csup\u003e1, 2, 3, 4\u003c/sup\u003e. Research into treatments is ongoing, and several medical interventions exist both to treat and prevent these conditions. A systematic review of 19 trials comparing indomethacin prophylaxis to placebo in preterm neonates found that indomethacin significantly reduced the incidence of PDA and severe intraventricular haemorrhage in very low or extremely low birth weight neonates\u003csup\u003e5\u003c/sup\u003e. Based on these results, indomethacin is widely used as prophylaxis in extremely low birth weight neonates for prevention of severe IVH and reduction in the incidence of PDA.\u003c/p\u003e \u003cp\u003eBronchopulmonary dysplasia (BPD) is the most common chronic lung disease in infants with up to 80% of infants born at 22\u0026ndash;24 weeks diagnosed with BPD\u003csup\u003e6, 7\u003c/sup\u003e. Despite the development of new interventions and changes to clinical practice, the prevalence of BPD in babies with a birth weight of 501 grams to 1 500 grams has only decreased from 31\u0026ndash;28% since 2005\u003csup\u003e7\u003c/sup\u003e. A systematic review found that prophylaxis with early hydrocortisone or dexamethasone was associated with lower rates of BPD at 36 weeks\u003csup\u003e8\u003c/sup\u003e. These results have led to the use of hydrocortisone prophylaxis to reduce the incidence of BPD in extremely preterm neonates.\u003c/p\u003e \u003cp\u003eUnfortunately, infants exposed to both prophylactic hydrocortisone and indomethacin are at increased risk of spontaneous intestinal perforation, which can be life threatening\u003csup\u003e8\u003c/sup\u003e. Since these two medications should not be used concomitantly, clinicians wishing to provide prophylaxis aimed at the prevention of PDA or BPD must choose between indomethacin and hydrocortisone, with limited evidence to support their choice. Information is needed to support the selection of either indomethacin or hydrocortisone for the prevention of PDA, BPD, and other complications of prematurity. This study aims to compare the outcomes of preterm neonates given either indomethacin or hydrocortisone prophylaxis to support this clinical decision.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design:\u003c/h2\u003e \u003cp\u003e A retrospective matched cohort study was conducted among extremely preterm neonates admitted to the Neonatal Intensive Care Unit (NICU) at Sunnybrook Health Sciences Centre in Toronto, Canada. Sunnybrook NICU is a high-performing tertiary perinatal center\u003csup\u003e9\u003c/sup\u003e that admits approximately 150 extremely low gestational age neonates (ELGANs) annually. Eligible participants included inborn or outborn neonates weighing less than 1000 grams and born at a gestational age of \u0026le;\u0026thinsp;27\u0026thinsp;+\u0026thinsp;6 weeks who were admitted to the Sunnybrook NICU, born between January 1, 2018 and January 22, 2022. Study participants were included if they were prescribed prophylactic indomethacin 0.1 mg/kg intravenous (IV) daily for 3 days, or prophylactic hydrocortisone 1 mg/kg IV daily divided into two doses for 7 days, then 0.5 mg/kg IV daily for 3 days for the prevention of BPD. Participants were included on an intention to treat basis, meaning they were included in the study group if they received at least one dose of the prophylaxis regimen and allocated to the group for which they initially received treatment. Exclusion criteria included the presence of major congenital or chromosomal anomalies, or membrane rupture greater than 2 weeks before delivery. Neonates were excluded if they received a dose of indomethacin or hydrocortisone other than the dose regimen prescribed above. The study was reviewed and approved by the Sunnybrook Health Sciences Centre Research Ethics Board (REB #5250) and was performed in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMatching:\u003c/h2\u003e \u003cp\u003eAfter inclusion and exclusion criteria were met, 419 neonates were eligible for the study. Of these, 389 received prophylactic indomethacin and 40 received prophylactic hydrocortisone. It was expected that fewer hydrocortisone-treated neonates would be eligible for the study, as studies supporting hydrocortisone prophylaxis were published more recently, and the use of hydrocortisone at Sunnybrook was a newer clinical practice. The selection of prophylactic drug, if any, occurred at the discretion of the attending neonatologist. Participants were matched by gestational age (\u0026plusmn;\u0026thinsp;7 days) and by maternal antenatal steroid use, defined as any antenatal steroid use or no antenatal steroid use, to account for this confounder. Sample size limited the number of matching parameters used. Gestational age and maternal antenatal steroid use were selected as matching criteria to maximize the number of study participants eligible for matching. Other relevant variables, such as chorioamnionitis, were not present in a high enough frequency to be used as a matching criterion but were adjusted for elsewhere in the analysis. Neonates were matched in a 4:1 ratio when feasible.