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Objectives: In fetuses with isolated left-sided congenital diaphragmatic hernia (LCDH), prenatal detection of severe pulmonary hypoplasia is important, as fetal therapy can improve survival. Cases with mild or moderate lung hypoplasia still carry a considerable risk of mortality and morbidity, but there has been less interest in the accurate prediction of outcome in these cases. In this study of fetuses with mild or moderate isolated LCDH, we aimed to investigate: (1) the association between intrapulmonary artery (IPA) Doppler findings and mortality at discharge; (2) whether adding IPA Doppler findings improves the prediction of mortality based on lung size and liver herniation; and (3) the association between IPA Doppler findings and early neonatal morbidity., Methods: This was a retrospective study of all consecutive fetuses assessed at the BCNatal and UZ Leuven hospitals between 2008 and 2020 with a prenatal diagnosis of isolated, non-severe LCDH, defined as observed-to-expected lung-to-head ratio (o/e-LHR) > 25%, that were managed expectantly during pregnancy followed by standardized neonatal management. An additional inclusion criterion was the availability of IPA Doppler measurements. The primary outcome was the association between IPA Doppler findings and mortality at discharge. Other predictors included o/e-LHR, liver herniation and gestational age at birth. Secondary outcomes were the association between IPA Doppler findings and the presence of pulmonary hypertension (PHT), need for supplemental oxygen at discharge and need for extracorporeal membrane oxygenation. IPA pulsatility index (PI) values were converted into Z-scores. Logistic regression analysis was performed to investigate the associations between predictor variables and outcome, and the best model was chosen based on the Nagelkerke R 2 ., Results: Observations for 70 non-severe LCDH cases were available. Fifty-four (77%) fetuses survived until discharge. On logistic regression analysis, higher IPA-PI was associated with an increased risk of mortality (odds ratio (OR), 3.96 (95% CI, 1.62-9.70)), independently of o/e-LHR (OR, 0.87 (95% CI, 0.79-0.97)). An IPA-PI Z-score cut-off of 1.8 predicted mortality with a detection rate of 69% and specificity of 93%. Adding IPA-PI to o/e-LHR improved significantly the model's performance (Nagelkerke R 2 , 46% for o/e-LHR + IPA-PI vs 28% for o/e-LHR (P < 0.002)), with a detection rate of 81% at a 10% false-positive rate. IPA-PI was associated with PHT (OR, 2.20 (95% CI, 1.01-4.59)) and need for oxygen supplementation at discharge (OR, 1.90 (95% CI, 1.10-3.40)), independently of lung size., Conclusions: In fetuses with mild or moderate LCDH, IPA-PI was associated with mortality and morbidity, independently of lung size. A model combining o/e-LHR with IPA-PI identified up to four in five cases that eventually died, despite being considered to have non-severe pulmonary hypoplasia. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Hepatoblastoma (HBL) is the most frequently detected malignant tumor of the liver in childhood. HBLs detected antenatally or up to 3 months after birth are considered congenital HBLs. We report a five-day-old female infant in whom a hepatic mass was detected at 20 weeks' gestation. At birth (36 weeks), the hepatic mass measured 12x6 cm, and she had respiratory distress. Pulmonary hypertension (PHT) was detected on echocardiographic evaluation. Despite dual medical therapy, her PHT did not improve. Histologically, the biopsy demonstrated a mixed epithelial-mesenchymal HBL with predominance of fetal morphology in the epithelial component. Chemotherapy was initiated on postnatal day 15; however, the baby died of respiratory failure on postnatal day 23. Conclusion: HBL is an embryonal tumor which can develop early in the intrauterine period. Although the mechanism is not known, it may cause PHT which would affect the prognosis negatively., (© 2020 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Pulmonary hypertension is a complex and progressive condition that is either idiopathic or heritable, or associated with one or multiple health conditions, with or without congenital or acquired cardiovascular disease. Recent developments have tremendously increased the armamentarium of diagnostic and therapeutic approaches in children and young adults with pulmonary hypertension that is still associated with a high morbidity and mortality. These modalities include non-invasive imaging, pharmacotherapy, interventional and surgical procedures, and supportive measures. The optimal, tailored diagnostic and therapeutic strategies for pulmonary hypertension in the young are rapidly evolving but still face enormous challenges: Healthcare providers need to take the patient's age, development, disease state, and family concerns into account when initiating advanced diagnostics and treatment. Therefore, there is a need for guidance on core and advanced medical training in paediatric pulmonary hypertension. The Association for European Paediatric and Congenital Cardiology working group "pulmonary hypertension, heart failure and transplantation" has produced this document as an expert consensus statement; however, all recommendations must be considered and applied in the context of the local and national infrastructure and legal regulations.

Pulmonary hypertension with transposition of the great arteries is associated with significant morbidity and mortality. At the worst end of the spectrum are patients who undergo extracorporeal support perioperatively. We describe our experience with three patients who received preoperative extracorporeal support and separated from cardiopulmonary bypass successfully on conventional postoperative care, with no significant deficits on follow-up.

Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving complicated intracellular networks concerned with the transduction of hypoxia-induced responses. Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. Hypoxia during gestation impacts both the mother and fetal development through interactions with an individual's genetic traits acquired over multiple generations by natural selection and changes in gene expression patterns by altering the epigenetic code. Changes in the epigenome determine "genomic plasticity," i.e., the ability of genes to be differentially expressed according to environmental cues. The genomic plasticity defined by epigenomic mechanisms including DNA methylation, histone modifications, and noncoding RNAs during development is the mechanistic substrate for phenotypic programming that determines physiological response and risk for healthy or deleterious outcomes. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue. The complex molecular and epigenetic interactions that may impact an individual's physiology and developmental programming of health and disease later in life are discussed.

