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Despite advances in caring for neonates with congenital diaphragmatic hernia (CDH), mortality and morbidity continues to be high. Additionally, the pathophysiology of cardiac dysfunction in this condition is poorly understood. Postnatal cardiac dysfunction in neonates with CDH may be multifactorial with origins in fetal life. Mechanical obstruction, competition from herniated abdominal organs into thoracic cavity combined with redirection of ductus venosus flow away from patent foramen ovale leading to smaller left-sided structures may be a contributing factor. This shunting decreases left atrial and left ventricular blood volume, which may result in altered micro- and macrovascular aberrations affecting cardiac development in the prenatal period. Direct mass effect from herniated intra-abdominal contents restricting cardiac growth and/or reduced left ventricular preload may contribute independently to left ventricular dysfunction in the absence of right ventricular dysfunction and or pulmonary hypertension. With variable clinical phenotypes of cardiac dysfunction, pulmonary hypertension, and respiratory failure in patients with CDH, there is increased need for individualized diagnosis and tailored therapy. Routine use of therapy such as inhaled nitric oxide and sildenafil that induces significant pulmonary vasodilation may be detrimental in left ventricle dysfunction, whereas in a patient with pure right ventricle dysfunction, they may be beneficial. Targeted functional echocardiography serves as a real-time tool for defining the pathophysiology and aids optimization of vasoactive therapy in affected neonates. KEY POINTS: · Cardiac dysfunction in neonates with CDH is multifactorial.. · Postnatal cardiac dysfunction in patients with CDH has its origins in fetal life.. · Right ventricular dysfunction contributes to systemic hypotension.. · Left ventricular dysfunction contributes to systemic hypotension.. · Supportive therapy should be tailored to clinical phenotype.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations., Methods: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches., Results: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein., Significance: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA., (© 2020 International League Against Epilepsy.)

Purpose: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10., Methods: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF., Results: Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling., Conclusion: Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.

The wall of the diaphragm can be affected by changes caused by physical trauma, allowing the passage of viscera between the abdominal cavity and thoracic cavity, thus reducing the space for pulmonary expansion, leading to the formation of hernia and possible death. Thus, we aimed to characterize, size and determine the topography of the diaphragmatic muscle in the Southern Tamandua, since clinical and surgical activities in wild animals have become a reality more and more present in veterinary medicine. We used six adult animals, x-rayed and dissected, followed by collection of fragments of muscular portions for histological analysis. Initially we observed that the animals presented 17 thoracic vertebrae, 3 lumbar vertebrae and 5 sacral vertebrae. The diaphragm was conformed by three segments: sternal, costal and right and left diaphragm pillar, with presence of tendinous centre that housed the passage of the caudal vena cava, called foramen of the caudal vena cava. Dorsally to the tendinous centre, already in the muscle portion, we located the esophageal and aortic hiatus. These findings, as well as the microscopic, were equivalent to that found in the general literature also, corroborating with descriptions already carried out in other mammals' diaphragms.

Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra (SDV), a burden of this microdeletion was observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis (CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three-generation family with spondylocostal dysostosis (SCD) was reported with a heterozygous stop-loss of TBX6. These observations questioned both on the inheritance mode and on the variable expressivity associated with TBX6-associated SDV. Based on a national recruitment of 56 patients with SDV, we describe four patients with variable SDV ranging from CS to SCD associated with biallelic variations of TBX6. Two patients with CS were carrying a proximal 16p11.2 microdeletion associated with the previously reported haplotype. One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin-binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from CS to SCD., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background  The aim of this study was to assess long-term pulmonary and diaphragmatic function in two cohorts of patients: the first one affected by diaphragmatic palsy (DP) who underwent plication reinforced by rib-fixed mesh and the second one affected by chronic diaphragmatic hernia (TDH) who underwent surgical reduction and direct suture. Materials and Methods  From 1996 to 2011, 10 patients with unilateral DP and 6 patients with TDH underwent elective surgery. Preoperative and long-term (12 months) follow-up assessments were completed in all patients, including pulmonary function tests (PFTs) with diffusion of the lung for carbon monoxide (DLCO), measure of maximum inspiratory pressure (MIP) assessed both in standing and in supine positions, blood gas analysis, chest computed tomographic (CT) scan, and dyspnea score. The Pearson chi-square test, Fisher exact test, and Student t -test were applied when indicated. Results  At long-term (12 months) postoperative follow-up, patients operated for DP showed a significant improvement in terms of forced expiratory volume in 1 second (FEV1%) (+ 18.2%, p  < 0.001), forced vital capacity (FVC%) (+ 12.8%, p  < 0.001), DLCO% (+ 8.3%, p  = 0.04), and Po 2 (+ 9.86 mm Hg, p  < 0.001) when compared with baseline values. Conversely, when considering the TDH group, only the levels of Po 2 were found to be significantly higher in the postoperative assessment (+ 8.3 mm Hg, p  = 0.04). Although MIP increased in both the groups after surgery, a persistent and significant decrease of MIP was detected in TDH group when comparing the levels assessed in supine position with those measured in the standing position ( p  < 0.001). Medical Research Council dyspnea scale improved in the DP group by a factor of 0.80 ( p  < 0.001) and in the TDH group by a factor of 0.33 ( p  = 0.175). Conclusion  In patients who underwent surgery for DP, good long-term results may be predicted in terms of pulmonary flows, volumes, and DLCO. Conversely, in patients who underwent elective surgery for chronic TDH, a persistent overall restrictive pattern, lower MIP values in supine position, and paradoxical motion could be expected., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Diprosopus is a subtype of symmetric conjoined twins with one head, facial duplication and a single trunk. Diprosopus is a very rare congenital anomaly., Methods: This is a systematic review of published cases and the presentation of two new cases born in Argentina. We estimated the prevalence of conjoined twins and diprosopus using data from the National Network of Congenital Anomalies of Argentina (RENAC)., Results: The prevalence of conjoined twins in RENAC was 19 per 1,000,000 births (95% confidence interval, 12-29). Diprosopus prevalence was 2 per 1,000,000 births (95% confidence interval, 0.2-6.8). In the systematic review, we identified 31 diprosopus cases. The facial structures more frequently duplicated were nose and eyes. Most frequent associated anomalies were: anencephaly, duplication of cerebral hemispheres, craniorachischisis, oral clefts, spinal abnormalities, congenital heart defects, diaphragmatic hernia, thoracic and/or abdominal visceral laterality anomalies. One of the RENAC cases and three cases from the literature had another discordant nonmalformed twin., Conclusion: The conjoined twins prevalence was similar to other studies. The prevalence of diprosopus was higher. The etiology is still unknown. The presence of visceral laterality anomalies may indicate the link between diprosopus and the alteration or duplication of the primitive node in the perigastrulation period (12-15 days postfertilization). Pregnancies of more than two embryos may be a risk factor for diprosopus. Given the low prevalence of this defect, it would be useful to perform studies involving several surveillance systems and international consortiums. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:993-1007, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Jarcho-Levin syndrome (JLS) is a rare axial skeletal growth disorder characterized by the presence of multi-level costovertebral malformations, a short neck, a short trunk, and kyphoscoliosis at birth. Neural tube defects appear to be common findings in patients with JLS, and chest hypoplasia frequently leads to respiratory insufficiency and death in early childhood. There have been no previous studies in the literature on the anesthetic management of JLS with neural tube defects and hydrocephalus. Therefore, we have reported a case of JLS in a female full-term newborn, who underwent surgery for myelomeningocele repair and ventriculoperitoneal shunting, with the associated anesthetic challenges and their management.

