Pulmonary Hypertension In Infants Research Articles

Multicentre, randomised controlled trial of physiological-based cord clamping versus immediate cord clamping in infants with a congenital diaphragmatic hernia (PinC): statistical analysis plan

BackgroundInfants born with congenital diaphragmatic hernia (CDH) are at high risk of respiratory insufficiency and pulmonary hypertension. Routine practice includes immediate clamping of the umbilical cord and endotracheal intubation. Experimental animal studies suggest that clamping the umbilical cord guided by physiological changes and after the lungs have been aerated, named physiological-based cord clamping (PBCC), could enhance the fetal-to-neonatal transition in CDH. We describe the statistical analysis plan for the clinical trial evaluating the effects of PBCC versus immediate cord clamping on pulmonary hypertension in infants with CDH (PinC trial).DesignThe PinC trial is a multicentre, randomised controlled trial in infants with isolated left-sided CDH, born ≥ 35.0 weeks of gestation. The primary outcome is the incidence of pulmonary hypertension in the first 24 h after birth. Maternal outcomes include estimated maternal blood loss. Neonatal secondary outcomes include mortality before discharge, extracorporeal membrane oxygenation therapy, and number of days of mechanical ventilation. Infants are 1:1 randomised to either PBCC or immediate cord clamping using variable random permutated block sizes (4–8), stratified by treatment centre and estimated severity of pulmonary hypoplasia (i.e. mild/moderate/severe). At least 140 infants are needed to detect a relative reduction in pulmonary hypertension by one third, with 80% power and 0.05 significance level. A chi-square test will be used to evaluate the hypothesis that PBCC decreases the occurrence of pulmonary hypertension. This plan is written and submitted without knowledge of the collected data. The trial has been ethically approved.Trial registrationClinicalTrials.gov NCT04373902 (registered April 2020).

Association of the respiratory severity score with bronchopulmonary dysplasia-associated pulmonary hypertension in infants born extremely preterm.

To test the hypothesis that elevations in the respiratory severity score (RSS) are associated with increased probability of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH). Retrospective cohort study of infants born extremely preterm admitted to a BPD center between 2010 and 2018. Echocardiograms obtained ≥ 36 weeks' post-menstrual age (PMA) were independently adjudicated by two blinded cardiologists to determine the presence/absence of BPD-PH. Multivariable logistic regression estimated the association between RSS and BPD-PH. BPD-PH was observed in 68/223 (36%) of subjects. The median RSS at time of echocardiography was 3.04 (Range 0-18.3). A one-point increase in the RSS was associated with BPD-PH, aOR 1.3 (95% CI 1.2-1.4), after adjustment for gestational age and PMA at time of echocardiography. Elevations in the RSS were associated with a greater probability of BPD-PH. Prospective studies are needed to determine the validity and performance of RSS as a clinical susceptibility/risk biomarker for BPD-PH.

Pulmonary hypertension associated with diazoxide: the SUR1 paradox.

The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the ABCC8 gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants. This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed. Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analysed data from the World Health Organization pharmacovigilance database (VigiBase). Significant disproportionality signals link diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models.

Information based similarity analysis of oxygen saturation recordings to detect Pulmonary hypertension in preterm infants

