Critically Appraised Summary Table (CAST) for the "Expectant Management vs Medication for Patent Ductus Arteriosus in Preterm Infants: The PDA Randomized Clinical Trial."

Objective To assess survival and neurodevelopmental outcome at 24 months’ corrected age (CA) for participants in the BeNeDuctus trial, comparing expectant management with early ibuprofen treatment in extremely preterm infants. Study design In this international, multicenter trial, extremely preterm infants (<28 weeks’ gestation) with echocardiographically confirmed PDA between 24-72 hours postnatal age were randomly assigned to expectant management or early ibuprofen treatment. Follow-up was scheduled at 24 months’ CA. The primary endpoint of this follow-up study was survival without neurodevelopmental impairment (Bayley Scales of Infant and Toddler Development III score of ≥85 on cognitive and motor domain). Additional outcomes included were biometry, abnormal neurologic examination, and vision or hearing impairment. Results Follow-up data were available for 234 of 273 patients (85.7%); 117 patients in each study arm. Assessment of the primary endpoint was available for 200/234 patients (85.5%). Survival without neurodevelopmental impairment did not differ between groups, with 51/104 (49%) in the expectant management group and 47/96 (49%) in the early ibuprofen treatment group (relative risk (RR) 1.00; 95% confidence interval 0.76-1.33). No significant differences were observed in the additional follow-up outcomes. Conclusions No difference was observed in survival without neurodevelopmental impairment at 24 months’ CA between the expectant management and early ibuprofen treatment group in the BeNeDuctus study sample. These results suggest no advantage of routine early ibuprofen treatment for survival and neurodevelopmental outcome.

BACKGROUND:Paracetamol is increasingly used as analgesic and to treat patent ductus arteriosus (PDA) in preterm infants, though preclinical data suggest it may potentially harm the developing lung. The BeNeDuctus trial compared expectant PDA management versus ibuprofen in infants with gestational age <28 weeks, allowing paracetamol for analgesia. In this secondary analysis of the trial, we investigated the potential association between paracetamol and the risk of bronchopulmonary dysplasia (BPD). METHODS:The 273 infants enrolled in the BeNeDuctus were classified into four subgroups based on their exposure to paracetamol (n = 30), ibuprofen (n = 87), paracetamol and ibuprofen (n = 49), or no exposure (control, n = 107). Multivariable logistic regression was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Confounders were selected based on a Directed Acyclic Graph. RESULTS:Compared with the control group, exposure to paracetamol alone (aOR 3.22, CI 1.05-9.89), ibuprofen alone (aOR 2.90, CI 1.40-6.03), or paracetamol and ibuprofen (aOR 3.88, CI 1.57-9.57) was associated with an increased odds of moderate-to-severe BPD. CONCLUSION:Our data suggest that paracetamol, used for pain management, increased the risk of moderate-to-severe BPD. This finding supports the calls for a thorough evaluation of the safety of paracetamol on the developing lungs of extremely preterm infants. IMPACT:Paracetamol is gaining interest as pharmacological treatment for patent ductus arteriosus (PDA) in extremely preterm infants. Safety is assumed, based on data from studies evaluating the effects of paracetamol exposure on liver function, although recently concerns on lung development are emerging. This study supports the urgent need for additional research on the safety of paracetamol as treatment option for PDA, but also for other indications in extremely preterm infants, with regard to lung development.

IMPACT:Furosemide increases renal prostaglandin synthesis and animal studies show reopening of the ductus arteriosus in rats exposed to furosemide. Nevertheless, large cohort studies in preterm infants do not support this hypothesis. Bartter syndrome, a rare genetic renal disorder with excessive fluid and salt-loss, is similar to continuous furosemide exposure. We hypothesize that Bartter syndrome could be considered as a natural experiment. Although most infants with Bartter syndrome are born prematurely, there are no cases found in literature with a patent ductus arteriosus which suggest that the contribution of furosemide to (re)opening of the ductus arteriosus in humans might be negligible.