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes:\u003c/h2\u003e \u003cp\u003eOutcomes of this exploratory study included overall mortality, BPD, PDA, PDA requiring surgical or procedural closure, late-onset sepsis, intraventricular hemorrhage, necrotizing enterocolitis, treatment with dexamethasone for evolving BPD, survival without oxygen supplementation at discharge, and pulmonary hemorrhage. BPD was defined as the use of oxygen, invasive or non-invasive ventilatory support, and/or high flow air when the infant reaches 36 weeks postmenstrual age, or at the time of discharge to a Level 2 hospital, whichever was earlier. PDA was diagnosed on echocardiography, and PDA requiring surgical closure included those managed using transcatheter percutaneous device closure or surgical ligation. Intraventricular hemorrhage was separated into grades I through IV based on the criteria outlined by the Canadian Neonatal Network. NEC (stage 2 or higher) was defined according to the Modified Bell\u0026rsquo;s Criteria. Treatment with dexamethasone for evolving BPD included neonates who had difficulty weaning from the ventilator who were treated with dexamethasone. Survival without oxygen supplementation at discharge included infants who survived and did not require respiratory support at the time of discharge. Pulmonary hemorrhage was defined as blood present in an endotracheal aspirate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData collection:\u003c/h2\u003e \u003cp\u003eParticipant health information was extracted from Sunnybrook Health Sciences Centre electronic health record systems. Clinically relevant maternal history was collected regarding the pregnancy and delivery of the study participant. Pharmacy records for all NICU-admitted patients were screened for study eligibility for patients born during the pre-specified study period.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis:\u003c/h2\u003e \u003cp\u003eDescriptive statistics were used to summarize the baseline characteristics of the study population, including maternal, antenatal and perinatal characteristics, illness severity and intensive care support in the first 24 hours of life. Continuous variables were presented as mean and standard deviation, or median and interquartile range, for parametric and skewed data, respectively. Categorical data were presented as count and percent. Differences in baseline characteristics were evaluated using the Student t-test or Wilcoxon rank-sum test for continuous variables (as appropriate) or chi-square test for categorical variables. Multivariable logistic regressions with generalized estimating equations were used to evaluate the association of prophylactic treatment with all outcomes, adjusting for chorioamnionitis and birth weight z-score, and accounting for clustering due to multiple gestation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 2 349 patient charts were screened, of which 1 920 did not meet inclusion criteria. Ten patients met exclusion criteria; nine were excluded for premature rupture of membranes greater than 2 weeks before delivery, and one neonate was excluded for the presence of congenital anomalies (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among 177 neonates included in the study, 40 received hydrocortisone (mean GA 24.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0 weeks, mean birth weight 650\u0026thinsp;\u0026plusmn;\u0026thinsp;126 grams) and were matched with 137 neonates who received prophylactic indomethacin (mean GA 24.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0 weeks, mean birth weight 684\u0026thinsp;\u0026plusmn;\u0026thinsp;133 grams). Of the 40 neonates in the hydrocortisone group, 31 were matched with indomethacin-treated neonates at a ratio of 4:1, 4 were matched in a 2:1 ratio, and 5 were matched in a 1:1 ratio. No eligible neonates included in the hydrocortisone group were unmatched. Baseline infant characteristics were similar between the indomethacin group and the hydrocortisone group, with the exception of positive blood cultures at birth, which was higher in the hydrocortisone group (15.0% vs 5.11%, p\u0026thinsp;=\u0026thinsp;0.04) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Maternal characteristics of pregnancy were also similar among the two study groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Neonatal illness severity and intensive care support required in the first 24 hours was also characterized and were similar with the exception of a higher SNAP II score in the hydrocortisone group compared to the indomethacin group (27.8 vs 21, p\u0026thinsp;=\u0026thinsp;0.02) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline infant and maternal characteristics.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIndomethacin\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;137)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHydrocortisone\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eInfant characteristics\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age (weeks), mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.70 (1.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.51 (0.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight (grams), mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e683.53 (132.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e650.00 (126.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZ-score, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.13 (0.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.26 (0.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (60.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (57.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInborn, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e111 (81.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (80.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwins, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (14.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (15.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriplets, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIUGR: birth weight\u0026thinsp;\u0026lt;\u0026thinsp;10th centile, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (5.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (10.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIUGR: birth weight\u0026thinsp;\u0026lt;\u0026thinsp;3rd centile, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (3.