Bronchopulmonary Dysplasia-associated Pulmonary Hypertension Research Articles

Use of Inhaled Nitric Oxide in Preterm Infants: Is There Sufficient Evidence?

Nitric oxide (NO) is a potent vasodilator. The inhaled form (iNO) improves outcomes in term infants with persistent pulmonary hypertension of the newborn (PPHN) or bronchopulmonary dysplasia-associated pulmonary hypertension in preterm infants. However, in preterm infants, the risks and benefits of iNO use are controversial. Substantial evidence reveals no significant impact on survival or other morbidities in preterm infants with iNO treatment, independent of indication, timing, or duration of use. Many scientific organizations do not recommend the use of iNO in preterm infants, except in unique clinical circumstances with echocardiographic findings of PPHN in the setting of presumed pulmonary hypoplasia.

Children with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension Treated with Pulmonary Vasodilators-The Pediatric Cardiologist Point of View.

Pulmonary hypertension in children with bronchopulmonary dysplasia (BPD-PH) significantly worsens the prognosis. Pulmonary vasodilators are often used in BPD-PH but the short-term outcome of treatment is not well described. The aim of this study was to evaluate BPD-PH children diagnosed beyond 36 weeks postmenstrual age treated with pulmonary vasodilators (sildenafil, bosentan, or both) and to assess the short and long-term effect of oral pulmonary vasodilators treatment. Twenty patients were included in the study. Cardiology evaluation (WHO-FC, NTproBNP, oxygen saturation, pulmonary to systemic pressure ratio PAP/SAP) was performed at diagnosis and after treatment initiation. In the majority of patients improvement in all evaluated factors was observed. No side effects of vasodilators were observed. PH resolved in 10 patients after a mean of 21.4 months of treatment. Six patients died. The number of poor prognostic factors commonly used to assess patients with pulmonary arterial hypertension (PAH) decreased significantly during BPD-PH treatment. The influence of BPD-PH perinatal risk factors on prognosis was considered but was not confirmed. In conclusion, the treatment of BPD-PH with pulmonary vasodilators was well tolerated and led to a clinical improvement with the possibility of discontinuation without recurrence of PH. Prognostic factors used in pediatric PAH risk stratification also seem to be useful in assessing treatment efficacy and prognosis in patients with BPD-PH.

Role of functional echocardiographic parameters in the diagnosis of bronchopulmonary dysplasia-associated pulmonary hypertension.

Echocardiogram (echo) is a commonly used noninvasive modality for the diagnosis of bronchopulmonary dysplasia associated pulmonary hypertension (BPD-PH). Though not considered the gold standard for the diagnosis of BPD-PH, it is an extremely valuable tool in the neonatal and pediatric population, especially when cardiac catheterization is not feasible. In addition to the traditional echo parameters that are used to assess the presence of BPD-PH, much attention has been recently placed on newer bedside echo measures, the so-called functional echo parameters, to aid and assist in the diagnosis. This review article provides a brief introduction to BPD-PH, describes the pitfalls of traditional echo parameters and details the newer echo modalities currently available for the diagnosis of neonatal PH.

Echocardiography evaluation of bronchopulmonary dysplasia-associated pulmonary hypertension: a retrospective observational cohort study

BackgroundEchocardiography has poor accuracy in grading the severity of pulmonary hypertension (PH) compared to cardiac catheterization. However, the relationship between degree of PH and prognostic outcomes remains uncertain. Our primary objective was to determine whether echocardiogram-assessed PH severity is associated with mortality and hospital readmission in the first year of life.MethodsA retrospective cohort study of infants born less than 32 weeks of gestational age with bronchopulmonary dysplasia (BPD) underwent echocardiography was performed. Echocardiograms were performed at 36–38 weeks postmenstrual age. Data during hospitalization and post-discharge collected at 1-year age were analyzed with cox regression models and logistic regression models to identify the association of PH severity with mortality and readmission. Area under curve (AUC) was calculated to examine the accuracy of these models to reflect the likelihood of outcomes.ResultsFifty-six of 237 (23.6%) infants were diagnosed as PH. Moderate and severe PH was significantly associated with mortality during the first one year of life (moderate PH vs. none HR =26.58, 95% CI: 4.40–160.78, P<0.001; severe PH vs. none HR =36.49, 95% CI: 5.65–235.84, P<0.001). Male, preeclampsia and inhaled nitric oxide were also associated with mortality. Mild PH was significantly associated with readmission (OR =2.42, 95% CI: 1.12–5.26, P=0.025), but not associated with mortality (HR =2.09, 95% CI: 0.43–10.18, P=0.36). The PH severity model based on echocardiography accurately informed mortality (AUC 0.79).ConclusionsEchocardiogram-assessed PH severity is associated with prognostic outcomes, including mortality and readmission in very preterm infants with BPD. The severity of PH based on echocardiography is a potential predictor of mortality in the first year of life.