Pulmonary hypertension (PH) is a complex cardiovascular condition associated with multiple morbidities and mortality risk in preterm infants. PH often complicates the clinical course of infants who have bronchopulmonary dysplasia (BPD), a more common lung disease in these neonates, causing respiratory deterioration and an even higher risk of mortality. While risk factors and prevalence of PH are not yet well defined, early screening and management of PH in infants with BPD are recommended by consensus guidelines from the American Heart Association. In this study, we propose a screening method for PH by applying a signal analysis technique to oxygen saturation in infants. Oxygen saturation data from infant groups with BPD (41 with and 60 without PH), recorded prior to their clinical PH diagnosis were analyzed in this study. An information-based similarity approach was applied to quantify the regularity of SpO2 fluctuations represented as binary words between adjacent five-minute segments. Similarity indices (SI) were observed to be lower in subjects with PH compared to those with BPD alone (p < 0.001). These measures were also assessed for performance in screening for PH. SI of 7-bit words, exhibited 80 % detection accuracy, 76 % sensitivity and specificity of 83 %. This index also exhibited a cross-validated mean (SD) F1-score of 0.80 (0.08) ensuring that sensitivity and recall of the screening were balanced. Similarity analysis of oxygen saturation patterns is a novel technique that can be potentially developed into a signal based early PH detection method to support clinical decision and care in this vulnerable population.

Pulmonary Hypertension in Infants and Children with Vein of Galen Malformation and Association with Clinical Outcomes

To assess the extent and resolution of pulmonary hypertension (PH), cardiovascular factors, and echocardiographic findings associated with mortality in infants and children with vein of Galen malformation (VOGM). We performed a retrospective review of 49 consecutive children with VOGM admitted to Boston Children's Hospital from 2007 to 2020. Patient characteristics, echocardiographic data, and hospital course were analyzed for 2 cohorts based on age at presentation to Boston Children's Hospital: group 1 (age ≤60days) or group 2 (age >60days). Overall hospital survival was 35 of 49 (71.4%); 13 of 26 (50%) in group 1 and 22 of 23 (96%) in group 2 (P<.001). High-output PH (P=.01), cardiomegaly (P=.011), intubation (P=.019), and dopamine use (P=.01) were significantly more common in group 1 than group 2. Among patients in group 1, congestive heart failure (P=.015), intubation (P<.001), use of inhaled nitric oxide (P=.015) or prostaglandin E1 (P=.030), suprasystemic PH (P=.003), and right-sided dilation were significantly associated with mortality; in contrast, left ventricular volume and function, structural congenital heart disease, and supraventricular tachycardia were not associated. Inhaled nitric oxide achieved no clinical benefit in 9 of 11 treated patients. Resolution of PH was associated with overall survival (P<.001). VOGM remains associated with substantial mortality among infants presenting at ≤60days of life owing to factors associated with high output PH. Resolution of PH is an indicator associated with survival and a surrogate end point for benchmarking outcomes.

Pharmacotherapy for Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Past, Present, and Future.

Approximately 8-42% of premature infants with chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD), develop pulmonary hypertension (PH). Infants with BPD-PH carry alarmingly high mortality rates of up to 47%. Effective PH-targeted pharmacotherapies are desperately needed for these infants. Although many PH-targeted pharmacotherapies are commonly used to treat BPD-PH, all current use is off-label. Moreover, all current recommendations for the use of any PH-targeted therapy in infants with BPD-PH are based on expert opinion and consensus statements. Randomized Control Trials (RCTs) are needed to determine the efficacy of PH-targeted treatments in premature infants with or at risk of BPD-PH. Prior to performing efficacy RCTs, studies need to be conducted to obtain pharmacokinetic, pharmacodynamic, and safety data for any pharmacotherapy used in this understudied and fragile patient population. This review will discuss current and needed treatment strategies, identify knowledge deficits, and delineate both challenges to be overcome and approaches to be taken to develop effective PH-targeted pharmacotherapies that will improve outcomes for premature infants with or at risk of developing BPD-PH.

Early nitric oxide is not associated with improved outcomes in congenital diaphragmatic hernia.