Diaphragmatic hernias (DH) occurring after pediatric liver transplantation (LT) are rare. However, such complications have been previously reported in the literature and treatment has always been surgical repair via laparotomy. We report our experience of minimally invasive thoracoscopic approach for repair of DH occurring after LT in pediatric recipients.From April 2010 to December 2014, 7 cases of DH were identified in pediatric LT recipient in Samsung Medical Center. Thoracoscopic repair was attempted in 3 patients. Patients' medical records were retrospectively reviewed.Case 1 was a 12-month-old boy, having received deceased donor LT for biliary atresia (BA) 5 months ago. He presented with dyspnea and left-sided DH was detected. Thoracoscopic repair was successfully done and the boy was discharged at postoperative day 7. Case 2 was a 13-month-old boy, having received deceased donor LT for BA 2 months ago. He presented with vomiting and right-sided DH was detected. Thoracoscopic repair was done along with primary repair of herniated small bowel that was perforated while attempting reduction into the peritoneal cavity. The boy recovered from the surgery without complications and was discharged on the 10th postoperative day. Case 3 was a 43-month-old girl, having received deceased donor LT for Alagille syndrome 28 months ago. She was diagnosed with right-sided DH during steroid pulse therapy for acute rejection. Thoracoscopic repair was attempted but a segment of necrotic bowel was noticed along with bile colored pleural effusion and severe adhesion in the thoracic cavity. She received DH repair with small bowel resection and anastomosis via laparotomy.Thoracoscopic repair was attempted in 3 cases of DH occurring after LT in pediatric recipients. With experience and expertise in pediatric minimally invasive surgery, thoracoscopic approach is feasible in this rare population of patients.

Background/purpose: Congenital diaphragmatic hernia (CDH) is a defect that presents high mortality because of pulmonary hypoplasia and hypertension. Mechanical ventilation changes signaling pathways, such as nitric oxide and VEGF in the pulmonary arterioles. We investigated the production of NOS2 and NOS3 and expression of VEGF and its receptors after ventilation in rat fetuses with CDH., Methods: CDH was induced by Nitrofen. The fetuses were divided into 6 groups: 1) control (C); 2) control ventilated (CV); 3) exposed to nitrofen (N-); 4) exposed to nitrofen ventilated (N-V), 5) CDH and 6) CDH ventilated (CDHV). Fetuses were harvested and ventilated. We assessed body weight (BW), total lung weight (TLW), TLW/BW ratio, the median pulmonary arteriolar wall thickness (MWT). We analyzed the expression of NOS2, NOS3, VEGF and its receptors by immunohistochemistry and Western blotting., Results: BW, TLW, and TLW/BW ratio were greater on C than on N- and CDH (p<0.05). The MWT was higher in CDH than in CDHV (p<0.001). CDHV showed increased expression of NOS3 (p<0.05) and VEGFR1 (p<0.05), but decreased expression of NOS2 (p<0.05) and VEGFR2 (p<0.001) compared to CDH., Conclusion: Ventilation caused pulmonary vasodilation and changed the expression of NOS and VEGF receptors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In animal models of congenital diaphragmatic hernia (CDH), tracheal occlusion (TO) has induced maturation of both airway spaces and vascular structures. Airway and vascular response to TO are assumed to occur in parallel. This study aims to describe and measure the relationship between airway and vascular maturation induced by TO., Methods: A rabbit model of CDH on gestational day (GD) 23 and TO on GD 28 (term = GD 31) has been used. Two study groups have been defined: DH (diaphragmatic hernia) and TO (DH treated with TO). Animals were collected on GD 30 and blood flow data of the pulmonary artery (pulsatility index (PI) and fractional moving blood volume) were ultrasonographically measured. Lung morphometry consisted of measurements of radial alveolar count (RAC) and arterial muscular thickness., Results: Animals in the DH group (n = 9) had the worst hemodynamic parameters; their lungs were hypoplastic and had the thickest arterial muscular layer. Animals in the TO group (n = 10) had all these effects reversed. There were no correlations among hemodynamic, airway, and vascular parameters, except for RAC and PI (r = -0.528, P = 0.043)., Conclusion: Airway and vascular maturation after TO appear to be uncorrelated effects. TO could trigger several pathways that separately regulate airway and vascular responses.

Little is known about long-term effects of neonatal intensive care on exercise capacity, physical activity, and fatigue in term borns. We determined these outcomes in 57 young adults, treated for neonatal respiratory failure; 27 of them had congenital diaphragmatic hernia with lung hypoplasia (group 1) and 30 had normal lung development (group 2). Patients in group 2 were age-matched, with similar gestational age and birth weight, and similar neonatal intensive care treatment as patients in group 1. All patients were born before the era of extracorporeal membrane oxygenation, nitric oxide administration, and high frequency ventilation. Exercise capacity was measured by cycle ergometry, daily physical activity with an accelerometry-based activity monitor, and fatigue by the fatigue severity scale. Median (range) VO2peak in mL/kg/min was 35.4 (19.6-55.0) in group 1 and 37.6 (15.7-52.7) in group 2. There was a between-group P-value of 0.65 for exercise capacity. Daily activity and fatigue were also similar in both groups. So, residual lung hypoplasia did not play an important role in this cohort. There were no significant associations between exercise capacity and perinatal characteristics. Future studies need to elucidate whether exercise capacity is impaired in patients with more severe lung hypoplasia who nowadays survive., (© 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the relationship between early right ventricular function measured by tissue Doppler imaging and early outcome measures in newborn infants with congenital diaphragmatic hernia., Design: Retrospective cohort study., Setting: Surgical neonatal ICU within a regional pediatric center., Patients: Twenty newborn infants with congenital diaphragmatic hernia., Interventions: None., Measurements and Main Results: Analysis of serial echocardiograms in a cohort of 20 infants with congenital diaphragmatic hernia was done. Tissue Doppler early diastolic and systolic myocardial velocities were measured to assess diastolic and systolic function, respectively, in the basal right ventricle. Pulmonary:systemic peak pressure ratio was estimated using velocity of tricuspid regurgitation. Physiologic, treatment, and early outcome data (duration of respiratory support and length of stay) were recorded. For analysis, duration of respiratory support was selected as the main outcome measure, and infants were divided into two groups based on median duration of respiratory support of 21 days: duration of respiratory support more than 21 days and duration of respiratory support less than 21 days. In 16 surviving infants, mean right ventricular early diastolic myocardial velocity on days 1 and 2 of life correlated with length of stay and duration of respiratory support (r = -0.75, p = 0.002 and r = -0.84, p = 0.0001, respectively). Mean pulmonary:systemic peak pressure ratio on days 1 and 2 of life did not significantly correlate with outcome measures. At receiver-operating characteristics analysis, averaged right ventricular early diastolic myocardial velocity on days 1 and 2 of life of less than 4.6 cm/s predicted duration of respiratory support more than 21 days, with 100% sensitivity and 88% specificity (area under the curve = 0.96, p = 0.002). Right ventricular early diastolic myocardial velocity was significantly lower in the first week of life in the duration of respiratory support more than 21-day group on days 1 and 2 and days 7 and 8. After surgery, right ventricular early diastolic myocardial velocity decreased in the duration of respiratory support more than 21-day group and was significantly lower at days 3 and 4 postoperative., Conclusions: Tissue Doppler imaging mean right ventricular early diastolic myocardial velocity on days 1 and 2 of life predicted early outcome in surviving infants with congenital diaphragmatic hernia. Right ventricular diastolic dysfunction is associated with disease severity in congenital diaphragmatic hernia. Right ventricular function may be optimized by delaying surgical repair in infants with severe congenital diaphragmatic hernia.