Background: Arteriovenous (AV) fistulae is an extremely rare disease of vascular malformation that involves fistulae formation between the systemic and pulmonary AV systems., Case Representation: This case report describes a rare systemic-pulmonary AV fistulae of congenital origin, accompanied by pulmonary hypertension, as determined by aortic angiography and echocardiography., Conclusion: Characteristics, diagnosis, and therapeutic approaches of this rare abnormality are explored.

Background: Persistent pulmonary hypertension is a well-known disease of the newborn that in most cases responds well to treatment with nitric oxide and treatment of any underlying causes. Genetic causes of persistent pulmonary hypertension of the newborn are rare. The TWIST1 gene is involved in morphogenetics, and deletions are known to cause Saethre-Chotzen syndrome. Deletions of PHF14 have never been reported in neonates, but animal studies have shown a link between severe defects in lung development and deletions of this gene. There have not, to the best of our knowledge, been any publications of a link between the genes TWIST1 and PHF14 and persistent pulmonary hypertension of the newborn, making this a novel finding., Case Presentation: We describe a white male neonate born at term to non-consanguineous white parents; he presented with dysmorphic features and a therapy-refractory persistent pulmonary hypertension. Array-based comparative genomic hybridization revealed the presence of a 14.7 Mb interstitial deletion on chromosome 7, encompassing the genes TWIST1 and PHF14., Conclusions: The TWIST1 gene can explain our patient's dysmorphic features. His severe persistent pulmonary hypertension has, however, not been described before in conjunction with the TWIST1 gene, but could be explained by involvement of PHF14, consistent with findings in animal experiments showing lethal respiratory failure with depletion of PHF14. These findings are novel and of importance for the clinical management and diagnostic workup of neonates with severe persistent pulmonary hypertension of the newborn and dysmorphic features.

Failure of the normal circulatory adaptation to extrauterine life results in persistent pulmonary hypertension of the newborn (PPHN). Although this condition is most often secondary to parenchymal lung disease or lung hypoplasia, it may also be idiopathic. PPHN is characterized by elevated pulmonary vascular resistance with resultant right-to-left shunting of blood and hypoxemia. Although the preliminary diagnosis of PPHN is often based on differential cyanosis and labile hypoxemia, the diagnosis is confirmed by echocardiography. Management strategies include optimal lung recruitment and use of surfactant in patients with parenchymal lung disease, maintaining optimal oxygenation and stable blood pressures, avoidance of respiratory and metabolic acidosis and alkalosis, and pulmonary vasodilator therapy. Extracorporeal membrane oxygenation is considered when medical management fails. Although mortality associated with PPHN has decreased significantly with improvements in medical care, there remains the potential risk for neurodevelopmental disability which warrants close follow-up of affected infants after discharge., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Omphalocele is one of the most common abdominal wall defects. Many newborn infants born with omphalocele present with significant respiratory distress at birth, requiring mechanical ventilatory support, and have clinical evidence of pulmonary hypertension. Little information exists on the prevalence of and risk factors associated with pulmonary hypertension in this cohort of infants., Objectives: To describe the prevalence of and risk factors associated with pulmonary hypertension among infants with omphalocele., Methods: This is a multicenter retrospective chart review of demographic data and clinical characteristics of infants with omphalocele admitted to the neonatal intensive care units of Loma Linda University Children's Hospital and Children's Mercy Hospital between 1994 and 2011. Echocardiogram images were reviewed for pulmonary hypertension, and statistical analyses were performed to identify risk factors associated with the presence of pulmonary hypertension., Results: Pulmonary hypertension was diagnosed in 32/56 (57%) infants with omphalocele. Compared to infants without pulmonary hypertension, infants with pulmonary hypertension were more likely to have a liver-containing defect (16/32 [50%] vs. 5/24 [21%], p = 0.03), require intubation at birth (18/32 [56%] vs. 6/24 [17%], p = 0.03), and die during initial hospitalization (12/32 [38%] vs. 2/24 [8%], p = 0.01)., Conclusion: The majority of infants with omphalocele have evidence of pulmonary hypertension which is associated with increased mortality. Echocardiograms to screen for pulmonary hypertension should be obtained at ≥2 days of life in infants with omphalocele, especially in those with liver within the omphalocele sac and/or in those infants who require intubation at birth to screen for pulmonary hypertension., (© 2017 S. Karger AG, Basel.)

Objective: To better understand the impact of persistent pulmonary hypertension (PPHN) on brain oxygenation in term asphyxiated newborns treated with hypothermia., Methods: The regional cerebral oxygenation saturation (rSO2) measured by near-infrared spectroscopy was compared to pre/post-ductal oxygen saturation and mean arterial blood pressure in three term asphyxiated newborns with documented PPHN during their first 4 days of life while they were being treated with hypothermia., Results: The cerebral oxygen saturation remained relatively stable when oxygen saturation was more than 92% and when there was no difference between pre- and post-ductal oxygen saturations. Episodes of desaturations with a difference between pre- and post-ductal saturations, as well as episodes of hypotension, caused a significant decrease in rSO2 in these newborns., Conclusion: This case series demonstrates that PPHN has a profound impact on brain oxygenation in term asphyxiated newborns treated with hypothermia during the first days of life after birth. PPHN may represent an additional risk factor for brain injury in these newborns during the first days of life.

Two cases of Shone syndrome with severe mitral and aortic valve problems and pulmonary hypertension were referred for heart-lung transplantation. Severely elevated pulmonary vascular resistance (PVR) was confirmed as was severe periprosthetic mitral and aortic regurgitation. Based on the severity of the valve lesions in both patients, surgery was decided upon and undertaken. Both experienced early pulmonary hypertensive crises, one more than the other, that gradually subsided, followed by excellent recovery and reversal of pulmonary hypertension and PVR. These cases illustrate Braunwald's concept that pulmonary hypertension secondary to left-sided valve disease is reversible., (© The Author(s) 2015.)