Two cases of neonatal splenic hemorrhage with acute cardiorespiratory failure are described in this report. The first case involves a full-term neonate who was found unresponsive without any witnesses and could not be successfully resuscitated. A postmortem diagnosis revealed a splenic hemorrhage. Second case is an extremely premature neonate who experienced a witnessed cardiovascular collapse on the 14th day of life. Rapid cardiovascular support was administered, resulting in a positive outcome. While splenic hemorrhage is commonly associated with traumatic events, these cases highlight the need of considering spontaneous splenic hemorrhages as a potential cause of acute neonatal compromise, even in the absence of birth-related trauma (e.g., asphyxia, prolonged labor, clavicle fractures, brachial plexus injuries). This report emphasizes the importance of including splenic hemorrhage timely in the differential diagnosis of neonatal cardiorespiratory instability, especially in the absence of more common diagnoses, and discusses the challenges associated with its recognition and treatment.

Persistent patency of the ductus arteriosus is common in premature infants, yet patent ductus arteriosus (PDA) management varies widely. In observational studies, PDA is associated with prolonged assisted ventilation, bronchopulmonary dysplasia (BPD), pulmonary hemorrhage, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), periventricular leukomalacia, cerebral palsy, renal impairment, and mortality. 1 Benitz W.E. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?. J Perinatol. 2010; 30: 241-252 Crossref PubMed Scopus (277) Google Scholar , 2 Siassi B. Emmanouilides G.C. Cleveland R.J. Hirose F. Patent ductus arteriosus complicating prolonged assisted ventilation in respiratory distress syndrome. J Pediatr. 1969; 74: 11-19 Abstract Full Text PDF PubMed Scopus (54) Google Scholar , 3 Kitterman J.A. Edmunds L.H. Gregory G.A. Heymann M.A. Tooley W.H. Rudolph A.M. Patent ducts arteriosus in premature infants. Incidence, relation to pulmonary disease and management. N Engl J Med. 1972; 287: 473-477 Crossref PubMed Scopus (164) Google Scholar , 4 Kluckow M. Evans N. Ductal shunting, high pulmonary blood flow, and pulmonary hemorrhage. J Pediatr. 2000; 137: 68-72 Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar , 5 Marshall D.D. Kotelchuck M. Young T.E. Bose C.L. Kruyer L. O'Shea T.M. Risk factors for chronic lung disease in the surfactant era: a North Carolina population-based study of very low birth weight infants. North Carolina Neonatologists Association. Pediatrics. 1999; 104: 1345-1350 Crossref PubMed Scopus (236) Google Scholar , 6 Ryder R.W. Shelton J.D. Guinan M.E. Necrotizing enterocolitis: a prospective multicenter investigation. Am J Epidemiol. 1980; 112: 113-123 Crossref PubMed Scopus (132) Google Scholar , 7 Drougia A. Giapros V. Krallis N. Theocharis P. Nikaki A. Tzoufi M. et al. Incidence and risk factors for cerebral palsy in infants with perinatal problems: a 15-year review. Early Hum Dev. 2007; 83: 541-547 Crossref PubMed Scopus (80) Google Scholar These associations led many clinicians to treat a PDA in all preterm infants. However randomized controlled trials (RCTs) of PDA treatment have failed to demonstrate significant reductions in clinically important outcomes. As an example, prophylactic indomethacin trials (for reducing IVH) demonstrate that indomethacin reduces incidence of symptomatic PDA, need for ligation, and IVH, but has no effect on BPD, NEC, long-term neurodevelopmental impairment (NDI) or death. 1 Benitz W.E. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?. J Perinatol. 2010; 30: 241-252 Crossref PubMed Scopus (277) Google Scholar ,8 Schmidt B. Davis P. Moddemann D. Ohlsson A. Roberts R.S. Saigal S. et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med. 2001; 344: 1966-1972 Crossref PubMed Scopus (617) Google Scholar Thus, it is unclear if PDA is part of the causal pathway for development of these morbidities.