Decreased lung vascular growth and pulmonary hypertension contribute to poor outcomes in congenital diaphragmatic hernia (CDH). Mechanisms that impair angiogenesis in CDH are poorly understood. We hypothesize that decreased vessel growth in CDH is caused by pulmonary artery endothelial cell (PAEC) dysfunction with loss of a highly proliferative population of PAECs (HP-PAEC). PAECs were harvested from near-term fetal sheep that underwent surgical disruption of the diaphragm at 60-70 days gestational age. Highly proliferative potential was measured via single cell assay. PAEC function was assessed by assays of growth and tube formation and response to known proangiogenic stimuli, vascular endothelial growth factor (VEGF), and nitric oxide (NO). Western blot analysis was used to measure content of angiogenic proteins, and superoxide production was assessed. By single cell assay, the proportion of HP-PAEC with growth of >1,000 cells was markedly reduced in the CDH PAEC, from 29% (controls) to 1% (CDH) (P < 0.0001). Compared with controls, CDH PAEC growth and tube formation were decreased by 31% (P = 0.012) and 54% (P < 0.001), respectively. VEGF and NO treatments increased CDH PAEC growth and tube formation. VEGF and VEGF-R2 proteins were increased in CDH PAEC; however, eNOS and extracellular superoxide dismutase proteins were decreased by 29 and 88%, respectively. We conclude that surgically induced CDH in fetal sheep causes endothelial dysfunction and marked reduction of the HP-PAEC population. We speculate that this CDH PAEC phenotype contributes to impaired vascular growth in CDH.

Objective: The objective of this study was to longitudinally evaluate the neurodevelopmental (ND) outcome in congenital diaphragmatic hernia (CDH) survivors during the first 3 years of life., Study Design: The study cohort consists of 47 CDH survivors that were enrolled in our prospective, follow-up program between July 2004 and September 2010, and underwent serial ND evaluations during the first 3 years of life. ND outcomes were evaluated using the Bayley Scales of Infant Development (BSID)-II or BSID-III. Persistent ND impairment was defined as a score that remained 79 for the cognitive, language and psychomotor domains at the most recent follow-up visit compared with the first assessment., Result: The median age at first and last evaluation was 8 (range, 5 to 15) and 29 (range, 23 to 36) months, respectively. During the follow-up, ND scores improved to average in 17%, remained average in 60%, remained delayed in 10%, improved from severely delayed to mildly delayed in 2% and deteriorated from average to delayed in 15%. Motor scores improved to average in 26%, remained average in 55%, remained delayed in 8% and improved from severely delayed to mildly delayed in 11%. Intrathoracic liver position (P=0.004), preterm delivery (P=0.03), supplemental O2 requirement at day of life 30 (P=0.007), age at discharge (P=0.03), periventricular leukomalacia (PVL; P=0.004) and initial neuromuscular hypotonicity (P=0.01) were associated with persistent motor delays. No relationship was found between patient's characteristics and the risk of persistent cognitive and language delays., Conclusion: (1) The majority of children with CDH are functioning in the average range by early preschool age, (2) most children who had early delays showed improvement in their ND outcome, (3) children showing delays in all the three domains were the least likely to show improvement and (4) CDH severity appears to be predictive of persistent psychomotor delays.

Normal pulmonary vascular development in infancy requires maintenance of low pulmonary vascular resistance after birth, and is necessary for normal lung function and growth. The developing lung is subject to multiple genetic, pathological and/or environmental influences that can adversely affect lung adaptation, development, and growth, leading to pulmonary hypertension. New classifications of pulmonary hypertension are beginning to account for these diverse phenotypes, and or pulmonary hypertension in infants due to PPHN, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). The most effective pharmacotherapeutic strategies for infants with PPHN are directed at selective reduction of PVR, and take advantage of a rapidly advancing understanding of the altered signaling pathways in the remodeled vasculature., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

The increased survival rate reached in infants with congenital diaphragmatic hernia (CDH) has shown a concomitant increase in late morbidity. Many complications including pulmonary damage, cardiovascular disease, gastro-intestinal disease, failure to thrive, neurocognitive defects and musculoskeletal abnormalities have been described. Long-term pulmonary morbidity in CDH consists of obstructive and restrictive lung function impairments due to altered lung structure and prolonged ventilatory support. Long-term consequences of pulmonary hypertension are unknown. Gastro-esophageal reflux disease (GERD) is also an important contributor to overall morbidity. Failure to thrive may be caused by GERD, insufficient intake due to oral aversion and increased caloric requirements due to pulmonary morbidity. Neurological outcome is determined by an increased risk of perinatal and neonatal hypoxemia in the first days of life of CDH patients. Many studies have addressed the substantial impact of the health problems described above, on the overall well-being of CDH patients, but only a few studies focus on the health-related quality of life. Considering the scattered data indicating substantial morbidity in long-term survivors of CDH, follow-up studies that systematically assess long-term sequelae are needed. Based on such studies, a more focused approach for routine multidisciplinary follow-up programs could be established. It is the goal of the French Collaborative Network to promote exchange of knowledge, future research and development of treatment protocols., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Objective: To evaluate the effect of early fetoscopic tracheal occlusion (FETO) (22-24 weeks' gestation) on pulmonary response and neonatal survival in cases of extremely severe isolated congenital diaphragmatic hernia (CDH)., Methods: This was a multicenter study involving fetuses with extremely severe CDH (lung-to-head ratio < 0.70, liver herniation into the thoracic cavity and no other detectable anomalies). Between August 2010 and December 2011, eight fetuses underwent early FETO. Data were compared with nine fetuses that underwent standard FETO and 10 without fetoscopic procedure from January 2006 to July 2010. FETO was performed under maternal epidural anesthesia, supplemented with fetal intramuscular anesthesia. Fetal lung size and vascularity were evaluated by ultrasound before and every 2 weeks after FETO. Postnatal therapy was equivalent for both treated fetuses and controls. Primary outcome was infant survival to 180 days and secondary outcome was fetal pulmonary response., Results: Maternal and fetal demographic characteristics and obstetric complications were similar in the three groups (P > 0.05). Infant survival rate was significantly higher in the early FETO group (62.5%) compared with the standard group (11.1%) and with controls (0%) (P < 0.01). Early FETO resulted in a significant improvement in fetal lung size and pulmonary vascularity when compared with standard FETO (P < 0.01)., Conclusions: Early FETO may improve infant survival by further increases of lung size and pulmonary vascularity in cases with extremely severe pulmonary hypoplasia in isolated CDH. This study supports formal testing of the hypothesis with a randomized controlled trial., (Copyright © 2013 ISUOG. Published by John Wiley & Sons, Ltd.)

