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Funder: Alma Mater Studiorum - Università di Bologna, Patent ductus arteriosus (PDA) is common among extremely preterm infants. In selected cases, surgical PDA ligation may be required. The timing for PDA ligation may depend upon a variety of factors, with potential clinical implications. We aimed to investigate the impact of different surgical PDA managements on ligation timing and neonatal outcomes. Inborn infants < 32 weeks of gestation and < 1500 g admitted at two tertiary Neonatal Intensive Care Units that underwent PDA ligation between 2007 and 2018 were enrolled in this retrospective cohort study and split into the following groups based on their surgical management: on-site bedside PDA ligation (ONS) vs. referral to an off-site pediatric cardiac surgery (OFS). Neonatal characteristics, surgical timing, and clinical outcomes of the enrolled infants were compared between the groups. Multivariate analysis was performed to evaluate the impact of PDA ligation timing on significantly different outcomes. Seventy-eight neonates (ONS, n = 39; OFS, n = 39) were included. Infants in the ONS group underwent PDA ligation significantly earlier than those in the OFS group (median age 12 vs. 36 days, p < 0.001) with no increase in postoperative mortality and complications. The multivariate analysis revealed a significant association between PDA ligation timing, late-onset sepsis prevalence (OR 1.045, 0.032), and oxygen need at discharge (OR 1.037, p = 0.025).Conclusions: Compared with off-site surgery, on-site bedside ligation allows an earlier surgical closure of PDA, with no apparent increase in mortality or complications. Earlier PDA ligation may contribute to reduced rates of late-onset sepsis and post-discharge home oxygen therapy, with possible cost-benefit implications. What is known: • Ineffective or contraindicated pharmacological closure of a hemodynamically significant PDA may require a surgical ligation. • Available literature comparing the effect of early vs. late PDA ligation on the main neonatal morbidities has yield contrasting results. What is new: • The availability of a cardiac surgery service performing bedside PDA ligation allows an earlier intervention compared to patient referral to an off-site center, with no difference in postoperative mortality and complications compared to off-site surgery. • Earlier PDA ligation was associated with a lower prevalence of late-onset sepsis and of oxygen need at discharge, with possible cost-benefit implications. more...

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies. more...

Optimal nutrition is essential to improve short- and long-term outcomes in newborns with congenital heart disease (CHD). Nevertheless, several issues on nutritional management and concerns about the potential risk of complications related to enteral feeding exist. This narrative review aims to summarize and discuss the available literature on enteral feeding in term infants with CHD. A wide variability in feeding management exists worldwide. Emerging approaches to improve nutritional status and outcomes in infants with CHD include: implementation of a standardized enteral feeding protocol, both preoperative and postoperative, clearly defining time of initiation and advancement of enteral feeds, reasons to withhold, and definitions of feeding intolerance; early minimal enteral feeding; enteral feeding in stable term infants on hemodynamic support; evaluation of enteral feeding in term infants with umbilical arterial catheters and during prostaglandin infusion; assessment and support of oro-motor skills; and promotion and support of breastfeeding and provision of mother’s own milk or donor milk when mother’s own milk is not available. As evidence from term infants is scarce, available observations and recommendations partially rely on studies in preterm infants. Thus, well-designed studies assessing standardized clinically relevant outcomes are needed to provide robust evidence and shared recommendations and practices. more...

Objective: To investigate the features of cardiorespiratory events in infants born preterm during the transitional period, and to evaluate whether different neonatal characteristics may correlate with event type, duration, and severity. Study design: Infants with gestational age (GA) more...