Objectives: To investigate the relationship between foetal haemodynamics and postnatal clinical presentation in patients with transposition of the great arteries using phase-contrast cardiovascular magnetic resonance., Background: A severe and irreversible form of persistent pulmonary hypertension of the newborn occurs in up to 5% of patients with transposition and remains an important cause of morbidity and mortality in these infants. Restriction at the foramen ovale and ductus arteriosus has been identified as a risk factor for the development of pulmonary hypertension, and this can now be studied with magnetic resonance imaging using a new technique called metric optimised gating., Methods: Blood flow was measured in the major vessels of four foetuses with transposition with intact ventricular septum (gestational age range: 35-38 weeks) and compared with values from 12 normal foetuses (median gestational age: 37 weeks; range: 34-40 weeks)., Results: We found significantly reduced flows in the ductus arteriosus (p<0.01) and foramen ovale (p=0.03) and increased combined ventricular output (p=0.01), ascending aortic (p=0.001), descending aortic (p=0.03), umbilical vein (p=0.03), and aorto-pulmonary collateral (p<0.001) flows in foetuses with transposition compared with normals. The foetus with the lowest foramen ovale shunt and highest aorto-pulmonary collateral flow developed fatal pulmonary vascular disease., Conclusions: We found limited mixing between the systemic and pulmonary circulations in a small group of late-gestation foetuses with transposition. We propose that the resulting hypoxia of the pulmonary circulation could be the driver behind increased aorto-pulmonary collateral flow and contribute to the development of pulmonary vascular disease in some foetuses with transposition.

Transient hyperinsulinism can occur in neonates following exposure to perinatal stress, such as intrauterine growth restriction and birth asphyxia. However, little is known about its pathophysiology and clinical manifestations. We report three neonatal cases of transient severe hyperinsulinism complicated with cardiopulmonary problems, thrombocytopenia, and marked erythroblastosis at birth. All cases showed signs of placental insufficiency, indicating that chronic hypoxia and malnutrition during fetal development might be associated with characteristic clinical features after birth. Perinatal stress-associated hyperinsulinism can be regarded as a systemic syndrome characterized by cardiopulmonary and hematological problems due to fetal chronic hypoxia.

Lung hypoplasia and pulmonary hypertension are classical features of congenital diaphragmatic hernia (CDH) and represent the main determinants of survival. The mechanisms leading to pulmonary hypertension in this malformation are still poorly understood, but may combine altered vasoreactivity, pulmonary artery remodeling, and a hypoplastic pulmonary vascular bed. Efforts have been directed at correcting the "reversible" component of pulmonary hypertension of CDH. However, pulmonary hypertension in CDH is often refractory to pulmonary vasodilators. A new emerging pattern of late (months after birth) and chronic (months to years after birth) pulmonary hypertension are described in CDH survivors. The true incidence and implications for outcome and management need to be confirmed by follow-up studies from referral centers with high patient output. In order to develop more efficient strategies to treat pulmonary hypertension and improve survival in most severe cases, the ultimate therapeutic goal would be to promote lung and vascular growth., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Delaying surgery for infants with CDH until they achieve clinical stability is common practice. Stability, however, is inconsistently defined, and many infants fail to reach pre-established criteria. We sought to determine if infants undergoing surgery without meeting pre-established criteria could achieve meaningful survival., Methods: All infants in the CAPSNet database were analyzed (2005-2010). Patients undergoing operative repair were divided into two groups based on whether they met strict (FiO2<0.40, conventional ventilation, preductal saturation >92%, no inotropes or vasodilators), or lenient (FiO2 <0.60, conventional ventilation, preductal saturation >88%, no vasodilators) criteria. Univariate analyses were performed comparing characteristics of those who survived after surgery (N=273) with those who did not (N=21)., Results: 294 patients (85%) survived to surgery. Predictors of post-operative survival included prenatal liver position (p=0.003), preoperative oxygen requirements (p=0.008), preoperative inotropes (p<0.0001), and non-conventional ventilation (p=0.004). Infants meeting strict criteria had increased survival (99%; p<0.0001). Infants meeting lenient criteria constituted 70% of survivors. Nearly one-third of survivors met neither strict nor lenient criteria., Conclusions: Infants with CDH can achieve good survival even when criteria for pre-operative stability are not met. We suggest that all infants should be repaired even if lenient criteria for ventilatory, inotrope, or vasodilator requirements are not achieved., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Little is known about liveborn CDH patients who die without surgery. We audited a national CDH cohort to determine whether these patients were different from patients who received CDH repair., Methods: A national CDH database was analyzed (2005-2009). After excluding infants with severe physiologic instability and genetic/congenital malformations, a potential surgical candidate (PSC) subgroup was identified. PSCs were compared to the operative group (OG) and the operative non-survivor (ONS) subgroup. Standard statistical analyses were performed., Results: Of 275 liveborns, 35 (13%) died without surgery. The PSC subgroup (n=11) had a median survival of 10 days (range: 3-18). Ten of 11 PSC infants were treated in ECMO centers, with 4 receiving ECMO. No differences in BW, GA, and rates of minor malformation were observed between PSC and OG patients. While neonatal illness severity (SNAP-II) predicted overall mortality, SNAP-II scores were similar between PSC and ONS groups (34 vs. 29; p=0.431). Furthermore, greater than 80% of infants with SNAP-II scores between 30 and 39 survived in the OG cohort., Conclusion: Our analysis demonstrated that PSCs were similar to infants offered surgery based on illness severity and the presence of congenital malformations. We suggest that criteria for surgical ineligibility be developed to standardize the selection of surgical candidates., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Respiratory difficulty resulting from congenital chylothorax is usually relieved by postnatal thoracentesis, closed chest drainage, and oxygen therapy. However, early occurrence of congenital chylothorax or accumulation of a large amount of chylous fluid sometimes leads to pulmonary hypoplasia or persistent pulmonary hypertension of the newborn, which requires further customized mechanical ventilatory support. In these cases, conventional mechanical ventilation is primarily used during initial treatment and is later replaced by high-frequency ventilation, but the advantages of inhaled nitric oxide treatment have rarely been described. This case suggests the benefits of inhaled nitric oxide in patients with congenital chylothorax, even when mechanical ventilation cannot improve respiratory distress because of severe pulmonary hypertension of the newborn leading to right cardiac dysfunction and possibly cholestasis., (© 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.)