Purpose of Review: This review summarizes the utility and efficacy of different imaging modalities in the diagnosis of diaphragmatic dysfunction., Recent Findings: Dynamic MRI of the diaphragm has been recently described in the literature as a tool allowing more detailed study of diaphragmatic dysfunction., Summary: The diaphragm is the primary muscle of ventilation. Diaphragmatic dysfunction can be partial or complete, unilateral or bilateral. The diagnosis is difficult to establish at certain times due to diversity of presentations and severity of symptoms. There are several causes of diaphragmatic dysfunction, which adds to the complexity of diagnostic workup. In this review, the basic anatomy and function of the diaphragm and the different pathologic processes that may affect its function will be presented. These processes may originate in the brain, spinal cord, phrenic nerve or the diaphragm itself. Furthermore, this article will review the utility and efficacy of different diagnostic modalities in the diagnosis of diaphragmatic dysfunction. Most of these imaging tools have been well known for several years, including plain chest radiographs, fluoroscopy and ultrasound. An emerging mode is magnetic resonance dynamic imaging, which is another potentially effective way of functional diaphragmatic imaging that is still not part of routine clinical practice.

Objectives: To investigate neonatal morbidity in fetuses with severe congenital diaphragmatic hernia (CDH) treated with fetoscopic endoluminal tracheal occlusion (FETO) and compare it with historical controls with less severe forms of CDH that were managed expectantly., Methods: This was a prospective, multicenter study on neonatal outcomes and prenatal predictors in 90 FETO survivors (78 left-sided, 12 right) and 41 controls from the antenatal CDH registry with either severe or moderate hypoplasia who were managed expectantly. We also investigated early neonatal morbidity indicators, including the need for patch repair, duration of mechanical ventilation and supplemental oxygen, age at full enteral feeding and incidence of pulmonary hypertension., Results: Gestational age at delivery was predictive of duration of assisted ventilation (P = 0.046), days on supplemental oxygen (P = 0.019) and age at full enteral feeding (P = 0.020). When delivery took place after 34 weeks' gestation, neonatal morbidity of FETO cases was comparable with that of expectantly managed cases with moderate hypoplasia., Conclusions: Fetal intervention for severe CDH is associated with neonatal morbidity that is comparable with that of an expectantly managed group with less severe disease., (Copyright © 2013 ISUOG. Published by John Wiley & Sons, Ltd.)

Introduction: Functional residual capacity (FRC) and lung clearance index (LCI) are sensitive parameters for early detection of airway disease in infancy. The closed helium dilution method has been applied to assess lung volume and ventilation inhomogeneity (VI) in spontaneously breathing infants., Aims: The aims of this study were as follows: (1) to assess applicability of the helium gas dilution technique in mechanically ventilated infants with high-risk congenital diaphragmatic hernia (CDH) and to evaluate changes in breathing patterns, lung volume, and VI during the first days of life before and after surgery, and (2) to analyze the possible correlation between changes in lung volume, cerebral hemodynamics, and oxygenation before and after surgical correction of CDH through near-infrared spectroscopy (NIRS) monitoring., Methods: Lung function tests were performed by multibreath washout traces with an ultrasonic flowmeter and helium gas dilution technique. For all babies, three acceptable FRC and LCI measurements were collected for each test (mean and SD of three measurements were calculated) before surgery (T0), 24 h after surgery (T1) during mechanical ventilation, and within 24 h after extubation in spontaneous breathing (T2). Cerebral and splanchnic hemodynamics were continuously monitored by NIRS during mechanical ventilation to evaluate relationships between changes in lung volume and capillary-venous oxyhemoglobin saturation in tissues. Fraction of inspired oxygen delivered was adjusted to keep oxygen saturation between 90% and 95%., Results: Thirteen CDH infants were studied; median GA = 38 weeks (range 35-41) and median BW = 3000 g (range 1850-3670). FRC and LCI significantly improved after extubation when compared with pre-surgical values. No differences were found in tidal volume (Vt) and NIRS monitoring before and after surgery and after extubation. Neither LCI nor FRC was correlated with NIRS values., Conclusions: Helium gas dilution technique is an applicable and reliable technique to measure lung volumes and ventilation inhomogeneity also in ventilated infants. NIRS is a non-invasive technique to monitor tissue oxygenation during surgery and mechanical ventilation. In CDH newborns these preliminary data show an improvement in both FRC and LCI after extubation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The development of new therapeutics has led to progress in the early management of congenital diaphragmatic hernia (CDH) in pediatric intensive care units (PICU). Little is known about the impact on the quality of life (QoL) of children and their family. The aim of this study was to assess the impact of CDH treated according to the most recent concepts and methods outlined above on child survivors' QoL and their parents' QoL., Patients and Methods: This study incorporated a cross-sectional design performed in two PICU (Marseille, France). Families of CDH survivors born between 1999 and 2008 were eligible. The following data were recorded: socio-demographics, antenatal history and delivery, initial hospitalization history. Self-reported data were collected by mail, including current clinical problems of the children (13-symptom list), children's QoL (Kidscreen-27 questionnaire), and parents' QoL (Short-Form 36 questionnaire). Children's QoL score was compared with controls and QoL of survivors of childhood leukemia. Parent's QoL was compared with controls. Non-parametric statistics were employed., Results: Forty-two families agreed to participate and questionnaires were completed by 32 of them. Twenty-one children had a current clinical problems related to CDH. All the QoL scores of CHD survivors were significantly lower compared with controls. The physical well-being dimension was significantly higher for CHD survivors compared with survivors of childhood leukemia. Gastro-esophageal reflux at discharge, antenatal diagnosis, length of stay in the PICU, and neuropsychological and respiratory issues significantly impacted QoL scores of children. The parents of CHD survivors had significantly poorer score in emotional role dimension compared with controls., Conclusion: The impact of CDH on QoL seems to be important and must be understood by clinicians who treat these children and their parents.