Key points: Non-invasive simultaneous multiparametric monitoring allows the in vivo evaluation of cerebral and cardiovascular haemodynamic responses to different types of recurrent episodes of intermittent hypoxia and/or bradycardia, also defined as cardio-respiratory events (CRE), in preterm neonates during postnatal transition. By decreasing left cardiac output, bradycardia further contributes to cerebral hypoxia during CRE. The presence of a haemodynamically significant patent ductus arteriosus results in a deeper impairment of cerebral oxygen status in response to CRE, whereas the brain-sparing remodelling of the fetal circulation resulting from placental insufficiency is associated with more favourable haemodynamic responses to intermittent hypoxia. During transition, the haemodynamic impact of CRE is influenced not only by the event type, but also by specific clinical features; this highlights the importance of developing individualized approaches to reduce the hypoxic burden in this delicate phase. Abstract: The present observational prospective study aimed to investigate cerebral and cardiovascular haemodynamic responses to different types of cardio-respiratory events (CRE) in preterm infants during postnatal transition, as well as evaluate the impact of relevant clinical characteristics. Infants with gestational age (GA) more...

The management of enteral feeds in preterm infants with a hemodynamically significant patent ductus arteriosus (hs-PDA) is a major challenge for neonatologists due to the fear of gastrointestinal (GI) complications. This review aims to analyze the available evidence on the complex relation between the presence and management of PDA, enteral feeding practices, and GI outcomes in the preterm population. There is limited evidence, based on small and heterogeneous trials, that hs-PDA may affect the splanchnic hemodynamic response to enteral feeds. While the presence of PDA seems a risk factor for adverse GI outcomes, the benefits of feeding withholding during pharmacological PDA treatment are controversial. The lack of robust evidence in support of or against a timely feeding introduction or feeding withholding during pharmacological PDA closure in preterm neonates does not allow to draw any related recommendation. While waiting for further data, the feeding management of this population should be carefully evaluated and possibly individualized on the basis of the infants’ hemodynamic and clinical characteristics. Large, multicentric trials would help to better clarify the physiological mechanisms underlying the development of gut hypoperfusion, and to evaluate the impact of enteral feeds on splanchnic hemodynamics in relation to PDA features and treatment. more...

Background: Infants born at 23–24 weeks' gestation have the highest risk of developing a hemodynamically significant patent ductus arteriosus (hsPDA), that is refractory to pharmacological closure requiring surgical ligation. Thus, these patients might have the greatest benefits from hsPDA closure, although previous studies on PDA closure were not focused on this population. Aim: To compare the occurrence of hsPDA, failure rate of the first course of ibuprofen in closing hsPDA, and need of surgical closure in infants born at 23+0–24+6 weeks' gestation to those in infants born at 25+0–28+6 weeks' gestation. Study design: This is a retrospective multicenter study including infants born at 23+0–28+6 weeks of gestation admitted to the neonatal care units from January 2013 to December 2017. All infants underwent echocardiographical assessment for hsPDA diagnosis and eventually pharmacological treatment, and surgical closure. Results: We studied a total of 842 infants of which 562 (67%) developed a PDA. Among those with PDA, 511 (91%) received a pharmacological treatment for a hsPDA. We found that a hsPDA occurred in 70% (106/151) of infants born at 23–24 weeks and in 59% (405/691) of infants born at 25–28 weeks of gestation (P < 0.001). Failure of closure with the first-treatment cycle (69 vs. 40%; P < 0.001) and need of surgical closure (19 vs 10%) were more frequent (P < 0.011) in infants born at 23–24 than 25–28 gestational weeks. Paracetamol vs. ibuprofen treatment and gestational age of 23–24 versus 25–28 weeks increased closure failure, while less severe RDS and maternal clinical chorioamnionitis decreased it. Conclusions: Among extremely preterm infants, infants born at 23–24 weeks of gestation have the highest risk of developing a hsPDA refractory to pharmacological treatment requiring surgical closure. Our findings support the need of individualized more careful strategies for hsPDA management in this special population. more...

Because of its possible effect on mesenteric blood flow, the presence of a hemodynamically significant patent ductus arteriosus (PDA) is often of concern for the introduction of enteral feeds in preterm neonates. Near-infrared spectroscopy allows a continuous monitoring of splanchnic oxygenation (SrSO2) and may provide useful hemodynamic information. This observational study evaluated SrSO2 patterns in response to first feed administration in 50 preterm infants more...