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (7.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPGAR score at 1 minute of life, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.55 (2.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.85 (2.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPGAR score at 5 minutes of life, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.74 (2.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.23 (2.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive blood culture at birth, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (5.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (15.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaternal characteristics\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age (years), mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.74 (5.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31. 48 (4.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo antenatal steroids, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (12.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (22.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntenatal steroids: 1 dose, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (27.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (22.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntenatal steroids: 2 doses, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 (59.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (52.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnosis of chorioamnionitis, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (10.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (22.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelivery by Cesarean section, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (55.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (70.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRupture of membranes\u0026thinsp;\u0026gt;\u0026thinsp;24 hours before delivery, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (21.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (25.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIllness severity and intensive care support in the first 24 hours\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSNAP II score, mean (SD) or *median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e*21 (13.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.82 (14.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory severity score at 6 hours of life, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e*6.72 (2.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e*6.83 (4.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotic exposure in the first 24 hours of life, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e125 (91.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (87.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRequired vasopressors in the first 24 hours of life, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (20.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (37.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eIUGR\u0026thinsp;=\u0026thinsp;intrauterine growth restriction\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOverall mortality was not different among neonates who received indomethacin prophylaxis compared with those who received hydrocortisone prophylaxis (20.4% vs 20.0%; aOR 1.07; 95% CI 0.94\u0026ndash;1.21; p\u0026thinsp;=\u0026thinsp;0.30). Neonates treated with indomethacin had a lower incidence of PDA (49.5% vs 93.8%; aOR 0.59; 95% CI 0.48\u0026ndash;0.73; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), and PDA requiring surgical or procedural closure (4.6% vs 21.9%, OR 0.59; 95% CI 0.39\u0026ndash;0.90, p\u0026thinsp;=\u0026thinsp;0.01) compared with hydrocortisone (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The incidence of late-onset sepsis was lower in the indomethacin group compared with the hydrocortisone group (35.8% vs 59.4% aOR 0.82, 95% CI 0.70\u0026ndash;0.97, p\u0026thinsp;=\u0026thinsp;0.02). Survival without oxygen supplementation at discharge was significantly higher in the indomethacin group compared to the hydrocortisone group (77% vs 50% aOR 2.44, 95% CI 1.16\u0026ndash;5.26, p\u0026thinsp;=\u0026thinsp;0.02). There was no difference in the incidence of BPD, IVH, NEC, pulmonary hemorrhage, spontaneous intestinal perforation, survival without morbidity, or the number of neonates treated with dexamethasone for evolving BPD among the indomethacin-treated neonates compared with the hydrocortisone-treated neonates.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical outcomes of indomethacin versus hydrocortisone prophylaxis in neonates with a birth weight less than 1000 grams and gestational age less than or equal to 27\u0026thinsp;+\u0026thinsp;6 weeks.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIndomethacin, N (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHydrocortisone, N (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdjusted Odds Ratio or *Odds Ratio (95% Confidence Interval)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28 (20.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.07 (0.94\u0026ndash;1.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatent ductus arteriosus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e54 (49.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (93.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.59 (0.48\u0026ndash;0.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePDA requiring surgical management\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (21.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e*0.59 (0.39\u0026ndash;0.