The aims of this study were to investigate whether early arterial blood gas analysis (ABGA) could define the severity of disease in infants with congenital diaphragmatic hernia (CDH). We conducted a retrospective study over a 21-yr period of infants diagnosed with CDH. Outcomes were defined as death before discharge, and extracorporeal membrane oxygenation requirements (ECMO) or death. A total 114 infants were included in this study. We investigated whether simplified prediction formula [PO2-PCO2] values at 0, 4, 8, and 12 hr after birth were associated with mortality, and ECMO or death. The area under curve (AUC) of receiver operating characteristic curve was used to determine the optimum ABGA values for predicting outcomes. The value of [PO2-PCO2] at birth was the best predictor of mortality (AUC 0.803, P < 0.001) and at 4 hr after birth was the most reliable predictor of ECMO or death (AUC 0.777, P < 0.001). The value of [PO2-PCO2] from ABGA early period after birth can reliably predict outcomes in infants with CDH.

Purpose: Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypertension which is often difficult to manage and a significant cause of morbidity and mortality. Our aim was to study the pulmonary artery reactivity in an animal model of CDH., Methods: To investigate the reactivity of the aorta and left pulmonary artery in a rabbit model of CDH, we studied the in vitro responses to the α1-adrenoceptor agonist phenylephrine (PE) and to both the muscarinic receptor agonist (ACh) and the nitric oxide (NO) donor sodium nitroprusside (SNP). Rabbits underwent surgery at 25 days of gestation. CDH was created in one fetus per horn (n = 8). Remaining fetuses were considered controls (n = 18). At term (30 days), the lung, left pulmonary artery, and aorta were dissected. In a separate group, endothelium was mechanically removed., Results: There were no differences in the contractile and relaxing responses of aorta in all groups. In left pulmonary artery, PE-induced contractions were significantly greater (p < 0.05) in CDH when compared with control group. The increased responsiveness to PE in CDH group was similar to that found in pulmonary artery without endothelium. The ACh-induced pulmonary artery relaxation was markedly reduced in CDH when compared with control group (p < 0.05), whereas no differences were found for SNP., Conclusion: Our results show increased contractility and impairment in endothelium-dependent relaxation of pulmonary artery in CDH, mimicking an endothelial dysfunction, with preserved response to endothelium-independent mechanism.

We report a neonate with left congenital diaphragmatic hernia and severe left ventricular dysfunction, in whom the blood flow in the transverse arch and its branches was supported in a retrograde fashion by patent ductus arteriosus. There was only minimal antegrade flow across the aortic valve and hemodynamic physiology resembled critical aortic stenosis, necessitating the immediate use of prostaglandin E1 infusion to maintain the patent ductus arteriosus., (© 2012 Wiley Periodicals, Inc.)

Congenital diaphragmatic hernia (CDH) is a common life-threatening birth defect. Recessive mutations in the FRAS1-related extracellular matrix 1 (FREM1) gene have been shown to cause bifid nose with or without anorectal and renal anomalies (BNAR) syndrome and Manitoba oculotrichoanal (MOTA) syndrome, but have not been previously implicated in the development of CDH. We have identified a female child with an isolated left-sided posterolateral CDH covered by a membranous sac who had no features suggestive of BNAR or MOTA syndromes. This child carries a maternally-inherited ~86 kb FREM1 deletion that affects the expression of FREM1's full-length transcripts and a paternally-inherited splice site mutation that causes activation of a cryptic splice site, leading to a shift in the reading frame and premature termination of all forms of the FREM1 protein. This suggests that recessive FREM1 mutations can cause isolated CDH in humans. Further evidence for the role of FREM1 in the development of CDH comes from an N-ethyl-N-nitrosourea -derived mouse strain, eyes2, which has a homozygous truncating mutation in Frem1. Frem1(eyes2) mice have eye defects, renal agenesis and develop retrosternal diaphragmatic hernias which are covered by a membranous sac. We confirmed that Frem1 is expressed in the anterior portion of the developing diaphragm and found that Frem1(eyes2) embryos had decreased levels of cell proliferation in their developing diaphragms when compared to wild-type embryos. We conclude that FREM1 plays a critical role in the development of the diaphragm and that FREM1 deficiency can cause CDH in both humans and mice.

Spondylocostal dysostosis (SCDO) is a genetic disorder characterized by severe malformation of the axial skeleton. Mesp2 encodes a basic helix-loop-helix type transcription factor that is required for somite formation. Its human homologue, Mesp2, is a gene affected in patients with SCDO and a related vertebral disorder, spondylothoracic dysostosis (STDO). This work investigated how the loss of Mesp2 affects axial skeleton development and causes the clinical features of SCDO and STDO. We first confirmed, by three-dimensional computed tomography scanning, that Mesp2-null mice exhibited mineralized tissue patterning resembling the radiological features of SCDO and STDO. Histological observations and in situ hybridization probing for extracellular matrix molecules demonstrated that the developing vertebral bodies in Mesp2-null mice were extensively fused with rare insertions of intervertebral tissue. Unexpectedly, the intervertebral tissues were mostly fused longitudinally in the vertebral column, instead of exhibiting extended formation, as was expected based on the caudalized properties of Mesp2-null somite derivatives. Furthermore, the differentiation of vertebral body chondrocytes in Mesp2-null mice was spatially disordered and largely delayed, with an increased cell proliferation rate. The quantitative three-dimensional immunofluorescence image analyses of phospho-Smad2 and -Smad1/5/8 revealed that these chondrogenic phenotypes were associated with spatially disordered inputs of TGF-β and BMP signaling in the Mesp2-null chondrocytes, and also demonstrated an amorphous arrangement of cells with distinct properties. Furthermore, a significant delay in ossification in Mesp2-null vertebrae was observed by peripheral quantitative computed tomography. The current observations of the spatiotemporal disorder of vertebral organogenesis in the Mesp2-null mice provide further insight into the pathogenesis of SCDO and STDO, and the physiological development of the axial skeleton., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Survival rates of patients with congenital diaphragmatic hernia (CDH) have improved to up to 80%. Little is known about long-term consequences of the disease and its treatment. We evaluated lung function and respiratory symptoms longitudinally in a previously studied cohort of CDH patients and age-matched non-CDH patients who underwent similar neonatal intensive care treatment., Study Design: We tested 27 young adults [mean (SD) age: 26.8 years (2.9)] with CDH and 30 non-CDH patients. Dynamic and static lung volumes, midexpiratory flows, and diffusion capacity were expressed as mean (SD) standard deviation scores. Prevalence of respiratory symptoms was evaluated with the European Community Respiratory Health Survey., Results: All data are expressed as mean (SD). FEF(25-75) in CDH patients had slightly deteriorated since childhood (CDH: -0.7 (1.4) vs. -1.6 (1.5), P < 0.001; non-CDH patients: 0.2 (1.4) vs. -0.3 (1.6), P = 0.038, ns). Diffusion capacity decreased in both groups (CDH: DL(CO) c 0.2 (1.1) vs. -1.5 (1.1), P <0.001; non-CDH: DL(CO) c 0.1 (0.4) vs. -1.1 (1.1), P < 0.001). Lung volumes were normal in both groups. The prevalence of asthma was higher than in the normal population (27.6% in patients and 30% in controls, P < 0.001)., Conclusions: Airflow obstruction and diffusion capacity deteriorated mildly from childhood into adulthood in survivors of CDH. The improved survival of patients with more severe forms of diaphragmatic hernia calls for long-term follow-up of lung function., (Copyright © 2012 Wiley Periodicals, Inc.)