Background: Pulmonary hypoplasia resulting from oligohydramnios or anhydramnios can cause severe respiratory compromise in newborn patients. We report a case of recurrent oligohydramnios in a mother with an ErbB4 mutation and speculate that the effects on the placenta through decreased vascularization contributed to oligohdyramnios and subsequent pulmonary hypoplasia in the newborn., Case: The pregnant mother in this case had two subsequent term pregnancies complicated by severe oligohydramnios. Both pregnancies resulted in live born female neonates with pulmonary hypoplasia, pneumothoraces, and pulmonary hypertension. The mother and second newborn, who died, were found to have the ErbB4 mutation. Examination of the placenta with that pregnancy showed decreased vascularity., Conclusion: ErbB4 may have important effects on placental development and hydramnios that also may affect neonatal pulmonary hypoplasia.

A neonate with pulmonary interstitial glycogenosis, pulmonary hypertension, and hypertrophic cardiomyopathy is described. The fatal outcome for this patient contrasts with the reported favorable prognosis associated with isolated pulmonary interstitial glycogenosis. To the authors' knowledge, the association of pulmonary interstitial glycogenosis and hypertrophic cardiomyopathy has not been reported previously. The authors have broadened the phenotype of pulmonary interstitial glycogenosis and demonstrate the diagnostic value of lung biopsy in cases of unexplained neonatal pulmonary hypertension.

Noncompaction cardiomyopathy (NCCM) is a recently recognized form of cardiomyopathy with a variable clinical presentation. This report describes NCCM of a newborn presenting with hydrops fetalis and pulmonary hypertension. To date, this has not been described in the literature. As knowledge of this condition grows, the need to recognize NCCM becomes more important.

Objective: To explore the association between the presence of maternal heart disease and maternal, perinatal, and infant outcomes., Methods: We conducted a population-based retrospective cohort study using Washington State birth certificates linked with hospital discharge records of mothers noted to have maternal congenital heart disease, ischemic heart disease, heart failure, or pulmonary hypertension. Women who gave birth between 1987 and 2009 (n=2,171) were compared with a sample of mothers without these conditions (n=21,710). We described characteristics of pregnant women with heart disease over time. Logistic regression estimated the association between chronic maternal heart disease and small-for-gestational-age (SGA) neonates as well as perinatal, postneonatal, and maternal death., Results: The proportion of births to women with reported heart disease increased 224% between the 1987 and 1994 and 2002 and 2009 calendar periods. Chronic maternal heart disease was associated with increased risk of SGA (62 additional SGA newborns per 1,000 births, 95% confidence interval [CI] 46-78; P<.001), perinatal death (14 additional deaths per 1,000 births, 95% CI 8-20; P<.001), postneonatal death (5 additional deaths per 1,000 births, 95% CI 2-9; P<.001), and maternal death (5 additional deaths per 1,000 births, 95% CI 2-9; P<.001)., Conclusion: The presence of chronic maternal heart disease is associated with elevated risk for poor maternal, perinatal, and postneonatal outcomes.

Background: Idiopathic pulmonary arterial hypertension (IPAH) remains a progressive fatal disease. Palliative Potts shunt has been proposed in children displaying suprasystemic IPAH., Methods: A retrospective multicenter study was performed to evaluate Potts shunt in pediatric IPAH., Results: Between 2003 and 2010, 8 children with suprasystemic IPAH and in World Health Organization functional class IV despite medical pulmonary arterial hypertension therapy underwent Potts shunt. Age at IPAH diagnosis ranged from 4 to 180 months (median age, 64 months). Surgical procedure was performed in a mean delay of 41.9±54.3 months (range, 4 to 167 months; median delay, 20 months) after IPAH diagnosis. Mean size of the Potts shunt was 9.25±3.30 mm. Two patients, whose medical pulmonary arterial hypertension therapy had been interrupted just after surgery, died at postoperative days 11 and 13 of acute pulmonary hypertensive crisis. After a mean follow-up of 63.7±16.1 months, the 6 children who were discharged from the hospital were alive. Functional status improved markedly in the 6 survivors, with a World Health Organization functional class I (n=4) or II (n=2) at last follow-up, consistent with significant improvement of 6-minute-walk distance (302±95 m [51%±20% of theoretical values] versus 456±91 m [68%±10% of theoretical values]; p=0.038) and decrease of brain natriuretic peptide levels (608±109 pg/mL versus 76±45 pg/mL; p=0.035). No Potts shunt was found to be restrictive at last echocardiography., Conclusions: Palliative Potts shunt constitutes a new alternative to lung transplantation in severely ill children with suprasystemic IPAH, carrying a prolonged survival and persistent improvement in functional capacities., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Data of 18 patients who underwent surgical repair of non-obstructed supracardiac total anomalous pulmonary venous connection between January 2007 and March 2011 were reviewed. The vertical vein was left patent in all patients as an elective surgical strategy. There was no operative mortality in patients with or without preoperative pulmonary infection, but there were significant differences in postoperative airway pressures, ventilation time, intensive care unit and hospital stay between the 2 groups. None of the patients demonstrated any flow in the vertical vein over a 30-day follow-up period. One patient had a mild anastomotic stricture and pulmonary venous hypoplasia. Operative repair of supracardiac total anomalous pulmonary venous connection can be carried out successfully without ligation of the vertical vein, and this strategy possibly reduces early postoperative morbidity and mortality, with no adverse effects detected in the short to midterm follow-up.