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBronchopulmonary dysplasia (Mild, moderate, and severe)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44 (40.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (53.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.69 (0.33\u0026ndash;1.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLate onset sepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39 (35.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (59.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.82 (0.70\u0026ndash;0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntraventricular hemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39 (35.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (46.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.97 (0.82\u0026ndash;1.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNecrotizing enterocolitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (18.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (28.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.93 (0.83\u0026ndash;1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurvival without oxygen supplementation at discharge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e82 (77.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.44 (1.16\u0026ndash;5.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreated with dexamethasone for evolving BPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43 (39.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.92 (0.79\u0026ndash;1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary hemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e*0.95 (0.84\u0026ndash;1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous intestinal perforation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13 (11.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e*1.00 (0.93\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurvival without morbidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37 (27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.45 (0.64\u0026ndash;3.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective cohort study of extremely preterm neonates treated with either prophylactic indomethacin or prophylactic hydrocortisone, there was no difference in mortality, though indomethacin prophylaxis was associated with reduced incidence of PDA, PDA requiring surgical or procedural closure, late-onset sepsis, and improved survival without home oxygen. A modest benefit to survival has been shown with indomethacin prophylaxis in a recent network meta-analysis which included 19 randomized-controlled trials comparing indomethacin prophylaxis to placebo or no therapy, including a total of 2877 neonates\u003csup\u003e10\u003c/sup\u003e. Our study may not demonstrate this survival benefit due to the small sample size or because of a difference in comparison group. The indomethacin group was diagnosed with less PDA and PDA requiring surgical or procedural closure in this study, which is consistent with the recent data although there was no difference in rates of IVH\u003csup\u003e10\u003c/sup\u003e. There were few outcome events of IVH in the overall study population so there was likely not enough power to detect any potential differences in rates of IVH. We also found a lack of benefit of hydrocortisone for the prevention of BPD, which differed from the results of the PREMILOC trial. We compared hydrocortisone to indomethacin whereas in the PREMILOC trial hydrocortisone was being compared to placebo which may partially account for this difference \u003csup\u003e8\u003c/sup\u003e. The mean gestational age was also lower in our study by about 2 weeks compared to the PREMILOC trial (study population mean GA 24.5 weeks compared to 26.4 weeks in PREMILOC). The benefit of hydrocortisone prophylaxis may be to facilitate earlier extubation and thus prevent dependence on mechanical ventilation to prevent the development of BPD. This may not be feasible among the extremely low gestational age population, which comprised the majority of our study population. The baseline rates of BPD at our study center are also relatively low\u003csup\u003e11\u003c/sup\u003e, so pharmacological interventions may not result in a detectable difference. It is unlikely that this result was affected by the baseline characteristics of the neonates. All infant, maternal, and resuscitation characteristics were similar, apart from positive blood cultures at birth and the SNAP-II score, a calculated score used as a predictor of neonatal mortality. The hydrocortisone group did have a statistically significantly higher score than the indomethacin group (27.8 versus 21), however this is not likely to be a clinically significant difference, since the difference between the groups was quite small, and both groups had a mean score below the SNAP-II score of 44 that is validated to predict neonatal mortality\u003csup\u003e13\u003c/sup\u003e. A higher proportion of neonates who received hydrocortisone were found to have positive blood cultures at birth compared to neonates who received indomethacin, although the absolute number was small in both groups (6 versus 7).\u003c/p\u003e \u003cp\u003eThere was no difference in the number of neonates requiring treatment for BPD with dexamethasone\u003csup\u003e14\u003c/sup\u003e. One potential benefit of hydrocortisone prophylaxis is that it may reduce neonatal exposure to higher doses of steroids, which can negatively impact neurodevelopmental outcomes\u003csup\u003e15,16\u003c/sup\u003e. It was noted in our study that some infants who received hydrocortisone prophylaxis went on to receive multiple courses of dexamethasone. If hydrocortisone-treated neonates still require dexamethasone, this may significantly reduce the perceived benefit of hydrocortisone and increase the overall cumulative steroid dose that these infants receive, ultimately leading to a higher probability of poor neurodevelopmental outcomes\u003csup\u003e16\u003c/sup\u003e. In the analysis of secondary outcomes of the PREMILOC study, early low-dose hydrocortisone was not associated with a statistically significant difference in full scale intelligence quotient (IQ) at 5 years of age, although some individual neurocognitive outcomes were significantly better in the hydrocortisone treated group.