The authors report a rare case of 17-year-old lady with late presentation of congenital diaphragmatic hernia. She presented with vague abdominal pain and was thought to have urinary tract infection, ruptured ovarian cyst, and appendicitis by different medical teams in the first few days. She eventually underwent a diagnostic laparoscopy with no significant findings. In the early postoperative recovery period, she suffered from severe cardiorespiratory distress and a large intestinal left diaphragmatic hernia was diagnosed subsequently. At further operation a strangulated loop of large bowel herniating through a left antero-lateral congenital diaphragmatic hernia was discovered, which was reduced and repaired with a prolene mesh through thoracotomy. She made an excellent recovery and was discharged a few days after the operation. The authors postulate a mechanism of positive pressure from laparoscopic surgery causing herniation of large bowel through a pre-existing diaphragmatic defect. This case highlights the diagnostic challenge of this disease due to its diverse clinical presentation, the importance of prompt diagnosis and intervention.

122 patients with different diseases of the diaphragm were operated on during 1963-2011 yy. The majority of patients - 76 (62.3%) - had hernias of the weak phrenic zones. 14 (11.5%) and 17 (14.0%) patients had posttraumatic hernia and phrenic relaxation, respectively. The majority of patients had no complaints and the disease was diagnosed on the X-ray examination. Rarely, the compression syndrome, caused by the translocation of the bowel into the thoracic cavity, was registered. That clinically emerged as short breath, heaviness sensation and cardiac rhythm disorders. The worked out reconstructive operations allow to cure such patients with minimal risk.

Distal 15q25.2 microdeletions have recently been reported as a copy number variation (CNV) locus for neurodevelopmental and neuropsychiatric disorders with variable outcome. In addition, more proximal microdeletions of 15q25.2 have been described as a susceptibility locus for cognitive deficits, congenital diaphragmatic hernia (CDH), and Diamond-Blackfan anaemia (DBA). We describe two patients with 15q25.2 deletion, one with the more distal deletion and the other with a deletion overlapping both the distal and proximal 15q25.2 deletions and compare them to the 18 so far reported patients with 15q25.2 deletions. We provide a characterization of the 15q25.2 microdeletions and contribute to the genotype-phenotype delineation for these two novel microdeletion syndromes., (Copyright © 2012 Wiley Periodicals, Inc.)

Noninvasive blood flow measurements based on Doppler ultrasound studies are the main clinical tool for studying the cardiovascular status of fetuses at risk for circulatory compromise. Usually, qualitative analysis of peripheral arteries and in particular clinical situations such as severe growth restriction or volume overload also of venous vessels close to the heart or of flow patterns in the heart is being used to gauge the level of compensation in a fetus. However, quantitative assessment of the driving force of the fetal circulation, the cardiac output remains an elusive goal in fetal medicine. This article reviews the methods for direct and indirect assessment of cardiac function and explains new clinical applications. Part 1 of this review describes the concept of cardiac function and cardiac output and the techniques that have been used to quantify output. Part 2 summarizes the use of arterial and venous Doppler studies in the fetus and gives a detailed description of indirect measurements of cardiac function (like indices derived from the duration of segments of the cardiac cycle) with current examples of their application., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Patients with congenital diaphragmatic hernia (CDH) may have abnormal lung development, which may cause detrimental effects on right ventricular (RV) function. This study aimed to determine if there are persistent echocardiographic differences in RV function in patients with CDH years after repair versus control patients., Methods: Patients who underwent repair for CDH were recruited. RV function was evaluated by strain analysis and tissue Doppler imaging (TDI). Wilcoxon's rank-sum test was used for analysis., Results: Seven CDH patients and 16 control patients were studied. There was no difference in age between the CDH and control groups (6.2±1.7 years vs. 5.7±1.7 years). TDI demonstrated significantly lower values in the RV early diastolic wave (12.8±1.5 cm/s vs. 16.1±3.1 cm/s) and RV systolic wave (10.2± 0.8cm/s vs. 13.4±1.3 cm/s) when comparing the CDH group and the control group. Interventricular apical septal strain was signifi cantly lower in the CDH group than in the control group (-20.1±4.6% vs. -25.4±4.1%). There was a trend towards lower strain values in the RV mid-lateral segment in the CDH group (-30.8±9.9% versus -39.7±6.0%, P=0.06) and a lower global RV strain (-27.8±3.0% vs. -31.1±3.1%, P=0.06)., Conclusions: Patients who underwent CDH repair continue to have differences in RV function years after repair. Follow-up is needed to determine how these differences impact cardiac function in adult survivors of CDH.

Infants with congenital diaphragmatic hernia (CDH) or anterior wall defects (AWD) can suffer abnormal antenatal lung growth, the risk, however, may be greater for CDH infants. The objectives of this study were to test the hypothesis that following surgical correction, CDH infants would have worse lung function at follow-up than AWD infants and to determine whether fetal lung volume (FLV) results correlated with the lung function results at follow-up. Thirteen infants with CDH and 13 infants with AWD had lung function measurements at a median age of 11 (range 6-24) months; 17 of the infants had had their FLV assessed. Lung function was assessed by plethysmographic measurement of lung volume (FRCpleth) and airway resistance (Raw). In addition, functional residual capacity was assessed by a helium gas dilution technique (FRCHe); tidal breathing parameters (T(PTEF) :Te) and compliance and resistance of the respiratory system (Crs and Rrs, respectively) were also determined. FLV was assessed using three-dimensional (3D) ultrasound and virtual organ computer aided analysis. The CDH compared to the AWD infants had a higher median FRCpleth (41 ml/kg vs. 37 ml/kg, P = 0.043) and a lower median Crs (1.45 ml/cm H(2) O/kg vs. 2.78 ml/cm H(2) O/kg, P = 0.041). FRCpleth results correlated significantly with FLV results (r = 0.721, P < 0.001). In conclusion, infants with CDH had significantly different lung function at follow-up than AWD infants. Our findings suggest FLV results may predict lung function abnormalities at follow-up in infants with surgically correctable anomalies., (Copyright © 2012 Wiley Periodicals, Inc.)

