Introduction: In premature neonates, the persistence of hemodynamically significant ductus arteriosus (hsPDA) can be associated with short- and long-term consequences, impairing their outcome. The correct strategy of management for such condition is under debate, especially regarding contraindications and/or side effects. In recent years, metabolomics was applied to several perinatal, pediatric, and adult conditions to investigate potential biomarkers of disease, which have become useful for early diagnosis and/or therapeutic management. Aim of the Study: The main purpose of our exploratory study was to asses, through 1H-NMR metabolomics analysis of urinary samples at birth, possible metabolic pathways differentiating, with a significant predictive power, those preterm neonates who will subsequently develop hsPDA and neonates of comparable gestational age (GA) who will undergo spontaneous ductal closure or the persistence of an irrelevant PDA (no-hsPDA). Moreover, we investigated potential prenatal or perinatal clinical factors potentially influencing the development of hsPDA. Materials and Methods: We enrolled n = 35 preterm neonates with GA between 24 and 32 weeks; urinary samples were collected within the first 12 h of life. Patients were closely monitored regarding intensive care, respiratory support, fluid balance and administered drugs; an echocardiogram was performed at 48-72 h. Results: Our results reported a significant correlation between lower GA at birth and the development of hsPDA. Moreover, neonates with GA ≤ 30w developing hsPDA were characterized by lower Apgar scores at 1' and 5', higher rates of perinatal asphyxia, higher need of delivery room resuscitation and subsequent surfactant administration. Interestingly, metabolomics analysis at birth detected a clear separation between the 1H-NMR urinary spectra of subjects GA ≤ 30w not developing hsPDA (n = 19) and those of subjects born at GA ≤ 30w in which hsPDA was confirmed at 48-72 h of life (n = 5). Conclusions: This is the first study applying metabolomics to investigate the PDA condition. Although preliminary and conducted on a limited sample, our results reveal that metabolomics could be a promising tool in the early identification of hsPDA, potentially superior to the clinical or laboratory predictive tools explored to date and even to the clinical observations and correlations in our sample, through the detection of specific urinary metabolites.

To assess the success rate of patent ductus arteriosus (PDA) transcatheter closure in preterm infants and to describe the nature of procedural adverse events and short-term clinical status.

Background: Patent ductus arteriosus (PDA) is a dramatically harmful disease in the neonatal period, in particular common in preterm infants, and our study was to determine related factors of PDA in preterm infants. Methods: A comprehensive literature review was conducted in PubMed, EMBASE, and Web of Science. The pooled odds ratio and standard mean difference were calculated to compare dichotomous and continuous variables, respectively. In addition, we also assessed the heterogeneity and publication bias and carried out sensitivity analysis for each related factor. Results: We included 45 studies with 87,419 individuals. After the primary analysis and a series of adjustments, results showed chorioamnionitis, lower gestational age, lower birth weight, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, respiratory distress syndrome, sepsis, surfactant treatment, ventilation, and lower platelet count had a positive correlation with PDA, while small for gestational age decreased the incidence of PDA in preterm infants. Besides, premature rupture of membranes, preeclampsia, antenatal steroids, male gender, mean platelet volume, and platelet distribution width were found to have no statistically significant relationship with PDA. Conclusion: Preterm infants with more immature characteristics generally have a higher likelihood to develop PDA. The prevention, diagnosis, and management of PDA may depend on these results, and effective measures can be taken accordingly.

