Congenital Diaphragmatic Hernia: 10-Year Evaluation of Survival, Extracorporeal Membrane Oxygenation, and Foetoscopic Endotracheal Occlusion in Four High-Volume Centres

Background: Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly with significant mortality. Objectives: The aim of this study was to determine if there were trends in survival over the last decade and to compare patient populations, treatment options, and survival rates between 4 high-volume centres, and hence determine which factors were associated with survival. Methods: In 4 high-volume CDH centres from the CDH EURO Consortium, data from all CDH patients born between 2004 and 2013 were analysed. The predictive value of variables known at birth and the influence of centre-specific treatments (extracorporeal membrane oxygenation, ECMO, and foetoscopic endotracheal occlusion, FETO) on survival were evaluated in multivariable logistic regression analyses. Results: Nine hundred and seventy-five patients were included in the analysis, of whom 274 (28.1%) died. ECMO was performed in 259 patients, of whom 81 (31.3%) died. One hundred and forty-five patients (14.9%) underwent FETO, and from those 76 patients (52.4%) survived. Survival differed significantly between years (p = 0.006) and between the 4 centres (p < 0.001). In the multivariable logistic regression analysis, lung-to-head ratio, gestational age at birth, ECMO, centre of birth, and year of birth were significantly associated with survival, whereas FETO was not. Conclusions: The patient populations were different between centres, which influenced outcomes. There was a significant variability in survival over time and between centres, which should be taken into consideration in the planning of future trials

Neurodevelopmental Outcome in High-Risk Congenital Diaphragmatic Hernia Patients: An Appeal for International Standardization

BACKGROUND: Since mortality in congenital diaphragmatic hernia (CDH) is decreasing, morbidity such as neurodevelopmental outcome is becoming increasingly important. OBJECTIVES: We evaluated neurodevelopmental outcome in high-risk CDH patients treated according to the CDH EURO Consortium standardized treatment protocol. METHODS: This observational, prospective cohort study was conducted in two European centers. Neurodevelopment of 88 patients (Rotterdam n = 49; Rome n = 39) was assessed at 12 and 24 months with the Bayley Scales of Infant Development (BSID)-II-NL (Rotterdam) or BSID-III (Rome). Data of the centers were analyzed separately. RESULTS: Cognition was normal in 77.8% of children from Rotterdam and in 94.8% from Rome at 12 months, and in 70.7 and 97.4%, respectively, at 24 months. Motor function was normal in 64.3% from Rotterdam and in 81.6% from Rome at 12 months and in 45.7 and 89.8%, respectively, at 24 months. Longer length of hospital stay (LoS) was associated with worse cognitive outcome and motor function; LoS, low socioeconomic status, and ethnicity were associated with lower cognition. CONCLUSIONS: At 2 years, most CDH patients have normal cognition, but are at risk for motor function delay. Due to differences in outcomes between centers, careful interpretation is needed before conclusions can be drawn for other centers. Future multicenter collaboration should not only focus on standardization of postnatal care, but also on international standardization of follow-up to identify risk factors and thereby reduce morbidity

The CoDiNOS trial protocol: an international randomised controlled trial of intravenous sildenafil versus inhaled nitric oxide for the treatment of pulmonary hypertension in neonates with congenital diaphragmatic hernia

INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on 'trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking. METHODS AND ANALYSIS: In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses. ETHICS AND DISSEMINATION: Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained. TRIAL REGISTRATION NUMBER: NTR6982; Pre-results

Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update

In 2010, the congenital diaphragmatic hernia (CDH) EURO Consortium published a standardized neonatal treatment protocol. Five years later, the number of participating centers has been raised from 13 to 22. In this article the relevant literature is updated, and consensus has been reached between the members of the CDH EURO Consortium. Key updated recommendations are: (1) planned delivery after a gestational age of 39 weeks in a high-volume tertiary center; (2) neuromuscular blocking agents to be avoided during initial treatment in the delivery room; (3) adapt treatment to reach a preductal saturation of between 80 and 95% and postductal saturation >70%; (4) target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical ventilation to be the optimal initial ventilation strategy, and (6) intravenous sildenafil to be considered in CDH patients with severe pulmonary hypertension. This article represents the current opinion of all consortium members in Europe for the optimal neonatal treatment of CDH