\u003csup\u003e17\u003c/sup\u003e On analysis of the outcome at 2 years of infants treated with dexamethasone there was no substantial difference in cerebral palsy or major disability between the dexamethasone and control groups.\u003csup\u003e18\u003c/sup\u003e There is however no definitive data on the neurodevelopmental outcomes of preterm infants exposed to both early low dose hydrocortisone followed by dexamethasone. We noted a lower incidence of PDA and PDA requiring surgical closure with indomethacin compared to hydrocortisone prophylaxis. These results are similar to the results from other studies\u003csup\u003e21\u003c/sup\u003e. Although a lower incidence of PDA may not be of clinical value if the PDAs were not hemodynamically significant and managed conservatively, the difference in PDA requiring surgical closure is quite significant\u003csup\u003e19\u003c/sup\u003e. One potential reason for a higher incidence of PDA requiring surgical closure with hydrocortisone is the potential delay in medical management of the PDA due to concerns of intestinal perforation. While hydrocortisone itself could cause intestinal perforation, an interaction between the steroid and cyclooxygenase inhibitors has been strongly implicated as a significant contributor for this effect.\u003csup\u003e20\u003c/sup\u003e As a result, medical management may have only commenced at the end of the ten-day course of hydrocortisone even in the presence of a hemodynamically significant PDA. This may also explain the higher incidence of survival without oxygen supplementation at discharge in the indomethacin group. In this study we also found a significantly higher incidence of late-onset sepsis with hydrocortisone compared with indomethacin. This is consistent with results from the PREMILOC trial, where neonates born at 24\u0026ndash;25 weeks gestational age treated with hydrocortisone were found to have a higher rate of late onset sepsis\u003csup\u003e21\u003c/sup\u003e. This may be caused by the immunosuppressive effects of corticosteroids.\u003csup\u003e22\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThere are a number of strengths of the study worth highlighting. Firstly, the samples were matched by gestational age and antenatal steroids, two characteristics that can greatly impact clinical outcomes. When possible, results were also adjusted by the birth weight z-score and the presence of maternal chorioamnionitis during the analysis process (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Furthermore, results from our study were consistent with previous studies. For example, the lower incidence of PDA with indomethacin is consistent with results from the TIPP trial, and the higher rate of sepsis with hydrocortisone aligns with findings from the PREMILOC trial, giving us further confidence in our results. There are some limitations to the study that are important to discuss. This study, as with many studies in neonatology, is limited by a small sample size which could lead to underpowered results. This is particularly important when considering the lack of difference in overall mortality in this study, as well as less common adverse outcomes such as IVH or NEC. We conducted a single-centre study which creates challenging follow-up for patients who are transferred to an outlying hospital. Sunnybrook is a tertiary care perinatal centre so neonates requiring surgery are transferred to a quaternary centre. Clinical outcome data were not available for all study participants, leading some study participants to be excluded from certain analyses. Finally, since there is limited evidence available and no standardized protocol at Sunnybrook for the selection of a prophylactic drug regimen, there is a risk of selection bias since the choice of medication was left up to the discretion of the attending physician, and though the matching and adjusting process minimizes this risk and baseline characteristics were similar, the risk is still present.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis retrospective study compared clinical outcomes in extremely preterm neonates treated with hydrocortisone versus indomethacin prophylaxis. There was no difference in mortality or BPD between prophylaxis with indomethacin compared with hydrocortisone. Indomethacin prophylaxis was associated with significantly less PDA, PDA requiring surgical or procedural closure, late-onset sepsis, and higher rates of survival without oxygen supplementation at discharge than hydrocortisone prophylaxis. Based on the results of this study, indomethacin may be preferred over hydrocortisone to prevent common complications of prematurity in extremely preterm neonates.