No consensus has been reached on which patent ductus arteriosus (PDAs) in preterm infants require treatment and if so, how, and when they should be treated. A prospective, multicenter, cohort study was conducted to compare the effects of conservative approaches and medical treatment options on ductal closure at discharge, surgical ligation, prematurity-related morbidities, and mortality. Infants between 240/7 and 286/7 weeks of gestation from 24 neonatal intensive care units were enrolled. Data on PDA management and patients' clinical characteristics were recorded prospectively. Patients with moderate-to-large PDA were compared. Among the 1,193 enrolled infants (26.7 ± 1.4 weeks and 926 ± 243 g), 649 (54%) had no or small PDA, whereas 544 (46%) had moderate-to-large PDA. One hundred thirty (24%) infants with moderate-to-large PDA were managed conservatively, in contrast to 414 (76%) who received medical treatment. Eighty (62%) of 130 infants who were managed conservatively did not receive any rescue treatment and the PDA closure rate was 53% at discharge. There were no differences in the rates of late-onset sepsis, necrotizing enterocolitis (NEC), retinopathy of prematurity, intraventricular hemorrhage (≥Grade 3), surgical ligation, and presence of PDA at discharge between conservatively-managed and medically-treated infants (p > 0.05). Multivariate analysis including perinatal factors showed that medical treatment was associated with increased risk for mortality (OR 1.68, 95% Cl 1.01-2.80, p = 0.046), but decreased risk for BPD or death (BPD/death) (OR 0.59, 95%Cl 0.37-0.92, p = 0.022). The preferred treatment options were ibuprofen (intravenous 36%, oral 31%), and paracetamol (intravenous 26%, oral 7%). Infants who were treated with oral paracetamol had higher rates of NEC and mortality in comparison to other treatment options. Infants treated before postnatal day 7 had higher rates of mortality and BPD/death than infants who were conservatively managed or treated beyond day 7 (p = 0.009 and 0.007, respectively). In preterm infants born at <29 weeks of gestation with moderate-to-large PDA, medical treatment did not show any reduction in the rates of open PDA at discharge, surgical or prematurity-related secondary outcomes. In addition to the high incidence of spontaneous closure of PDA in the first week of life, early treatment (<7 days) was associated with higher rates of mortality and BPD/death.

Introduction: Echocardiography (ECHO) with color flow Doppler is considered as the gold standard to identify a hemodynamic patent ductus arteriosus (hs-PDA). However, the optimal diagnostic and therapeutic management for newborns with hs-PDA is still controversial. We aimed to investigate two clinical strategies: (1) targeted treatment based on ECHO criteria and (2) treatment based on ECHO criteria in addition to clinical signs and symptoms. Materials and Methods: This is a cohort study including all neonates consecutively admitted in the Neonatal Intensive Care Unit of University La Sapienza in Rome, with gestational age <32 weeks or body birth weight <1,500 g and with a diagnosis of hs-PDA as confirmed by ECHO evaluation performed within 72 h of life. We classified the babies in two cohorts: (A) pharmacological treatment immediately after ECHO screening and (B) pharmacological therapy for PDA was administered when the relevance of a hs-PDA was associated with clinical signs of hemodynamic instability. Results: We considered as primary outcome newborns who survived without any morbidities (A: 48.1% vs. B: 22.2%, p = 0.022). In particular, we found that the rate of intraventricular hemorrhage stage ≥2 was increased in cohort B (A: 3.7% vs. B 24.4%, p = 0.020). A multivariate analysis showed that assignment to cohort A independently influences the primary outcome. Conclusions: Adopting an hs-PDA management option based on ECHO-directed therapy regardless of symptoms may reduce the morbidity and improve the survival of very low birth weight infants.