We present a case of a neonate with VACTERL-like association, with the VACTERL association defined as the non-random association of vertebral, anal, cardiac, esophageal, renal/kidney, and limb defects, as manifested by a hemivertebra, imperforate anus, and digit anomalies, in rare association with duodenal atresia and right-sided diaphragmatic hernia. This constellation is previously undescribed and may offer insight into the pathogenesis of VACTERL and associated birth defects., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The characteristics of pulmonary arterial hypertension (PAH), including pathology, symptoms, diagnosis and treatment are reviewed in children and adults. The histopathology seen in adults is also observed in children, although children have more medial hypertrophy at presentation. Both populations have vascular and endothelial dysfunction. Several unique disease states are present in children, as lung growth abnormalities contribute to pulmonary hypertension. Although both children and adults present at diagnosis with elevations in pulmonary vascular resistance and pulmonary artery pressure, children have less heart failure. Dyspnoea on exertion is the most frequent symptom in children and adults with PAH, but heart failure with oedema occurs more frequently in adults. However, in idiopathic PAH, syncope is more common in children. Haemodynamic assessment remains the gold standard for diagnosis, but the definition of vasoreactivity in adults may not apply to young children. Targeted PAH therapies approved for adults are associated with clinically meaningful effects in paediatric observational studies; children now survive as long as adults with current treatment guidelines. In conclusion, there are more similarities than differences in the characteristics of PAH in children and adults, resulting in guidelines recommending similar diagnostic and therapeutic algorithms in children (based on expert opinion) and adults (evidence-based).

Fetal valproate syndrome (FVS) results from prenatal exposure to valproic acid. It is characterized by a distinctive facial appearance, a cluster of minor and major anomalies and central nervous system dysfunction. We describe a 2-month-old male infant with the typical dysmorphic features characteristic of FVS. He had a persistent left superior vena cava draining into a dilated coronary sinus and mild pulmonary hypertension. There was a history of maternal intake of sodium valproate during pregnancy.

When the normal cardiopulmonary transition fails to occur, the result is persistent pulmonary hypertension of the newborn. Severe persistent pulmonary hypertension of the newborn is estimated to occur in 2 per 1000 live-born term infants, and some degree of pulmonary hypertension complicates the course of >10% of all neonates with respiratory failure. This review article discusses the vascular abnormalities that are associated with neonatal pulmonary hypertension, including recognition of its role in severe bronchopulmonary dysplasia in preterm infants. A systematic review of the evidence for common therapies including inhaled nitric oxide, high-frequency ventilation, surfactant, and extracorporeal life support is included. Finally, this field is rapidly evolving, and the rationale for promising new treatment approaches is reviewed, including inhibition of phosphodiesterases and scavengers of reactive oxygen species.

Congenital diaphragmatic hernia (CDH) is a congenital anomaly that presents with a broad spectrum of severity dependent upon components of pulmonary hypoplasia and pulmonary hypertension. While advances in neonatal care have improved the overall survival of CDH in experienced centers, mortality and morbidity remain high in a subset of CDH infants with severe CDH. The most important prenatal predictor of outcome in left-sided CDH is liver position. More precise and reproducible prenatal predictive parameters need to be developed to allow standardization of results between centers and appropriate design of clinical trials in CDH. Thus far, all randomized trials comparing prenatal intervention to standard postnatal therapy have shown no benefit to prenatal intervention. Although recent non-randomized reports of success with balloon tracheal occlusion (and release) are promising, prenatal therapy should not be widely adopted until a well-designed prospective randomized trial demonstrating efficacy is performed. The increased survival and subsequent morbidity of CDH survivors has resulted in the need to provide resources for the long-term follow-up and support of the CDH population., (Copyright 2009. Published by Elsevier Ltd.)

Congenital unilateral absence of a pulmonary artery is a rare anomaly most frequently accompanied by other cardiovascular anomalies. We report a 10-year-old girl presenting with fatigue and recurrent hemoptysis who was initially misdiagnosed with idiopathic pulmonary hemosiderosis. Her symptoms did not resolve despite treatment so she was referred to our center for further evaluation. We carried out an angiography which revealed the absence of the right pulmonary artery and multiple collaterals originating from the right subclavian and right internal mammary arteries supplying the right lung. During the follow-up the patient developed a severe episode of pulmonary infection and pulmonary hypertension which responded well to medical treatment. Physicians should be aware of the congenital absence of the right pulmonary artery especially in patients presenting with recurrent respiratory symptoms. Although this condition is generally considered to have a good prognosis, close observation is mandatory in order to prevent further complications and comorbidities.

Unlabelled: Prostacyclin is a pulmonary vasodilator and is produced by prostacyclin synthase and stimulates adenylate cyclase (AC) via the prostacyclin receptor (IP) to produce cAMP. Forskolin is a direct stimulant of AC. Phosphodiesterase 3 hydrolyzes cAMP and is inhibited by milrinone., Objective: To characterize the prostacyclin-AC-cAMP pathway in the ovine ductal ligation model of persistent pulmonary hypertension of the newborn (PPHN)., Setting: University-based laboratory animal facility., Subjects: Lambs delivered to time-dated pregnant ewes., Interventions: Fifth generation pulmonary arteries (PA) and lung parenchyma were isolated from control fetal lambs (n = 8) and fetal lambs with PPHN induced by antenatal ductal ligation (n = 9). We studied relaxation responses to various agonists (milrinone, forskolin, prostacyclin, and iloprost, a prostacyclin analog) that increase cAMP in PA after half-maximal constriction with norepinephrine and pretreatment with propranolol +/- indomethacin. Lung protein levels of prostacyclin synthase, IP, AC2, and phosphodiesterase 3A were analyzed by Western blot and cAMP by enzyme-linked immunoassay., Main Results: Milrinone relaxed control and PPHN PA and pretreatment with indomethacin significantly impaired this response. Relaxation to milrinone, prostacyclin, and iloprost were significantly impaired in PA from PPHN lambs. Pretreatment with milrinone markedly enhanced relaxation to prostacyclin and iloprost in PPHN PA, similar to relaxation in control PA. Relaxation to forskolin was similar in control and PPHN PAs indicating normal AC activity. Protein levels of prostacyclin synthase and IP were decreased in PPHN lungs compared with control, but AC2, cAMP, and phosphodiesterase 3A remained unchanged., Conclusions: Prostacyclin and iloprost are dilators of PAs from PPHN lambs and their effect is enhanced by milrinone. This combination therapy may be an effective strategy in the management of patients with PPHN.