Congenital diaphragmatic hernia (CDH) is a congenital anomaly associated with an increased mortality and morbidity. In this article, we review the currently known etiological and pathogenic factors in CDH., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

The majority of what is known in the recent literature regarding human milk studies in the neonatal intensive care setting is specific to term and/or preterm infants (including very-low-birth-weight preterm infants). However, there is a lack of human milk and breastfeeding literature concerning infants with congenital anomalies, specifically infants diagnosed with congenital diaphragmatic hernia (CDH). By applying human milk research conducted among other populations of infants, this article highlights how human milk may have a significant impact on infants with CDH. Recent human milk studies are reviewed and then applied to the CDH population in regard to respiratory and gastrointestinal morbidities, as well as infection and length of stay. In addition, clinical implications of these relationships are discussed and suggestions for future research are presented.

Objective: Evaluation of lung function parameters and additional use of prostaglandin E1 (PGE1) for the stabilisation of cardiopulmonary function in patients with congenital diaphragmatic hernia (CDH) and pulmonary hypertension (PHT)., Design: Observational study., Patients: Between 2007 and 2009 8 patients with CDH have been treated in our pediatric intensive care unit (gestational age 34 + 0 - 40 + 4 weeks, birth weight 2 160-3 840 g). All patients required respiratory support. Gentle mechanical ventilation adapted to the degree of pulmonary hypoplasia based on serially measurements of lung function parameters to find appropriate ventilator settings has been performed., Main Results: Functional residual capacity (FRC) and compliance of the respiratory system in all patients were markedly reduced. A FRC between 9.3-10.6 ml/kg and compliance between 1.1-1.8 ml/kPa/kg indicated pronounced hypoplasia of the lungs. Doppler flow patterns through the arterial duct were classified into left-to-right, right-to-left and bidirectional shunting and correlated to the degree of PHT. The additional use of PGE1 to reopen the arterial duct and to stabilize right ventricular function led to an amelioration of severe PHT and preoperative stabilisation in 2 newborns with pronounced pulmonary hypoplasia. All patients underwent successful surgery, and did not show any complications after 2 years follow-up., Conclusion: Measurements of lung function parameters and adaptation of mechanical ventilation to the degree of pulmonary hypoplasia and additional therapy with PGE1 may help to improve the outcome in CDH patients., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Infants and children with repaired congenital diaphragmatic hernia (CDH) often continue to show delayed growth and development that may be, in part, secondary to unrecognized persistence of increased pulmonary vascular resistance (PVR)., Methods: Data were reviewed from all patients ages 6-36 mo with repaired CDH who underwent cardiac catheterization from 2007 to 2010 and were compared to data from a control population of patients undergoing percutaneous closure of a patent ductus arteriosus (PDA). Indexed pulmonary blood flow (Qp), mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), and PVR were examined., Results: Data from 8 CDH patients and 10 control patients were examined. The mPAP (22.5 ± 3.33 vs. 18.2 ± 4.13 mm Hg) and PVR (3.66 ± 0.79 vs. 1.22 ± 0.4 iwU (indexed Wood's units)) were both significantly elevated in the CDH population, whereas the Qp (4.08 ± 1.43 vs. 6.82 ± 1.46 l/min/m(2)) was significantly lower in this population. There was no significant difference in pulmonary capillary wedge pressure (PCWP). Less than half of the CDH patients had signs of pulmonary hypertension (PH) on echocardiogram., Discussion: Our data suggest that children who are ages 6-36 mo with repaired CDH have significantly increased PVR compared with controls and early consideration of cardiac catheterization may be warranted.

The pathophysiology of congenital diaphragmatic hernia (CDH) is constituted by pulmonary hypoplasia and pulmonary hypertension (PH). We previously reported successful treatment with imatinib of a patient with CDH. This study examines the effect of antenatal imatinib administration on the pulmonary vasculature in a rat model of CDH. Pregnant rats were given nitrofen to induce CDH. Controls were given olive oil. Half of the CDH fetuses and half of the controls were treated with imatinib antenatally E17-E21, rendering four groups: Control, Control+Imatinib, CDH, and CDH+Imatinib. Lung sections were obtained for morphometry and immunohistochemistry, and protein was purified for Western blot. Effects of nitrofen and imatinib on Ki-67, caspase-3, PDGF-B, and PDGF receptors were analyzed. Imatinib significantly reduced medial wall thickness in pulmonary arteries of rats with CDH. It also normalized lumen area and reduced the proportion of fully muscularized arteries. Imatinib also caused medial thinning in the control group. Cell proliferation was increased in CDH, and this proliferation was significantly reduced by imatinib. PDGF-B and PDGFR-β were upregulated in CDH, and imatinib treatment resulted in a downregulation. PDGFR-α remained unchanged in CDH but was significantly downregulated by imatinib. Antenatal imatinib treatment reduces development of medial wall thickness and restores lumen area in pulmonary arteries in nitrofen-induced CDH. The mechanism is reduced cell proliferation. Imatinib is an interesting candidate for antenatal therapy for PH in CDH, but potential side effects need to be investigated and more specific targeting of PDGF signaling is needed.

Fetal echocardiography was initially used to detect structural anomalies but has more recently also been proposed to assess fetal cardiac function. This review summarizes technical issues and limitations in fetal cardiac function evaluation, as well as its potential research and clinical applications. Functional echocardiography has been demonstrated to select high-risk populations and to be associated with outcome in several fetal conditions including intrauterine growth restriction, twin-to-twin transfusion syndrome, maternal diabetes, and congenital diaphragmatic hernia. Fetal heart evaluation is challenging due to the smallness and high heart rate of the fetus and restricted access to the fetus far from the transducer. Due to these limitations and differences in cardiac function which are related to fetal maturation, cardiovascular parameters should be validated in the fetus and used with caution. Despite these precautions, in expert hands and with appropriate ultrasound equipment, evaluation of cardiac function is feasible in most fetuses. Functional fetal echocardiography is a promising tool that may soon be incorporated into clinical practice. Research is warranted to further refine the contribution of fetal cardiac assessment to the diagnosis, monitoring, or prediction of outcomes in various fetal conditions., (Copyright © 2012 S. Karger AG, Basel.)