Background: A meta-analysis published in 2015 showed a significant association between low platelet counts in the first day(s) of life and risk of patent ductus arteriosus (PDA). The meta-analysis pooled data from 11 studies cohorts (3,479 preterm infants). Objective: To update the meta-analysis by adding new studies on the topic and including other platelet parameters different from platelet counts. Methods: PubMed/Medline and Embase databases were searched. Random-effects risk ratios (RR) and differences in means (DM) and 95% confidence intervals (CI) were calculated. Results: We included 31 studies (7,638 infants). Meta-analysis showed that the risk of developing any PDA was significantly associated with platelet counts<150 × 109/L (11 studies, RR 1.58, 95% CI 1.28 to 1.95), and <100 x 109/L (7 studies, RR 1.61, 95% CI 1.14 to 2.28), but not <50 x 109/L (4 studies, RR 1.34, 95% CI 0.77 to 2.32). Risk of developing hemodynamically significant PDA (hsPDA) was significantly associated with platelet counts<150 x 109/L (12 studies, RR 1.33, 95% CI 1.09 to 1.63), and <100 x 109/L (7 studies, RR 1.39, 95% CI 1.06 to 1.82), but not <50 x 109/L (6 studies, RR 1.24, 95% CI 0.86 to 1.79). Infants with hsPDA had significantly lower mean platelet counts (19 studies, DM 22.0 x 109, 95% CI 14.9 to 29.1) and platelet mass (11 studies, DM 214.4, 95% CI 131.2 to 297.5) and significantly higher platelet distribution width (PDW, 9 studies, DM -0.53, 95% CI -1.01 to -0.05) than infants without hsPDA. Meta-analysis could not demonstrate significant differences in mean platelet volume (MPV). Conclusion: Compared to the previous analysis, this updated meta-analysis included 21 additional studies that provide stronger evidence of the association between low platelet counts and PDA/hsPDA. Other platelet parameters such as platelet mass and PDW are also associated with hsPDA risk. However, the low number of platelets may be an epiphenomenon associated with the maturity and clinical stability of preterm infants rather than a contributing factor in the pathogenesis of PDA.

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.

Background: Currently, the first line treatment of persistent ductus arteriosus (PDA) is either indomethacin or ibuprofen. However, the potentially life-threatening side effects associated to their use have prompted physicians to look for alternative options. The incorporation of paracetamol as an alternative to ibuprofen in the management of PDA is still based on insufficient clinical evidence. Hence, more clinical trials are needed to establish a therapeutic role for paracetamol in the management of PDA that take into consideration short- and long-term safety and efficacy outcomes. Study Design: This is a non-inferiority, randomized, multicenter, double-blinded study to evaluate the efficacy, and safety of intravenous (IV) paracetamol vs. IV ibuprofen (standard treatment) for PDA in preterm patients with a gestational age ≤ 30 weeks. At baseline, patients will be randomized (1:1) to treatment with paracetamol or ibuprofen. The primary endpoint is closure of the ductus after the first treatment course. Secondary endpoints are related to effectiveness (need for a second treatment course, rescue treatment, reopening rate, time to definitive closure, need for surgical ligation), safety (early and long-term complications), pharmacokinetics, and pharmacodynamics, pharmacogenetics, pharmacoeconomics, and genotoxicity. Long-term follow-up to 24 months of corrected postnatal age will be performed using Bayley III neurodevelopmental scale. Trial Registration: ClinicalTrials.gov Identifier: NCT04037514. EudraCT: 2015-003177-14.

Background: Indomethacin and ibuprofen, two commonly used prostaglandin inhibitors, are the drugs of choice for patent ductus arteriosus. However, paracetamol is an alternative choice when these drugs are ineffective or contraindicated. This study aimed to confirm paracetamol's efficacy and safety compared with those of other drugs or placebos for patent ductus arteriosus closure in premature infants. Methods: We conducted a literature search using the Cochrane Library, PubMed, CINAHL, and EMBASE databases for randomized controlled trials and quasi-randomized controlled trials. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to direct the process and PICO (P, population; I, intervention/interest; C, comparator; O, outcome) principle to constitute the theme. We combined the research data through qualitative summaries or meta-analyses. Results: The final analyses included 15 trials (N = 1,313). No significant differences were noted between paracetamol and ibuprofen except for shorter mean days needed for patent ductus arteriosus closure, lower risk of gastrointestinal bleeding, and hyperbilirubinemia. No significant difference existed between paracetamol and indomethacin. Oral paracetamol was more effective than placebo in infants weighing 1,501-2,500 g. Conclusions: Our study findings tentatively conclude that paracetamol can induce early patent ductus arteriosus closure without significant side effects but that its efficacy is not superior to that of indomethacin.