Objectives: To investigate the potential value of antenatally determined total fetal lung volume (TFLV) by magnetic resonance imaging (MRI) in the prediction of the postnatal survival in congenital diaphragmatic hernia (CDH)., Methods: We examined fetuses with isolated CDH, in which MRI was used at 22-38 weeks of gestation to measure TFLV and assess intrathoracic herniation of abdominal viscera, that were liveborn after 30 weeks of gestation and had postnatal follow-up until death or discharge from hospital. Regression analysis was used to investigate the effect on survival of gestational age at diagnosis, observed to expected (o/e) TFLV, intrathoracic herniation of the liver, side of CDH, gestational age at MRI, institution, year and gestational age at delivery. In 76 fetuses measurements of o/e TFLV and the lung area to head circumference ratio (LHR) were performed within 2 weeks of each other; in these cases o/e TFLV and o/e LHR were compared for their prediction of postnatal survival., Results: In the 148 cases that fulfilled the entry criteria, multiple regression analysis demonstrated that significant predictors of survival were the presence or absence of intrathoracic herniation of the liver and o/e TFLV. The area under the receiver-operating characteristics curves for prediction of postnatal survival from o/e TFLV was 0.786 (standard error, 0.059; P < 0.001) and that from o/e LHR was 0.743 (standard error, 0.069; P = 0.001)., Conclusions: In the assessment of fetuses with CDH, MRI-based o/e TFLV is useful in the prediction of postnatal survival., ((c) 2008 ISUOG. Published by John Wiley & Sons, Ltd.)

Netherton syndrome is a rare genodermatosis characterized by ichthyosiform scaling, hair shaft abnormalities, and atopic features. Affected infants typically have delayed growth and development, immune abnormalities with recurrent infections, and intermittent aminoaciduria. We report a 23-day-old girl who presented with severe primary pulmonary hypertension, exfoliative erythroderma, and trichorrhexis invaginata. Genetic studies confirmed a premature termination mutation R350X in exon 12 of SPINK5. This mutation further supports the genotypic-phenotypic prediction that severe sequela result from premature termination mutations. To our knowledge, this is the first instance of Netherton syndrome associated with primary pulmonary hypertension to be reported. Further postulated is a possible link between excessive desquamation of fetal skin and respiratory failure in a neonate with Netherton syndrome.

Background: Pulmonary arterial hypertension has been reported to be observed in association with acquired portal hypertension. However, the contribution of congenital anomalies occurring in the portal system to the development of pulmonary arterial hypertension remains to be elucidated., Methods: Nine patients with congenital portosystemic venous shunt were studied from January 1990 through September 2005., Results: Patent ductus venosus was detected in 5 patients, including 3 patients with an absence of the portal vein. The presence of either a gastrorenal or splenorenal shunt was evident in another 4 patients. Six patients had a history of hypergalactosemia with normal enzyme activities, as seen during neonatal screening. Six (66.7%) of the 9 patients were identified to have clinically significant pulmonary arterial hypertension (mean pulmonary artery pressure: 34-79 mm Hg; pulmonary vascular resistances: 5.12-38.07 U). The median age at the onset of pulmonary arterial hypertension was 12 years and 3 months. Histologic studies of lung specimens, which were available in 4 of the 9 patients with congenital portosystemic venous shunt, showed small arterial microthrombotic lesions in 3 patients. This characteristic finding was recognized even in the congenital portosystemic venous shunt patients without PAH., Conclusions: This study demonstrated thromboembolic pulmonary arterial hypertension to be a crucial complication in congenital portosystemic venous shunt, and this pathologic state may be latently present in patients with pulmonary arterial hypertension of unknown etiology.

Background: In congenital diaphragmatic hernia (CDH), pulmonary hypertension increases right ventricle (RV) afterload, which could impair heart function and contribute to poor outcome for most affected infants. Nevertheless, the real significance of vascular pulmonary alterations in perinatal hemodynamics is largely unknown. It is defined that ventricular pressure overload induces increased myocardium gene expression of B-type natriuretic peptide (BNP) and components of the renin-angiotensinogen and endothelin (ET)-1 systems. Our aim was to evaluate perinatal myocardium expression of these genes associated with ventricular pressure overload in a nitrofen-induced CDH rat model., Methods: In the nitrofen-induced CDH rat model, fetuses from dated pregnant Sprague-Dawley rats at 15.5, 17.5, 19.5 and 21.5 days postcoitum as well as newborn pups were assigned to 3 experimental groups: control, nitrofen (exposed to nitrofen, without CDH), and CDH (exposed to nitrofen, with CDH). Myocardial samples collected from the RV and left ventricle (LV) were processed for quantification of messenger RNA (mRNA) of BNP, angiotensinogen, and ET-1., Results: The perinatal expression of BNP, angiotensinogen, and ET-1 mRNA in the RV and LV of the control group revealed daily changes. During gestation, the expression of BNP and angiotensinogen mRNA underwent significant oscillation compared with control in both nitrofen-exposed fetuses, although we cannot identify significant differences between the nitrofen and CDH groups. After birth, we found a significant increasing expression of all studied genes only in the RV of CDH pups., Conclusions: Perinatal myocardial quantification of BNP, angiotensinogen, and ET-1 mRNA levels suggests that both nitrofen-exposed and control pups revealed prenatal variations of expression of the studied genes. Moreover, CDH is associated with significant molecular alterations only in the RV after birth.