Ductus Arteriosus in Fetal and Perinatal Life

The ductus arteriosus represents an essential vascular structure connecting the pulmonary artery and the aorta. Over the past decades, there has been substantial advancement in our understanding of both the fundamental and clinical aspects of the ductus arteriosus. In particular, the clarification of the regulatory mechanisms governing ductal patency in critical stages such as the fetal and the perinatal period has enabled optimal management of both physiological and pathological conditions in which the ductus arteriosus plays a crucial role. Furthermore, a more in-depth understanding of the regulatory mechanisms controlling this fundamental structure has facilitated the development of advanced therapeutic strategies and personalized interventions. In the present review, we provide a comprehensive overview of the ductus arteriosus during fetal and perinatal life, encompassing its physiological functions, pathological conditions, and clinical implications. Through this examination, we aim to contribute to a broader understanding of the ductus arteriosus’ role in these critical developmental stages and its significance in clinical practice

Defective Leukocyte β2 Integrin Expression and Reactive Oxygen Species Production in Neonates.

Neonates are highly susceptible to bacterial infections, which represent a major source of mortality and morbidity in this age category. It is recognized that β2 integrins play a critical role in innate immunity by mediating leukocyte vascular adhesion, transmigration and bacterial phagocytosis. Therefore, we aimed to assess if the impaired immune functions seen in newborns may derive, in part, from a transient insufficient β2 integrin expression. In the present study we measured baseline lymphocyte function-associated antigen-1 (LFA-1 or CD11a/CD18), macrophage-1 antigen (MAC-1 or CD11b/CD18) and leukocyte integrin p150-95 (CD11c/CD18) expression on cord blood, and on the third day of life in a cohort of 35 healthy neonates, compared with a control group of 12 healthy adults. For any of the three β2 integrins, the expression on polymorphonuclear cells was significantly lower on cord blood than in adults and increased from birth to day 3. We also compared superoxide radical (SR) production in these neonates with 28 non-smoking adults. SR production in response to integrin stimulation by Zymosan was significantly lower at birth than in adults, and it decreased further in the third day of life. These findings suggest that innate immune impairment in newborns may be, in part, accounted for by a lower β2 integrin expression on phagocytes in the neonatal period, but also by a functional impairment of free radical production

Nutritional Strategies for Preterm Neonates and Preterm Neonates Undergoing Surgery: New Insights for Practice and Wrong Beliefs to Uproot

The nutrition of preterm infants remains contaminated by wrong beliefs that reflect inexactitudes and perpetuate old practices. In this narrative review, we report current evidence in preterm neonates and in preterm neonates undergoing surgery. Convictions that necrotizing enterocolitis is reduced by the delay in introducing enteral feeding, a slow advancement in enteral feeds, and the systematic control of residual gastric volumes, should be abandoned. On the contrary, these practices prolong the time to reach full enteral feeding. The length of parenteral nutrition should be as short as possible to reduce the infectious risk. Intrauterine growth restriction, hemodynamic and respiratory instability, and patent ductus arteriosus should be considered in advancing enteral feeds, but they must not translate into prolonged fasting, which can be equally dangerous. Clinicians should also keep in mind the risk of refeeding syndrome in case of high amino acid intake and inadequate electrolyte supply, closely monitoring them. Conversely, when preterm infants undergo surgery, nutritional strategies are still based on retrospective studies and opinions rather than on randomized controlled trials. Finally, this review also highlights how the use of adequately fortified human milk is strongly recommended, as it offers unique benefits for immune and gastrointestinal health and neurodevelopmental outcomes

Role of microRNAs in Congenital Diaphragmatic Hernia-Associated Pulmonary Hypertension

Epigenetic regulators such as microRNAs (miRNAs) have a key role in modulating several gene expression pathways and have a role both in lung development and function. One of the main pathogenetic determinants in patients with congenital diaphragmatic hernia (CDH) is pulmonary hypertension (PH), which is directly related to smaller lung size and pulmonary microarchitecture alterations. The aim of this review is to highlight the importance of miRNAs in CDH-related PH and to summarize the results covering this topic in animal and human CDH studies. The focus on epigenetic modulators of CDH-PH offers the opportunity to develop innovative diagnostic tools and novel treatment modalities, and provides a great potential to increase researchers’ understanding of the pathophysiology of CDH

Is counselling for CCAM that difficult? Learning from parental experience

Objective: Cystic adenomatoid malformations (CCAM) are relatively rare developmental abnormalities of the lung. Despite outcome is usually benign, parents often exhibit high anxiety level. The purpose of the present study was to collect parents’subjective experience of communication of diagnosis when expecting a fetus with CCAM