Aim: To develop a novel clinical scoring system for predicting hemodynamically significant patent ductus arteriosus (hsPDA) in extremely low birth weight (ELBW) infants. Methods: A prospective observational study was conducted among ELBW infants born in the study center during a 6-month period. Fourteen items were selected on a literature review basis and weighed by severity on an arbitrary 1-4 scale, the sum of which represented the Scoring preterm Infants for PDA cLinically without Echocardiographic evaluation (SIMPLE) score. The SIMPLE scores were compared at several time points during the first 3 days of life between two groups of patients: those with an hsPDA at echocardiography and those without. Results: A total of 48 ELBW infants were enrolled, of which 30 infants developed hsPDA. The SIMPLE scores of the infants with hsPDA were significantly greater than those of the infants who did not develop hsPDA. Cut-off SIMPLE scores that were significantly associated with detection of symptomatic hsPDA at each evaluation time point were identified. Conclusions: SIMPLE is the first scoring system that depends on the risk factors and clinical findings of ELBW infants for early prediction of hsPDA. It is simple, objective and easy to perform, and it does not require any additional tests and/or echocardiographic evaluation. We suggest that SIMPLE can be used as a screening tool for determining the need for echocardiographic evaluation in ELBW infants in order to minimize the number of unnecessary pediatric cardiology consultations.

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.

The optimal management strategy for patent ductus arteriosus in preterm infants remains a topic of debate. Available evidence for a treatment strategy might be biased by the delayed spontaneous closure of the ductus arteriosus in preterm infants, which appears to depend on patient characteristics. We performed a systematic review of all literature on PDA studies to collect patient characteristics and reported numbers of patients with a ductus arteriosus and spontaneous closure. Spontaneous closure rates showed a high variability but were lowest in studies that only included preterm infants with gestational ages below 28 weeks or birth weights below 1,000 g (34% on day 4; 41% on day 7) compared to studies that also included infants with higher gestational ages or higher birth weights (up to 55% on day 3 and 78% on day 7). The probability of spontaneous closure of the ductus arteriosus keeps increasing until at least 1 week after birth which favors delayed treatment of only those infants that do not show spontaneous closure. Better prediction of the spontaneous closure of the ductus arteriosus in the individual newborn is a key factor to find the optimal management strategy for PDA in preterm infants.

Background: Patent ductus arteriosus (PDA) treatment remains controversial. Modeling on the predictive capacity of early spontaneous PDA closure would help in decision-making. Aim: To design a predictive model of early spontaneous PDA closure. Methods: As part of a trial to assess efficacy and safety of two ibuprofen treatment schemes for PDA, infants below 29 weeks' gestation were scanned between 18 and 72 h of birth, and serially if indicated. PDA treatment was decided based on echocardiography signs of lung overflow or systemic hypoperfusion and clinical criteria. A PDA score that included the echocardiographic parameters significantly associated with treatment prescription was retrospectively applied. Perinatal variables and screening score were included in a backwards elimination model to predict early spontaneous closure. Results: Among 87 eligible infants (27 weeks' gestation; age at screening 45 h), 21 received ibuprofen at 69 h of life [screening score = 7 (IQR = 5-8.5); score at treatment = 9 (IQR = 8-9)], while 42 infants had conservative management, [screening score = 1 (IQR = 0-4)]. Twenty four infants were excluded (ibuprofen contraindication, declined consent or incomplete echocardiography). Screening score showed an AUC = 0.93 to predict early spontaneous PDA closure, [cut-off value = 4.5 (sensitivity = 0.90, specificity = 0.86)]. The predictive model for early spontaneous PDA closure followed the equation: Log (p/1-p) = -28.41 + 1.23* gestational age -0.87* PDA screening score. Conclusions: A predictive model of early spontaneous PDA closure that includes gestational age and the screening PDA score is proposed to help clinicians in the decision- making for PDA treatment. In addition, this model could be used in future intervention trials aimed to prevent PDA related morbidities to improve the eligibility criteria.