Enteroviruses are among the most common causes of acute viral illness worldwide, and in neonates, the clinical course of these infections is heterogeneous. Severe complications, such as myocarditis, are associated with high mortality rates. In this case report, we present the clinical course of premature twins born at 35 weeks of gestational age, suffering from a severe neonatal enterovirus infection with cardiac involvement, which proved fatal in one of the twins. This course led to prompt identification in the other twin and facilitated timely transfer to a neonatal intensive care unit with neonatal hemodynamic expertise, and facilitated the timely transfer to a neonatal intensive care nit with hemodynamic expertise and immediate availability of AZCMO would it have been indicated. Early supportive therapy in the other twin contributed to a positive outcome. Therefore, we emphasize the importance of early recognition in averting adverse consequences. As a recommendation, we propose routine screening of enterovirus in viral panels for febrile newborns.

BACKGROUND Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).

To gain insight in the availability of guidelines, diagnostic criteria, and treatment strategies and whether clinical equipoise regarding optimal treatment for patent ductus arteriosus (PDA) in prematurity is present. We hypothesized that (co-)authors of PDA-related papers were more likely to screen for a PDA and would treat earlier and more aggressively. An international internet-based survey between September 2019 and March 2020 in which we collected (1) baseline characteristics; (2) availability of guidelines; (3) screening strategy for PDA; (4) diagnostic criteria for hemodynamic significance; (5) treatment strategy; and (6) metrics of treatment efficacy. Finally, ten clinical equipoise statements were posed on a Likert scale. In total, 144 surveys were sent, of which 71/144 (49%) surveys could be analyzed with 56/71 (79%) fully completed surveys. The respondents, mainly neonatologists in a level III neonatal intensive care unit, of whom 36/71 (51%) had (co-)authored a publication on the PDA, highlighted a lack of national guidelines, heterogeneous approach to screening strategies, and marked variability in diagnostic criteria to assess hemodynamic significance, treatment strategies and effect measurement. No major significant differences were observed between respondents who did or did not (co-)author a publication on the PDA. Respondents who screened for PDA scored significantly higher on the need for screening, early and aggressive treatment. Remarkably, the scores of all statements regarding clinical equipoise varied widely. Conclusions : Our survey highlights the lack of guidelines and enormous heterogeneity in current practice. Current evidence is not robust enough to harmonize current treatment strategies into (inter)national guidelines. What is Known: • Patent ductus arteriosus (PDA) incidence is inversely related to gestational age. • Although early pharmacological treatment induces PDA closure, optimal treatment is debated due to the lack of beneficial effects on outcome. What is New: • In the absence of (inter)national guidelines, diagnostic and treatment strategies are heterogeneous and contradictory, even in a selected hemodynamically- interested group. • Different PDA screening strategies did, while PDA publication status did not, show significant differences in treatment strategy and responses to equipoise statements.

In this retrospective analysis, the Newborn Life Support (NLS) test scenario performance of participants of the Dutch Neonatal Advanced Life Support (NALS) course was assessed. Characteristics of participants and total amount of failures were collected. Failures were subdivided in (1) errors of omission; (2) errors of commission; and (3) unspecified if data was missing. Pearson’s chi-squared test was used to assess differences between participant groups. In total, 23 out of 86 participants (27%) failed their NLS test scenario. Life support course instructors in general (20/21) passed their test scenario more often compared to other participants (43/65) ( p = 0.008). In total 110 fail items were recorded; the most common errors being not assessing heart rate (error of omission) ( n = 47) and inadequate performance of airway management (error of commission) ( n = 24). Conclusion : A substantial part of NALS participants failed their NLS test scenario. Errors of omission could be reduced by the availability of a checklist/NLS algorithm. Life support course instructors possibly make less errors of commission due to retention of skills by teaching these skills at least twice a year. Therefore, our study suggests that neonatal basic life support skills should be retained by local assurance of training programmes. What is Known: • Retention of skills after life support courses decreases after three months. • Adherence to newborn life support guidelines is suboptimal . What is New: • NLS performance is suboptimal in participants for advanced neonatal life support. • Most common failures are not assessing heart rate and inadequate airway management.