Inhaled nitric oxide (iNO) is widely used for the management of infants with congenital diaphragmatic hernia (CDH); however, evidence of benefit is limited. This is a multicenter cohort study using data from the Congenital Diaphragmatic Hernia Study Group between 2015 and 2020. The impact of early iNO use in the first 3 days of life prior to ECLS use on mortality or ECLS use was explored using multivariate logistic regression models and subgroup analyses. Of the 1777 infants, 863 (48.6%) infants received early iNO treatment. Infants receiving iNO had lower birth weight, larger defect size, more severe pulmonary hypertension, and abnormal ventricular size and function. After controlling for these factors, early iNO use was associated with increased mortality (aOR 2.06, 95% CI 1.05-4.03, P = 0.03) and increased ECLS use (aOR 3.44, 95% CI 2.11-5.60, P < 0.001). Subgroup analyses after stratification by echocardiographic characteristics and defect size revealed no subgroup with a reduction in mortality or ECLS use. Use of iNO in the first 3 days of life prior to ECLS was not associated with a reduction in mortality or ECLS use in either the regression models or the subgroup analyses. The widespread use of iNO in this vulnerable population requires reconsideration. Evidence to support widespread use of iNO for infants with congenital diaphragmatic hernia is limited. The use of iNO in the first 3 days of life was associated with significantly increased mortality and ECLS use. Stratification by echocardiographic characteristics and defect size did not reveal a subgroup that benefited from iNO. Even the subset of patients with R-to-L shunts at both ductal and atrial levels, a surrogate for elevated pulmonary arterial pressures in the absence of significantly decreased LV compliance, did not benefit from early iNO use. Early iNO therapy was of no benefit in the management of acute pulmonary hypertension in infants with congenital diaphragmatic hernia, supporting reconsideration of its use in this population.

The levels of postpartum depression, anxiety, and hopelessness of the mothers of infants receiving therapeutic hypothermia in NICU

ABSTRACT The aim of this study was to evaluate anxiety, postpartum depression (PPD), and hopelessness in the mothers of newborns receiving therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) in NICU. A total of 104 mothers and infants were analyzed as a study group with HIE (n = 52) and a control groups of non-HIE (n = 52). All the mothers completed The State-Trait Anxiety, Beck Hopelessness and Edinburgh Postpartum Depression Scales (EPDS). The EPDS scores, the rate of PPD, state-trait anxiety and hopelessness levels were similar in the two groups. In the HIE group, chest compression and persistent pulmonary hypertension in infants were associated with maternal anxiety, hopelessness, and PPD. The absence of a statistical difference between the two groups in the current study does not mean that these differences do not exist. These results demonstrate the need for further detailed studies on this subject.

Diagnosis and management of pulmonary hypertension in infants with bronchopulmonary dysplasia: a guide for paediatric respiratory specialists.

To identify those BPD patients most at risk of developing PH.To be aware of detection, multidisciplinary management, pharmacological treatment and monitoring strategies for BPD-PH patients.To understand the potential clinical course for patients with BPD-PH and that evidence on efficacy and safety of PH-targeted pharmacotherapy in BPD-PH is limited.

The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1).

To assess the impact of milrinone administration on time spent on nitric oxide (iNO) in infants with acute pulmonary hypertension (aPH). We hypothesized that intravenous milrinone used in conjunction with iNO would reduce the time on iNO therapy and the time spent on invasive ventilation in infants ≥34 weeks gestation with a diagnosis of aPH. We aimed to assess the practicality of instituting the protocol and contributing to a sample size calculation for a definitive multicentre study. This was a multicentre, randomized, double-blind, two arm pilot study, with a balanced (1:1) allocation. Infants with a gestation ≥34 weeks and a birth weight ≥2000 grams aPH, an oxygenation index of ≥10, and commenced on iNO were eligible. Participants on iNO were assigned to either a milrinone infusion (intervention) or a normal saline infusion (placebo) for up to 35 h. The primary outcome was time on iNO and feasibility of conducting the protocol. The trial was terminated early after 4 years of enrollment due to poor recruitment. Four infants were allocated to the intervention arm and 5 to the placebo arm. The groups were well matched for baseline variables. No differences were seen in any of the primary or secondary outcomes. Conducting an interventional trial in the setting of acute pulmonary hypertension in infants is not feasible using our current approach. Future studies in this area require alternative trial design to improve recruitment as this topic remains understudied in the neonatal field. www.isrctn.com ; ISRCTN:12949496; EudraCT Number:2014-002988-16.