Minimally invasive repair for a Bochdalek congenital diaphragmatic hernia has been performed over the last few years with mixed results. Although the anomaly has been approached from both the abdomen and the chest, the defect can be difficult to close as the posterolateral region may be difficult to reach with precise suturing using standard rigid laparoscopic instruments. The articulating instruments of robotic surgery offer a substantial improvement in degrees of freedom and may help over come these obstacles. However, other limitations including instrument length in relation to patient size need to be accounted for when planning a robotic procedure in small children. We present a robotic repair of a foramen of Bochdalek congenital diaphragmatic in a 2.2 kg neonate using and abdominal approach with the Da Vinci Surgical Robot (Intuitive Surgical, Sunnyvale, CA).

Pulmonary hypertension (PH) in newborns and infants can present in its idiopathic form or complicate a long list of other diseases. Most of these conditions are either pulmonary or cardiovascular in origin. In the present review our current knowledge regarding pathophysiology, structural changes, diagnosis, and available treatment options for PH in the age group below 1 year of age is summarized. New treatment options available in adults including endothelin receptor antagonists (ETRA) and phosphodiesterase (PDE) inhibitors are presented and the need for randomized controlled trials in newborns and infants is emphasized. Future candidates for pharmacotherapy of PH in infants include among others vasoactive intestinal polypeptide (VIP), PDE-3 and PDE-4 inhibitors, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and adrenomedullin (ADM).

Background: Many neonates with severe persistent pulmonary hypertension of the newborn (PPHN) are nonresponders to inhaled nitric oxide (iNO). Milrinone is a promising adjunctive therapy because of its pulmonary vasodilator properties and cardiotropic effects., Design: Case series of neonates with severe PPHN (defined as oxygenation index [OI] >20, failure of iNO therapy, and echocardiographic confirmation of PPHN)., Setting: Tertiary neonatal intensive care unit., Subjects: Full-term (> or =37 weeks) neonates with severe PPHN who received intravenous milrinone., Measurements: The primary end point was the effect of intravenous milrinone on OI and hemodynamic stability over a 72-hour study period. Secondary end points examined included duration of iNO and degree of cardiorespiratory support., Results: Nine neonates at a mean gestation of 39.25 +/- 2.76 weeks, birth weight of 3668 +/- 649.1 g, and baseline OI of 28.1 +/- 5.9 received milrinone treatment after a poor initial response to iNO treatment. Intravenous milrinone was commenced at a median age of 21 hours (range, 18-49 hours), and patients were treated for median of 70 hours (range, 23-136). Oxygenation index was significantly reduced after milrinone treatment, particularly in the immediate 24 hours of treatment (8.0 +/- 6.6, P < .001). There was a significant improvement in heart rate (179 +/- 15.2 vs 149.6 +/- 22.4, P < .001) over the same period. Infants who received milrinone did not develop systemic hypotension; in fact, there was a nonsignificant trend toward improved blood pressure., Conclusions: Intravenous milrinone produces early improvements in oxygenation without compromising systemic blood pressure.

We describe a neonate with ductal-dependent congenital heart disease on extracorporeal membrane oxygenation (ECMO) for persistent pulmonary hypertension, who required markedly high doses of prostaglandin E1 (PGE1) to maintain patency of the ductus arteriosus: The effects of ECMO on the pharmacokinetics of PGE1 are discussed.

A term (39-wk-old) male neonate exhibited respiratory distress and anuria within 2 days of birth. The patient was diagnosed with pulmonary hypertension, polycystic kidney disease, and heart failure; his initial B-type natriuretic peptide concentration was 2460 pg/ml. After minimal response to loop diuretics, the patient was given an infusion of nesiritide 0.01 microg/kg/minute, with no loading dose. Urine output increased over 400%, and cardiac function improved. Nesiritide was titrated to 0.03 microg/kg/minute with no hypotension, decreased renal function, or adverse cardiac sequelae over the next 6 days. No subsequent changes in cardiac function occurred during the infant's stay in a progressive care unit, but he died at age 5.5 months due to sepsis. This case report demonstrates the successful first use of nesiritide therapy in a neonate with renal disease. Further studies are warranted to evaluate the safety and administration of this agent in the neonatal patient population.

In patients with hypoplastic left heart syndrome (HLHS) and intact atrial septum, the blood entering the left atrium cannot egress. Emergency treatment interventionally or surgically is mandatory immediately after birth. We describe a patient with HLHS and intact atrial septum who underwent successful transvenous atrial septostomy immediately after birth. When the interatrial communication became restrictive, stent implantation into the arterial duct and into the atrial septum was performed on the 7th day of life. Despite good hemodymanic response, the lung damage was severe and persistent, rendering staged surgical correction impossible. The child died on the 23rd day of life. Autopsy showed patent and correct placed stents in the duct and the atrial septum. There was severe dilatation of pulmonary lymphatic and venous vessels, suggestive of long-standing pulmonary venous hypertension. In conclusion, this form of HLHS has a poor prognosis despite early and aggressive interventional treatment.

Congenital diaphragmatic hernia (CDH) usually occurs sporadically. The prognosis remains poor, with a 50% perinatal mortality rate. Most deaths result from hypoxemia due to lung hypoplasia and abnormal development of pulmonary vasculature that results in persistent pulmonary hypertension. Our current understanding of the pathogenesis of CDH is based on an assumption linking herniation of abdominal viscera into the thorax with compression of the developing lung. Pulmonary hypoplasia, however, can also result from reduced distension of the developing lung secondary to impaired fetal breathing movements. Moreover, a nitrofen-induced CDH model shows that lung hypoplasia precedes the diaphragmatic defect, leading to a "dual-hit hypothesis." Recent data reveal the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH. We describe the clinical and epidemiological aspects of human CDH, the metabolic and molecular aspects of the retinoid-signaling pathway, and the implications of retinoids in the development of the diaphragm and the lung. Finally, we highlight the existing links between CDH and disruption of the retinoid-signaling pathway, which may suggest an eventual use of retinoids in the treatment of CDH., (Copyright 2005 Wiley-Liss, Inc.)