Introduction: Premature birth is a leading cause of neonatal morbidity and mortality. Since gestational age at birth is the most important predictive factor of adverse neonatal outcomes, strategies to postpone premature labor are of major importance. Studies on tocolytic drugs show that COX inhibitors such as indomethacin are superior to others in terms of efficiency in delaying birth, but results concerning neonatal outcomes associated with prenatal exposure to these drugs show controversial results. Indomethacin is also used in the postnatal age for pharmacologic treatment of patent ductus arteriosus (PDA), but no data concerning the effects of antenatal exposure on postnatal ductal patency are available.Methods: In this study, we focused primarily on the association between antenatal indomethacin (AI) and postnatal patency of ductus arteriosus while our secondary aim was to highlight any possible influence of AI exposure on adverse neonatal outcomes. We performed a retrospective analysis of 241 medical records of newborns born before 33 weeks' gestation and exposed to antenatal tocolysis. Obstetrical data and neonatal outcomes of newborns exposed to AI were compared to those of neonates exposed to other tocolytic drugs. Early ductal closure (EDC) was defined when functional echocardiography performed within 24 hours of life showed a closed duct. Occurrence of intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), respiratory distress syndrome (RDS), chronic lung disease (CLD), necrotizing enterocolitis (NEC), sepsis, and PDA were compared between the groups and the diagnosis of at least one of III-IV grade IVH, PVL, CLD, sepsis, surgical NEC, or death was defined as a severe outcome.Results: The univariate analysis showed that infants in the AI group were at a higher risk of IVH, CLD, RDS, sepsis, and PDA. The incidence of severe outcomes also appeared to be higher in this group, while no effect of AI on PDA was observed. Since we noticed that infants exposed to AI had a lower gestational age and worse clinical conditions at birth when compared to the controls, we considered this as a confounding factor. To overcome this bias, we performed a multivariate analysis that evidenced no significant role of AI on the occurrence of severe outcomes. On the other hand, a possible association was confirmed for all degrees of IVH (OR: 3.16, 95% CI : [1.41; 7.05]) and sepsis (OR: 2.81, 95% CI: [1.24; 6,28]).Conclusions: The unexpected result shown by the multivariate analysis was the association between AI exposure and EDC (OR: 2.52, 95% CI: [1.02; 6.21]). This result, which has never been evidenced in previous studies, has great clinical importance. It is well known that PDA is more frequent at lower gestational ages, thus reducing the incidence of PDA could lead to an improvement of overall outcomes in extremely preterm newborns. more...

A 70-year-old man was admitted because of a 6-month history of progressive dyspnoea on exertion. The medical history showed that he suffered from patent ductus arteriosus (PDA) that was closed at 35 years of age by surgical ligation. Subsequently, up to year 1992, no evidence of residual left-to-right shunt was found. When he first came to our attention, we performed an echocardiographic test evidencing left ventricular dilation and contractile dysfunction and a recurrence of PDA. To exclude other possible causes of congestive heart failure, we performed several tests, including a coronary angiogram that showed coronary atherosclerosis without significant lesions. The haemodynamic study confirmed that the PDA was associated with a mild pulmonary hypertension with a QP: QS of 2: 1. The patient did not report any cardiovascular risk factor. Therefore, we concluded that PDA was responsible for congestive heart failure in this patient. We performed percutaneous closure of PDA, which was able to reverse left ventricular dilation and dysfunction, improving the patient's symptoms, at 1 month as well as 4 months after the interventional procedure. Although this kind of device is frequently used in the paediatric population, adult patients may present different challenges in proper management, such as poor visualization, calcification and pulmonary hypertension. In the description of the case reported here, we show that a PDA can present as congestive heart failure in the elderly. Percutaneous closure can be very effective in ameliorating left ventricular performance as well as symptoms. more...