Novel biomarkers of bronchopulmonary dysplasia and bronchopulmonary dysplasia-associated pulmonary hypertension.

ObjectiveTo quantify and compare levels of potential biomarkers in neonates with i) Bronchopulmonary dysplasia (BPD); ii) BPD-associated pulmonary hypertension (BPD-PH); iii) PH without BPD; and iv) neonates without lung disease at ~36 weeks postmenstrual age.Study DesignMultiple potential biomarkers were measured in plasma samples of 90 patients using a multi-spot enzyme-linked immunosorbent assay. Statistical tests done included one-way ANOVA to compare levels of biomarkers between different groups.ResultsHigher levels of ICAM-1 were present in infants with BPD and correlated with its severity. Infants with BPD have significantly higher levels of ANG-2 and lower levels of ANG-1. Infants with PH have higher levels of: IL-6, IL-8, IL-10, and TNF-α. Infants with BPD-PH, have significantly lower levels of MCP-1 and higher levels of IL-1β than in infants with PH without BPD.ConclusionICAM-1 may be used as a specific biomarker for diagnosis of BPD and its severity.

Targeting Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension (BPD-PH): Potential Role of the FGF Signaling Pathway in the Development of the Pulmonary Vascular System.

More than 50 years after the first description of Bronchopulmonary dysplasia (BPD) by Northway, this chronic lung disease affecting many preterm infants is still poorly understood. Additonally, approximately 40% of preterm infants suffering from severe BPD also suffer from Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH), leading to a significant increase in total morbidity and mortality. Until today, there is no curative therapy for both BPD and BPD-PH available. It has become increasingly evident that growth factors are playing a central role in normal and pathologic development of the pulmonary vasculature. Thus, this review aims to summarize the recent evidence in our understanding of BPD-PH from a basic scientific point of view, focusing on the potential role of Fibroblast Growth Factor (FGF)/FGF10 signaling pathway contributing to disease development, progression and resolution.

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice.

Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a significant lung morbidity of infants, and disrupted lung angiogenesis is a hallmark of this disease. We observed that extracellular signal-regulated kinases (ERK) 1/2 support angiogenesis in vitro, and hyperoxia activates ERK1/2 in fetal human pulmonary microvascular endothelial cells (HPMECs) and in neonatal murine lungs; however, their role in experimental BPD and PH is unknown. Therefore, we hypothesized that Tie2 Cre-mediated deficiency of ERK2 in the endothelial cells of neonatal murine lungs would potentiate hyperoxia-induced BPD and PH. We initially determined the role of ERK2 in in vitro angiogenesis using fetal HPMECs. To disrupt endothelial ERK2 signaling in the lungs, we decreased ERK2 expression by breeding ERK2flox/flox mice with Tie-Cre mice. One-day-old endothelial ERK2-sufficient (eERK2+/+) or –deficient (eERK2+/−) mice were exposed to normoxia or hyperoxia (FiO2 70%) for 14 d. We then performed lung morphometry, gene and protein expression studies, and echocardiography to determine the extent of inflammation, oxidative stress, and development of lungs and PH. The knockdown of ERK2 in HPMECs decreased in vitro angiogenesis. Hyperoxia increased lung inflammation and oxidative stress, decreased lung angiogenesis and alveolarization, and induced PH in neonatal mice; however, these effects were augmented in the presence of Tie2-Cre mediated endothelial ERK2 deficiency. Therefore, we conclude that endothelial ERK2 signaling is necessary to mitigate hyperoxia-induced experimental BPD and PH in neonatal mice. Our results indicate that endothelial ERK2 is a potential therapeutic target for the management of BPD and PH in infants.

The impact of placental pathology discordance in multiple gestation pregnancies on bronchopulmonary dysplasia-associated pulmonary hypertension.

Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) may either be concordant or discordant between multiple gestation births. Abnormal placental development, particularly maternal vascular malperfusion, may account for discordance in BPD-PH through fetal programming mechanisms. Maternal vascular malperfusion is a placental histologic lesion associated with intrauterine growth restriction and BPD-PH. We conducted a retrospective longitudinal cohort study of infants born <29 weeks gestation with available placental histology at Prentice Women's Hospital in Chicago from 2005–2012. The primary outcome was discordant BPD-PH associated with placental maternal vascular malperfusion. We secondarily assessed whether the risk of BPD-PH and placental lesions was different among infants of multiple (compared to singleton) gestations. The cohort consisted of 135 multiple gestation infants and 355 singletons. In a separate cohort of 39 singletons and 35 multiples, associations between 12 cytokines and angiogenic growth factors in cord blood plasma for biomarker discordance, maternal vascular malperfusion, and bronchopulmonary dysplasia were explored. Among multiples, discordant maternal vascular malperfusion was not associated with BPD-PH (OR = 1.9 (0.52, 6.9); p = 0.33) in infants exposed to placental maternal vascular malperfusion. However, singleton infants were more likely to develop BPD-PH (compared to multiples) after adjusting for mode of delivery, chorioamnionitis, chronic hypertension, placental abruption, small-for-gestational age birth weight, and gestational age (aOR = 2.7 (1.2, 5.8); p = 0.038). Singletons were more likely to be small-for-gestational age (11% vs 4%, p = 0.025) and have placental lesions compared to their multiple-gestation counterparts (96% vs 81%, p < 0.001), principally severe maternal vascular malperfusion (17% vs 4%, p < 0.001) and chronic inflammation (32% vs 11%, p < 0.001). Increased risk of BPD-PH in singleton pregnancies <29 weeks gestation compared to multiples may be related to increased frequency of these histologic lesions. Placental pathology in singleton and multiple gestation pregnancies may serve as an early biomarker to predict BPD-PH.

Cardiac Magnetic Resonance Imaging Evaluation of Neonatal Bronchopulmonary Dysplasia-associated Pulmonary Hypertension.

Rationale: Patients with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) have increased morbidity and mortality. Noninvasive assessment relies on echocardiograms (echos), which are technically challenging in this population. Improved assessment could augment decisions regarding PH therapies.Objectives: We hypothesized that neonatal cardiac magnetic resonance imaging (MRI) will correlate with BPD severity and predict short-term clinical outcomes, including need for PH therapies for infants with BPD.Methods: A total of 52 infants (31 severe BPD, 9 moderate BPD, and 12 with either mild or no BPD) were imaged between 39 and 47 weeks postmenstrual age on a neonatal-sized, neonatal ICU-sited 1.5-T magnetic resonance (MR) scanner. MR left ventricular eccentricity index (EI), main pulmonary artery-to-aorta (PA/AO) diameter ratio, and pulmonary arterial blood flow were determined. Echos obtained for clinical indications were reviewed. MRI and echo indices were compared with BPD severity and clinical outcomes, including length of stay (LOS), duration of respiratory support, respiratory support at discharge, and PH therapy.Measurements and Main Results: PA/AO ratio increased with BPD severity. Increased PA/AO ratio, MR-EI, and echo-EIs were associated with increased LOS and duration of respiratory support. No correlation was seen between pulmonary arterial blood flow and BPD outcomes. Controlling for gestational age, birth weight, and BPD severity, MR-EI was associated with LOS and duration of respiratory support. Increased PA/AO ratio and MR-EI were associated with PH therapy during hospitalization and at discharge.Conclusions: MRI can provide important image-based measures of cardiac morphology that relate to disease severity and clinical outcomes in neonates with BPD.

Acute Vasoreactivity Testing during Cardiac Catheterization of Neonates with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension

To assess whether better baseline pulmonary hemodynamics or positive acute vasoreactivity testing (AVT) during cardiac catheterization are associated with improved outcomes in infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). This retrospective, single-center study included 26 premature neonates with BPD who underwent catheterization to evaluate PH. AVT was assessed with exposure to 100% fractional inspired oxygen with or without inhaled nitric oxide. AVT was positive if the patient met the Barst criteria or increased shunt volume and decreased pulmonary vascular resistance index by >50%. At baseline, the median pulmonary artery mean pressure was 29mm Hg (IQR, 24-35) and the pulmonary vascular resistance index was 5.3 units*m2 (IQR, 3.5-6.9). Nine patients (35%) had a positive AVT response, which was associated with a decreased risk of death or tracheostomy by 2-year follow-up (hazard ratio, 0.15; P=.02). Baseline pulmonary hemodynamics and the presence of left ventricular diastolic dysfunction were not associated with late outcomes in this cohort. We found that 35% of infants with BPD who underwent catheterization had positive AVT and that a positive response was associated with better long-term outcomes than nonresponders. AVT better distinguishes higher from lower risk PH in infants with BPD than baseline pulmonary hemodynamics. AVT may aid in the assessment of disease severity and management of BPD-associated PH.