Systemic Inflammation Is Associated with Pulmonary Hypertension in Isolated Giant Omphalocele: A Population-Based Study.

Our objective is to determine perinatal factors contributing to the development of pulmonary hypertension (PH) in patients with isolated giant omphaloceles (GO). All cases of omphaloceles that underwent prenatal and postnatal care at the University Hospital of Lille between 1996 and 2021 were reviewed. We included all infants with isolated GO, including at least a part of the liver, who were treated by delayed surgical closure. Prenatal and postnatal data were recorded and correlated with postnatal morbidities. We compared outcomes between a group of infants with GO who developed PH and infants with GO with no PH. We identified 120 infants with omphalocele. Fifty isolated GO cases fulfilled the inclusion criteria of our study. The incidence of PH was 30%. We highlighted a prolonged inflammatory state, defined as a CRP superior to 15 mg/L, platelets higher than 500 G/L, and white blood cells higher than 15 G/l for more than 14 days in patients who developed PH. This event occurred in 73% of patients with PH versus 21% of patients without PH (p < 0.05). Late-onset infection was not different between the two groups. We speculate that prolonged inflammatory syndrome promotes PH in infants with GO treated with delayed surgical closure.

Prediction of survival in infants with congenital diaphragmatic hernia and the response to inhaled nitric oxide

The use of inhaled nitric oxide (iNO) in treating pulmonary hypertension in infants with congenital diaphragmatic hernia (CDH) is controversial. Our aims were to identify factors associated with survival in CDH infants and whether this was influenced by the response to iNO. Results of CDH infants treated in a tertiary surgical and medical perinatal centre in a ten year period (2011–2021) were reviewed. Factors affecting survival were determined. To assess the response to iNO, blood gases prior to and 30 to 60 min after initiation of iNO were analysed and PaO2/FiO2 ratios and oxygenation indices (OI) calculated. One hundred and five infants were admitted with CDH; 46 (43.8%) infants died. The CDH infants who died had a lower median observed to expected lung to head ratio (O/E LHR) (p < 0.001) and a higher median highest OI on day 1 (HOId1) (p < 0.001). HOId1 predicted survival after adjusting for gestational age, Apgar score at 5 min and O/E LHR (odds ratio 0.948 (95% confidence intervals 0.913–0.983)). Seventy-two infants (68.6%) received iNO; 28 survived to discharge. The median PaO2 (46.7 versus 58.8 mmHg, p < 0.001) and the median PaO2/FiO2 ratio (49.4 versus 58.8, p = 0.003) improved post iNO initiation. The percentage change in the PaO2/FiO2 ratio post iNO initiation was higher in infants who survived (69.4%) compared to infants who died (10.2%), p = 0.018.Conclusion: The highest OI on day 1 predicted survival. iNO improved oxygenation in certain CDH infants and a positive response was more likely in those who survived.What is Known:• The use of iNO is controversial in infants with CDH with respect to whether it improves survival.What is New:• We have examined predictors of survival in CDH infants including the response to iNO and demonstrated that the highest oxygenation index on day 1 predicted survival (AUCROC =0.908).• Certain infants with CDH responded to iNO and those with a greater response were more likely to survive.