Background: The development of necrotizing enterocolitis (NEC) in neonates with patent ductus arteriosus (PDA) is not well-understood. Our aim was to find risk factors for NEC in children with a significant PDA and to assess differences in mortality and duration of hospital stay between patients with PDA and those with PDA and NEC. Methods: We performed a retrospective single center case control study including infants with PDA scheduled for treatment. We compared multiple patient data between patients with PDA and those with PDA and NEC from 2004 to 2018 using 1:2 and 1:1 matching. Results: We used 1:2 matching with 26 NEC patients (cases) and 52 PDA patients without NEC (controls) and 1:1 matching with 5 NEC patients and 5 PDA patients without NEC. NEC patients had lower Apgar score (1'), more congenital malformations, more suspected sepsis, less hypotension, higher minimum platelet count and higher CRP-values during the week before NEC (P < 0.05, respectively). The mortality was higher in NEC cases [29% (9/31)] compared to the control patients [2% (1/57), P < 0.001]. Lower Apgar score (1') was correlated with an increased risk of NEC stage III. Hypotension was inversely correlated with the odds of NEC (OR 0.3). Conclusions: NEC increased mortality in infants with PDA. Hypotension did not increase the risk of NEC in infants with PDA. Routine clinical parameters were not able to predict NEC in infants who suffer from PDA.

Aims and Objectives: Malnutrition is common in children with congenital heart disease and may contribute to adverse outcomes. This study evaluates the impact of pre-operative nutritional status on outcomes after congenital heart surgery. Methods: We conducted a retrospective cohort study enrolling children under 10 years old who underwent congenital heart surgery at a tertiary children's hospital from 2012 to 2016. Patients who had patent ductus arteriosus ligation only, genetic syndromes, or global developmental delay were excluded. Outcome measures included 30-day mortality, intensive care unit (ICU) length of stay (LOS), hospital LOS, duration of mechanical ventilation, and number of inotropes used post-operatively. We performed univariate/multivariable logistic regression analysis, adjusting for age, cyanotic cardiac lesion, co-morbidity, and Risk Adjustment for Congenital Heart Surgery (RACHS-1) score. Results: Three hundred two children of median age 16.2 [interquartile range (IQR) 3.1, 51.4)] months were included. The most common cardiac lesions were ventricular septal defect (27.8%), atrial septal defect (17.9%), and Tetralogy of Fallot (16.6%). Median weight-for-age z-score (WAZ) was -1.46 (IQR -2.29, -0.61), height-for-age z-score (HAZ) was -0.94 (IQR -2.10, -0.10), and body mass index (BMI)-for-age z-score (BAZ) was -1.11 (IQR -2.19, -0.30). In multivariable analysis, there was an increased risk of 30-day mortality for WAZ ≤-2 vs. WAZ >-2 [adjusted odds ratio (aOR): 4.01, 95% CI: 1.22, 13.13; p = 0.022]. For HAZ ≤-2 vs. HAZ > -2, there was increased risk of hospital LOS ≥ 7 days (aOR: 2.08, 95% CI: 1.12, 3.89; p = 0.021), mechanical ventilation ≥48 h (aOR: 2.63, 95% CI: 1.32, 5.24; p = 0.006) and of requiring ≥3 inotropes post-operatively (aOR: 3.00, 95% CI: 1.37, 6.59; p = 0.006). Conclusion: In children undergoing congenital heart surgery, WAZ ≤ -2 is associated with higher 30-day mortality, while HAZ ≤ -2 is associated with longer durations of hospital LOS and mechanical ventilation, and increased risk of use of 3 or more inotropes post-operatively. Future studies are necessary to develop safe and efficacious peri-operative nutritional interventions, particularly in patients with WAZ and HAZ ≤ -2.