Context: There is an ongoing debate on the optimal management of patent ductus arteriosus (PDA) in preterm infants. Identifying subgroup of infants who would benefit from pharmacological treatment might help.Objective: To investigate the modulating effect of the differences in methodological quality, the rate of open-label treatment, and patient characteristics on relevant outcome measures in randomized controlled trials (RCTs).Data Sources: Electronic database search between 1950 and May 2020.Study Selection: RCTs that assessed pharmacological treatment compared to placebo/no treatment.Data Extraction: Data is extracted following the PRISMA guidelines. Outcome measures were failure to ductal closure, surgical ligation, incidence of necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, periventricular leukomalacia, intraventricular hemorrhage (IVH) grade ≥3, retinopathy of prematurity and mortality.Results: Forty-seven studies were eligible. The incidence of IVH grade ≥3 was lower in the treated infants compared to the placebo/no treatment (RR 0.77, 95% CI 0.64–0.94) and in the subgroups of infants with either a gestational age <28 weeks (RR 0.77, 95% CI 0.61–0.98), a birth weight <1,000 g (RR 0.77, 95% CI 0.61–0.97), or if untargeted treatment with indomethacin was started <24 h after birth (RR 0.70, 95% CI 0.54–0.90).Limitations: Statistical heterogeneity caused by missing data and variable definitions of outcome parameters.Conclusions: Although the quality of evidence is low, this meta-analysis suggests that pharmacological treatment of PDA reduces severe IVH in extremely preterm, extremely low birth weight infants or if treatment with indomethacin was started <24 h after birth. No other beneficial effects of pharmacological treatment were found.

Abstract Background Controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy. Methods/design The BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24–72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent. The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data. Trial registration ClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28.

Objective: This study aims to evaluate outcome after conservative management (no pharmacological/surgical intervention other than fluid restriction, diuretics, or ventilator adjustments) compared with active (pharmacological and/or surgical) treatment for patent ductus arteriosus (PDA) in preterm infants and analyze differences in outcome between randomized controlled trials (RCTs) and cohort studies. Study Design: This is a systematic literature review using PubMed, EMBASE, and Cochrane library. RCTs and cohort studies comparing conservative management with active treatment were included. Meta-analysis was used to compare conservative management with any active (pharmacological and/or surgical), any pharmacological (non-prophylactic and prophylactic), and/or surgical treatment for mortality as primary and major neonatal morbidity as secondary outcome measure. Fixed-effect analysis was used, unless heterogeneity ( I 2 ) was >50%. Outcome is presented as relative risk (RR) with 95% confidence interval. Results: Twelve cohort studies and four RCTs were included, encompassing 41,804 and 720 patients, respectively. In cohort studies, conservative management for PDA was associated with a significantly higher risk for mortality (RR, 1.34 [1.12–1.62]) but a significantly lower risk for bronchopulmonary dysplasia (RR, 0.55 [0.46–0.65]), necrotizing enterocolitis (RR, 0.85 [0.77–0.93]), intraventricular hemorrhage (RR, 0.88 [0.83–0.95]), and retinopathy of prematurity (RR, 0.47 [0.28–0.79]) compared with any active PDA treatment. Meta-analysis of the RCTs revealed no significant differences in outcome between conservative management and active treatment. Conclusion: No differences in mortality or morbidity for conservative management compared with active treatment regimens were observed in RCTs. Findings from cohort studies mainly highlight the lack of high-quality evidence for conservative management for PDA in preterm infants.