Episodes of apnea and periodic breathing in premature infants with BPD-associated pulmonary hypertension

Premature infants with bronchopulmonary dysplasia-associated pulmonary hypertension have a longer persistence of apnea of prematurity and periodic breathing. We hypothesized that apnea of prematurity and periodic breathing may be associated with the persistence of pulmonary hypertension in infants with bronchopulmonary dysplasia.The aim of the study was to determine the characteristics of apnea episodes and periodic breathing in premature infants with bronchopulmonary dysplasia-associated pulmonary hypertension.Characteristics of children and research methods. Cardiorespiratory monitoring was conducted on 27 premature infants born at 22 0/7 — 29 0/7 weeks of gestation with a body weight of &lt;1000 grams. All infants had bronchopulmonary dysplasia, and 14 infants with severe bronchopulmonary dysplasia were diagnosed pulmonary hypertension (main cohort).Results. The group of infants with bronchopulmonary dysplasia + pulmonary hypertension had lower average SpO2, higher desaturation index and apnea/hypopnea index as compared to infants without pulmonary hypertension. Four infants from the main cohort had obstructive apnea index of ˃1 events/hour and had high values of 1,1; 2,5; 5,8, and 8,6/hour. In the comparison group, only one infant had a high obstructive apnea index (1,1/hour). Eleven infants(78%) with pulmonary hypertension had episodes of periodic breathing, at the same time only six infants (46%) in the group without pulmonary hypertension had such episodes. Periodic breathing episodes with a drop of SpO2 &lt;90% were registered in 82% of cases in the main cohort and in 67% of cases in infants of the comparison group.Conclusion. Premature infants with bronchopulmonary dysplasia and pulmonary hypertension had more significant decrease in mean SpO2, increased desaturation index and apnea/hypopnea index and tend to have obstructive apnea index &gt;1/hour and longer periodic breathing than infants without pulmonary hypertension.

Relationship Between Postnatal Pulmonary Arterial Pressure and Altered Diastolic Function in Neonates with Down Syndrome

To assess the influence of diastolic dysfunction on the evolution of pulmonary hypertension in neonates with Down Syndrome over the early newborn period. This was a prospective observational cohort study. Echocardiography was performed three times over the first week of life in both Down syndrome and control cohorts. Measurements of pulmonary arterial pressure in addition to left ventricular (LV) and right ventricular systolic and diastolic function were collected. Seventy babies with Down syndrome and 60 control infants were enrolled. Forty-eight of the infants with Down syndrome (69%) were born with congenital heart disease (CHD). Echocardiography surrogates of pulmonary hypertension and myocardial function remained significantly impaired in the Down syndrome group in comparison with control infants (all P<.01). In the Down syndrome group, LV early diastolic strain rate was independently associated with measures of pulmonary hypertension while controlling for gestational age, cesarean delivery, and the presence of CHD (P<.01). Intrinsic LV diastolic impairment is directly associated with higher indices of pulmonary hypertension in infants with Down syndrome and may be a contributing factor to its evolution.

Neonatal pulmonary hypertension after severe early-onset fetal growth restriction: post hoc reflections on the Dutch STRIDER study

The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02).Conclusion: Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a “rebound” vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action.What is Known:• In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo.What is New:• The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension.• The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed.

Факторы риска, диагностика, скрининг и терапия легочной гипертензии у детей с бронхолегочной дисплазией

Objective of the Review: on the basis of domestic and foreign conciliation documents and the results of our own research, to present up-to- date information about a dangerous complication of bronchopulmonary dysplasia - pulmonary hypertension. Key Points: pulmonary hypertension is a common complication of bronchopulmonary dysplasia, which has antenatal, perinatal and postnatal risk factors. The presence of risk factors, respiratory failure, bronchial obstruction in a child with bronchopulmonary dysplasia is the basis for excluding pulmonary hypertension by echocardiography, which allows to detect an increase in pressure in the pulmonary artery, indirect signs of pulmonary hypertension. An obligatory method of treatment of pulmonary hypertension in children with bronchopulmonary dysplasia is oxygen therapy. With insufficient effectiveness of oxygen therapy, treatment is sequentially carried out with sildenafil, bosentan, and nitric oxide. Conclusion: Since the clinical manifestations of pulmonary hypertension in children with bronchopulmonary dysplasia are indistinguishable from the symptoms of the underlying lung disease, timely screening of this complication and the appointment of therapy are necessary. Keywords: bronchopulmonary dysplasia, pulmonary hypertension, chronic pulmonary hypertension in infants, diagnosis, therapy.