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebronchopulmonary dysplasia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eELGANs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eextremely low gestational age neonates\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egestational age\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIUGR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintrauterine growth restriction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintravenous\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIVH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintraventricular haemorrhage\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNEC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enecrotizing enterocolitis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNICU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneonatal intensive care unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePDA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epatent ductus arteriosus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest (includes financial disclosures):\u0026nbsp;\u003c/strong\u003eThe authors declare no competing conflicts of interest or financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/Support:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRole of Funder/Sponsor (if any):\u0026nbsp;\u003c/strong\u003eN/A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration (if any):\u0026nbsp;\u003c/strong\u003eN/A\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGlass HC, Costarino AT, Stayer SA, Brett CM, Cladis F, Davis PJ. Outcomes for extremely premature infants. Anesth Analg. 2015;120(6):1337\u0026ndash;51. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1213/ANE.0000000000000705\u003c/span\u003e\u003cspan address=\"10.1213/ANE.0000000000000705\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 25988638; PMCID: PMC4438860.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSkidmore MD, Rivers A, Hack M. Increased risk of cerebral palsy among very low-birthweight infants with chronic lung disease. Dev Med Child Neurol. 1990;32(4):325\u0026thinsp;\u0026ndash;\u0026thinsp;32. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1469-8749.1990.tb16944.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1469-8749.1990.tb16944.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 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Respiratory Care October 2021, 66 (10) 1618\u0026ndash;1629; DOI: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4187/respcare.08401\u003c/span\u003e\u003cspan address=\"10.4187/respcare.08401\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2010;2010(7):CD000174. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/14651858.CD000174.pub2\u003c/span\u003e\u003cspan address=\"10.1002/14651858.CD000174.pub2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 20614421; PMCID: PMC7045285.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGilfillan M, Bhandari A, Bhandari V. 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PMID: 31144162; PMCID: PMC6647381.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmidt B, Roberts RS, Fanaroff A, Davis P, Kirpalani H, Nwaesei C, \u003cem\u003eet al.\u003c/em\u003e TIPP Investigators. Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP). \u003cem\u003eJ Pediatr\u003c/em\u003e. 2006;148(6):730\u0026ndash;734. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jpeds.2006.01.047\u003c/span\u003e\u003cspan address=\"10.1016/j.jpeds.2006.01.047\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 16769377.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShaffer ML, Baud O, Lacaze-Masmonteil T, Peltoniemi OM, Bonsante F, Watterberg KL. Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis. J Pediatr. 2019;207:136\u0026ndash;142.e5. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jpeds.2018.10.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jpeds.2018.10.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2018 Nov 8. PMID: 30416014.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4473323/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4473323/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eIndomethacin and hydrocortisone prophylaxis may improve clinical outcomes when administered to extremely preterm neonates. However, they cannot be administered together and there is limited evidence to support which therapy may be most beneficial.\u003c/p\u003e\u003ch2\u003eStudy Design:\u003c/h2\u003e \u003cp\u003eA retrospective matched cohort study was conducted in neonates less than 28 weeks gestational age (GA) and birth weight less than 1000 grams who received prophylaxis with indomethacin or hydrocortisone. Multivariable logistic regression analysis was used to evaluate clinical outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 177 neonates, 40 treated with prophylactic hydrocortisone were matched with 137 neonates treated with prophylactic indomethacin. Indomethacin-treated neonates had significantly lower incidence of PDA, PDA requiring surgical closure, late-onset sepsis, and higher rates of survival without oxygen supplementation at discharge. There was no difference in mortality, BPD, NEC, or IVH.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eWhen compared to hydrocortisone, indomethacin prophylaxis was associated with more favorable outcomes.\u003c/p\u003e","manuscriptTitle":"Retrospective study of clinical outcomes with hydrocortisone versus indomethacin prophylaxis in preterm neonates","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-13 02:23:19","doi":"10.21203/rs.3.rs-4473323/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4e2f81d0-a1af-44a6-8cf0-03db44794c28","owner":[],"postedDate":"June 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":32551118,"name":"Health sciences/Medical research/Outcomes research"},{"id":32551119,"name":"Health sciences/Health care/Therapeutics/Drug therapy"}],"tags":[],"updatedAt":"2024-06-14T08:31:53+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-13 02:23:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4473323","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4473323","identity":"rs-4473323","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}