Objectives: To endeavor to explain why some graduates of extracorporeal membrane oxygenation (ECMO) therapy develop sensorineural hearing loss (SNHL) whereas others do not, to study the variability seen in the degree of SNHL, to attempt to explain why some graduates with SNHL experience progressive worsening whereas others do not, and to describe the time course of the onset of SNHL on the basis of identified risk factors., Design: A retrospective chart review with proportional-hazards regression analysis to identify specific risk factors for SNHL from a list of patient and treatment variables., Setting: Children's Hospital Boston, a pediatric tertiary-care facility and ECMO center., Patients: Neonatal ECMO graduates born in 1986-1994 who survived to discharge and underwent audiologic evaluations (n = 111) and a random sample of ECMO graduates who survived to discharge and did not undergo audiologic evaluations (n = 30)., Outcome Measures: Audiologic data, including the presence or absence of SNHL, the severity of SNHL at the most recent evaluation, the stability or progressive worsening of hearing (with the first evaluation compared with the most recent evaluation), and the occurrence of delayed-onset SNHL., Results: Twenty-nine (26%) of 111 ECMO graduates who underwent audiologic testing had SNHL at the last evaluation. Of these 29 subjects with SNHL, 21 (72%) had progressive SNHL, of whom 14 (48%) had delayed-onset SNHL. The age of identification of SNHL ranged from 4 months to 8 years 11 months. Factors identified with proportional-hazards regression analyses as being associated significantly with the time to onset of SNHL were a primary diagnosis of congenital diaphragmatic hernia (hazard ratio: 2.60), length of ECMO therapy (hazard ratio: 7.18), and number of days children received aminoglycoside antibiotics (hazard ratio: 5.56). Kaplan-Meier "time-to-event" curves were constructed to illustrate the time course of onset of SNHL, as affected by each of the variables identified as significant risk factors., Conclusions: These findings illustrate the need for early, routine, audiologic evaluations throughout childhood for all ECMO graduates. Children at even greater risk for developing SNHL because of a history of congenital diaphragmatic hernia, prolonged ECMO therapy, and/or a lengthy course of aminoglycoside antibiotic therapy should be monitored even more closely throughout childhood, depending on the child's individual risk indicators, as suggested here. On the basis of these risk indicators, efforts can be made to minimize the risk of hearing loss while a child is being treated with ECMO. In addition, these risk indicators can assist with counseling families of ECMO graduates regarding the child's specific risk of developing SNHL and how it can be managed should it occur.

Total anomalous pulmonary venous return (TAPVR) is a rare congenital heart defect that occurs when all four pulmonary veins connect to the systemic venous circulation. We describe a full-term male neonate who presented with cyanosis and mild tachypnea shortly after birth. One umbilical artery and the umbilical vein were catheterized, and oxygen treatment was provided. Four echocardiograms indicated severe pulmonary hypertension and were negative for any congenital heart defects. After the umbilical artery catheter was removed, high partial pressure of oxygen was detected in blood samples drawn from the umbilical venous catheter that was positioned below the diaphragm. Based on this finding, TAPVR was suspected and confirmed with angiography through a central venous catheter. The neonate underwent a successful surgical repair to correct the cardiac defect.

An infant with myocardial infarction due to congenital stenosis of the left coronary artery with consecutive left ventricular dysfunction and mitral regurgitation developed refractory pulmonary hypertension (PHT) and recurrent PHT crises. Catecholamines to support cardiac function, or pulmonary vasodilators like inhaled nitric oxide showed no effect. Treatment with Levosimendan (Simdax), a new inodilator, combining both inotropic and pulmonary vasodilating effects, improved left ventricular dysfunction, increased cardiac index, decreased pulmonary vascular resistance and reduced frequency and extent of the PHT crises. This case may suggest the use of Levosimendan as a long-term inotropic agent and pulmonary vasodilator in children with depressed cardiac function.

Background/purpose: The renin-angiotensin system plays an important role in pulmonary artery remodelling. Several polymorphisms of genes encoding for components of the renin angiotensin system such as the angiotensin converting enzyme (ACE), the angiotensinogen (AGT) gene, and the angiotensin II type 1 receptor (ATIR) have been associated with the development of pulmonary hypertension. The aim of this study was to investigate the ACE I/D genotype, the M235 T polymorphism of the AGT gene and the A1166 C polymorphism of AT1R in the lungs of congenital diaphragmatic hernia (CDH) complicated by persistent pulmonary hypertension (PPH) in the newborn., Methods: Genomic DNA was extracted from archival paraffin-embedded lung tissue from 13 newborns with CDH complicated by PPH and from 9 controls. Genotyping for the I/D-ACE, the M235 T-AGT, and the A1166 C-ATIR gene polymorphisms were determined by a polymerase chain reaction-based method with appropriate restriction digest when required., Results: In controls, ACE genotype distribution of DD, ID, and II was 11%, 33%, and 55%, respectively, whereas in CDH it was 70%, 15%, and 15%, respectively. The ACE-DD genotype was significantly higher in CDH compared with controls (P <.05). In CDH samples, the prevalence of AGT-MM genotype was lower (8% v. 33%; P <.05), whereas the AGT-TT genotype was higher (61% v. 22%; P <.05) compared with controls. There were no differences in allele frequencies of AT1R between CDH patients and controls., Conclusions: These data suggest that D allele of the ACE gene insertion/deletion polymorphism and angiotensinogen M235 T polymorphism may be associated with PPH in newborns with congenital diaphragmatic hernia.