Intrapulmonary artery Doppler to predict mortality and morbidity in fetuses with mild or moderate left-sided congenital diaphragmatic hernia.

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 R2 . 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 R2 , 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.

A Case of Congenital Hepatoblastoma Coexisting with Pulmonary Hypertension.

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.

Recommendations from the Association for European Paediatric and Congenital Cardiology for training in pulmonary hypertension.

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.

Successful preoperative bridge with extracorporeal membrane oxygenation in three neonates with D-transposition of the great vessels and pulmonary hypertension.

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.

Gestational Hypoxia and Developmental Plasticity.

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.

Systemic-pulmonary arteriovenous fistulae with pulmonary hypertension: A case report.

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.

Severe persistent pulmonary hypertension of the newborn and dysmorphic features in neonate with a deletion involving TWIST1 and PHF14: a case report.

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.

High Prevalence of Pulmonary Hypertension Complicates the Care of Infants with Omphalocele.

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.

Persistent pulmonary hypertension of the newborn.

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.

Effect of persistent pulmonary hypertension on brain oxygenation in asphyxiated term newborns treated with hypothermia.

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 Late Shone Syndrome With Pulmonary Hypertension: Heart-Lung Transplant or Valve Surgery?

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.

Transient neonatal hyperinsulinism with adaptation disorders: a report of three cases.

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.

MRI shows limited mixing between systemic and pulmonary circulations in foetal transposition of the great arteries: a potential cause of in utero pulmonary vascular disease.

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.

Understanding and treating pulmonary hypertension in congenital diaphragmatic hernia.

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.

Hipertiroidismo neonatal e hipertensión pulmonar / Neonatal hyperthyroidism and pulmonary hypertension

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Stability prior to surgery in Congenital Diaphragmatic Hernia: is it necessary?

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.

Congenital diaphragmatic hernia (CDH) mortality without surgical repair? A plea to clarify surgical ineligibility.

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.

Congenital chylothorax and pulmonary hypertension complicated with heart failure and hepatopathy.

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.