Pulmonary hypertension in infants with bronchopulmonary dysplasia: risk factors, mortality and duration of hospitalisation.

Pulmonary hypertension (PH) is a complication of bronchopulmonary dysplasia (BPD) and associated with increased mortality and morbidity. Our aim was to identify, in infants with BPD, the effect of PH on health-care utilisation and health related cost of care. An electronic data recording system was used to identify infants≤32weeks of gestation who developed BPD. PH was classified as early (≤28days after birth) or late (>28days after birth). In the study period, 182 infants developed BPD; 22 (12.1%) developed late PH. Development of late PH was associated with a lower gestational age [24.6 (23.9-26.9) weeks, p=0.001] and a greater need for positive pressure ventilation on day 28 after birth (100%) compared to infants without late PH (51.9%) (odds ratio (OR) 19.5, 95% CI: 2.6-148), p<0.001. Late PH was associated with increased mortality (36.4%) compared those who did not develop late PH (1.9%) after adjusting for gestational age and ventilation duration (OR: 26.9, 95% CI: 3.8-189.4), p<0.001. In infants who survived to discharge, late PH development was associated with a prolonged duration of stay [147 (118-189) days] compared to the infants that did not develop late PH [109 (85-149) days] (p=0.03 after adjusting for gestational age). Infants who had late PH had a higher cost of stay compared to infants with BPD who did not develop late PH (median £113,494 vs. £78,677, p=0.016 after adjusting for gestational age). Development of late PH was associated with increased mortality, a prolonged duration of stay and higher healthcare cost.

Association of Persistent Pulmonary Hypertension in Infants With the Timing and Type of Antidepressants In Utero

Association of Persistent Pulmonary Hypertension in Infants With the Timing and Type of Antidepressants In Utero

Pertussis Toxin Promotes Pulmonary Hypertension in an Infant Mouse Model of Bordetella pertussis Infection.

Pertussis, caused by Bordetella pertussis, is a reemerging disease that can produce severe disease manifestations in infants, including pulmonary hypertension (PH). B. pertussis-induced PH is a major risk factor for infection-induced death, but the molecular mechanisms promoting PH are unknown and there is no effective treatment. We examined B. pertussis-induced PH in infant and adult mouse models of pertussis by Fulton index, right heart catheterization, or Doppler echocardiogram. Our results demonstrate that B. pertussis-induced PH is age related and dependent on the expression of pertussis toxin by the bacterium. Hence, pertussis toxin-targeting treatments may ameliorate PH and fatal infant infection.

Atypical Causes of Severe Pulmonary Hypertension in Infancy.

Pulmonary hypertension (PH) is a progressive disease characterized by elevated pulmonary arterial pressure (PAP). It is defined for both adults and children as mean PAP exceeding 20 mmHg and pulmonary vascular resistance of at least 3 Woods Units (WU; indexed to body surface area in children).1 A more appropriate suggested definition of PH in infants is a ratio of pulmonary artery systolic pressure to the systemic arterial systolic pressure above 0.4.2 In addition, cardiac catheterization derived mean pulmonary artery pressures to mean systemic arterial pressure ratio >0.75 indicating severe pulmonary hypertension has been associated with worse outcome in children.1 PH can be life-threatening and often presents within hours after birth. Persistent PH of the newborn (persistent pulmonary hypertension of the newborn [PPHN]) is a common etiology of PH in infants, occurring in 0.4 to 6 per 1000 live births with increasingly higher frequency reported at earlier gestational ages.1,3,4 However, rare etiologies of pulmonary hypertension can go unrecognized and may present outside the neonatal period.5 We present 4 atypical cases of severe pulmonary hypertension and review how early recognition informed prognosis and guided timely intervention.