Objective: Severe pulmonary hypoplasia and pulmonary arterial hypertension are associated with reduced survival in congenital diaphragmatic hernia (CDH). We aimed to determine whether fetal endoscopic tracheal occlusion (FETO) improves survival in cases of severe isolated CDH., Methods: Between May 2008 and July 2010, patients whose fetuses had severe isolated CDH (lung-to-head ratio < 1.0, liver herniation into the thoracic cavity and no other detectable anomalies) were assigned randomly to FETO or to no fetal intervention (controls). FETO was performed under maternal epidural anesthesia supplemented with fetal intramuscular anesthesia. Tracheal balloon placement was achieved with ultrasound guidance and fetoscopy between 26 and 30 weeks of gestation. All cases that underwent FETO were delivered by the EXIT procedure. Postnatal therapy was the same for both treated fetuses and controls. The primary outcome was survival to 6 months of age. Other maternal and neonatal outcomes were also evaluated., Results: Twenty patients were enrolled randomly to FETO and 21 patients to standard postnatal management. The mean gestational age at randomization was similar in both groups (P = 0.83). Delivery occurred at 35.6 ± 2.4 weeks in the FETO group and at 37.4 ± 1.9 weeks in the controls (P < 0.01). In the intention-to-treat analysis, 10/20 (50.0%) infants in the FETO group survived, while 1/21 (4.8%) controls survived (relative risk (RR), 10.5 (95% CI, 1.5-74.7), P < 0.01). In the received-treatment analysis, 10/19 (52.6%) infants in the FETO group and 1/19 (5.3%) controls survived (RR, 10.0 (95% CI, 1.4-70.6) P < 0.01)., Conclusion: FETO improves neonatal survival in cases with isolated severe CDH., (Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.)

Retrograde flow in the aortic arch identifies inadequate cardiac output in neonates with congenital heart disease. We present a left congenital diaphragmatic hernia (CDH) infant with retrograde flow in the arch that normalized after CDH repair. We hypothesize transient inadequacy of the left heart; prostaglandins might play a pivotal role.

Background/purpose: Advances in management of patients with congenital diaphragmatic hernia (CDH) have improved mortality rates but with a risk of increased pulmonary morbidity. The prognosis for CDH survivors remains difficult to predict owing to the lack of adequate methods. We used single photon emission computed tomography (SPECT) to measure the regional distribution of ventilation and perfusion in CDH infants to quantify the degree of lung function impairment and relate it to neonatal clinical disease severity., Methods: Single photon emission computed tomography was performed in 12 CDH infants at the mean age of six months. Ventilation and perfusion were traced with 5 MBq Technegas and technetium-labelled albumin macro-aggregates, respectively. Neonatal clinical data collected during the patient's stay in the pediatric intensive care unit was correlated with the SPECT data., Results: Single photon emission computed tomography revealed varying degrees of ventilation-perfusion abnormalities which correlated with the presence of pulmonary artery hypertension, days on ventilator and days on extracorporeal membrane oxygenation., Conclusions: The grade of clinical disease severity in infants following CDH repair is closely related to the ventilation-perfusion abnormality as seen using SPECT. The persistence of pulmonary artery hypertension into the postoperative neonatal period appears to be an important pathophysiological factor related to ventilation-perfusion abnormalities. Single photon emission computed tomography provides valuable clinical information for patient follow-up., (Copyright © 2011. Published by Elsevier Inc.)

Aims: (i) To compare the ratio of right ventricular systolic to diastolic duration (SD/DD) in infants with congenital diaphragmatic hernia (CDH) and normal controls and (ii) to examine its association, if any, with outcomes in CDH., Methods:   Retrospective chart and echocardiographic review of consecutive neonates (<1 month old) with CDH and term controls without structural heart defects. Right ventricular SD/DD was calculated by a single reader., Results: Infants with CDH (n = 29) were comparable to controls (n = 27) in their mean (SD) age [2.2 (3.3) vs. 2 (4.0) days], birthweight [3 (0.67) vs. 3 (0.69) kg] and proportion of males (48.2% vs. 72.4%). The DD and SD/DD were significantly abnormal in the CDH group, compared to controls. Among infants with CDH, those who died (n = 15) and those who died or required ECMO (n = 17) had significantly shorter DD and higher SD/DD ratio. At a cut-off of 1.3, SD/DD ratio had a sensitivity of 92.8 (95% CI 64-99%) and specificity of 61.5 (32-85%) for prediction of mortality. Significant independent associations with mortality were observed with antenatal diagnosis (p = 0.003) and higher SD/DD ratio (p = 0.04)., Conclusion: The right ventricular SD/DD ratio is a sensitive objective prognostic marker in infants with CDH. Further studies incorporating SD/DD ratio as a guide to intervention are warranted., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Background: Gastroesophageal reflux (GER) is frequently observed in children treated for congenital diaphragmatic hernia (CDH) at birth, as well as esophageal dysmotility, that has been hypothesized to be caused by innervatory anomalies. The aim of this study is to evaluate GER and dysmotility in young patients with CDH using pH-multichannel intraluminal impedance., Methods: Thirty children (17 boys and 13 girls) who underwent repair for CDH between 2002 and 2007 with a median age of 5.2 years (range, 3-10 years) were included in the study. All patients were operated on with a subcostal laparotomy incision and had a left-sided diaphragmatic defect. The defect repair required an artificial patch (Goretex, Gore Medical, Flagstaff, AZ) in 8 patients (27%) because of its size. We described impedance reflux parameters and some specific motility parameters studied on 10 standardized swallows., Results: The incidence of GER was 86%. Reflux was mainly nonacidic, postprandial, and short-term and reached only the distal esophagus. Esophageal dysmotility was observed only in the distal esophagus., Conclusions: With the use of pH-multichannel intraluminal impedance, both GER and esophageal motility in patients with congenital malformations can be analyzed. In patients with CDH, impaired motility seems to involve only the distal esophagus. In this group, the specific pattern of reflux is probably caused by the involvement of gastroesophageal junction, without significant intrinsic innervation abnormalities as observed in patients with esophageal atresia., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The objective of this review was to provide a critical overview of our current understanding on the neurocognitive, neuromotor, and neurobehavioral development in congenital diaphragmatic hernia (CDH) patients, focusing on three interrelated clinical issues: (1) comprehensive outcome studies, (2) characterization of important predictors of adverse outcome, and (3) the pathophysiological mechanism contributing to neurodevelopmental disabilities in infants with CDH. Improved survival for CDH has led to an increasing focus on longer-term outcomes. Neurodevelopmental dysfunction has been recognized as the most common and potentially most disabling outcome of CDH and its treatment. While increased neuromotor dysfunction is a common problem during infancy, behavioral problems, hearing impairment and quality of life related issues are frequently found in older children and adolescence. Intelligence appears to be in the low normal range. Patient and disease specific predictors of adverse neurodevelopmental outcome have been defined. Imaging studies have revealed a high incidence of structural brain abnormalities. An improved understanding of the pathophysiological pathways and the neurodevelopmental consequences will allow earlier and possibly more targeted therapeutic interventions. Continuous assessment and follow-up as provided by an interdisciplinary team of medical, surgical and developmental specialists should become standard of care for all CDH children to identify and treat morbidities before additional disabilities evolve and to reduce adverse outcomes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)