Bronchopulmonary dysplasia-associated pulmonary hypertension

Chronic respiratory sequelae are a major health problem in surviving premature infants. Despite immense improvement in the care of premature infants, the rate of bronchopulmonary dysplasia (BPD) and pulmonary morbidities have remained the same or even slightly increased over the past decades. BPD results from the impairment of lung development following premature birth, and the resultant dysregulated pulmonary vasculature leads to chronic pulmonary hypertension (PH). It is seen more commonly in the setting of moderate to severe BPD. A high index of suspicion is necessary to diagnose PH in BPD. Diagnosis is most commonly done by echocardiogram, but cardiac catheterization may be required to delineate the cardiac structure, cardio-pulmonary vasculature and myocardial function. Once the diagnosis is made, a multidisciplinary approach for management of these patients is suggested, aiming to optimize management of BPD and use of various pulmonary vasodilators. The various therapeutic agents available help reduce pulmonary vascular resistance by acting on the nitric oxide (NO), prostacyclin and/or endothelin pathways. Serial echocardiograms and measurement of biomarkers are used to evaluate the response to therapy. Currently there is not much evidence to support optimal management approaches, but the recent guidelines published by the Pediatric Pulmonary Hypertension Network (PPHNet) provide practical recommendations for screening and management of these infants.

Bronchopulmonary Dysplasia Associated Pulmonary Hypertension – A Survey of Current Practices in USA and Canada

Bronchopulmonary Dysplasia Associated Pulmonary Hypertension – A Survey of Current Practices in USA and Canada

Developmental outcomes of preterm infants with bronchopulmonary dysplasia-associated pulmonary hypertension at 18\u201324\u2009months of corrected age

BackgroundOwing to advances in the critical care of premature infants with bronchopulmonary dysplasia (BPD), BPD-associated pulmonary hypertension (PH) is becoming a growing concern. However, only few investigations were available on neurodevelopmental outcomes in preterm infants with PH. Therefore, this study aimed to identify the impact of PH on growth and neurodevelopment at 18–24 months of corrected age (CA).MethodsWe retrospectively analyzed the medical records of 394 infants (aged < 28 weeks of gestation) admitted to the neonatal intensive care unit between 2005 and 2014. Among the surviving infants, 123 returned for follow-up evaluations including the Bayley Scales of Infant and Toddler Development, third Edition (Bayley-III) screening tests and growth assessment at 18–24 months of CA. Among the 81 infants with moderate or severe BPD, 20 met the criteria for PH. Baseline characteristics and outcomes were compared in infants who developed BPD-associated PH (PH group, n = 20) and moderate or severe BPD infants who did not develop PH (non-PH group, n = 61).ResultsCompared to the non-PH group, the PH group showed significantly lower cognitive (85 vs. 95, p = 0.004), language (81 vs. 89, p = 0.040), and motor (88 vs. 94, p = 0.010) scores of the Bayley-III at 18–24 months of CA. Cognitive delay was found in 45.0% (9/20) of PH infants. In addition, z-scores of weight (− 1.4 ± 1.3 vs. -0.6 ± 1.1%, p = 0.011) and HC (− 1.2 ± 1.8 vs. 0.53 ± 1.0%, p = 0.035) were significantly lower in the BPD with PH group. With the subgroup analysis in infants with severe BPD only, the cognitive score was consistently lower and poorer and weight gain after discharge was identified in infants with PH and severe BPD.ConclusionPH was a worsening factor of non-optimal growth and poor neurodevelopmental outcome in preterm infants with BPD at 18–24 months of CA. Our findings suggest the importance of close developmental follow-up and recognition of that risk to help optimize the outcome of preterm infants with PH.

Clinical Characteristics, Presentation, and Outcomes of Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension

Clinical Characteristics, Presentation, and Outcomes of Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension

The Impact of Pulmonary Hypertension in Preterm Infants with Severe Bronchopulmonary Dysplasia through 1 Year

To assess the effect of pulmonary hypertension on neonatal intensive care unit mortality and hospital readmission through 1 year of corrected age in a large multicenter cohort of infants with severe bronchopulmonary dysplasia. This was a multicenter, retrospective cohort study of 1677 infants born <32 weeks of gestation with severe bronchopulmonary dysplasia enrolled in the Children's Hospital Neonatal Consortium with records linked to the Pediatric Health Information System. Pulmonary hypertension occurred in 370 out of 1677 (22%) infants. During the neonatal admission, pulmonary hypertension was associated with mortality (OR 3.15, 95% CI 2.10-4.73, P < .001), ventilator support at 36 weeks of postmenstrual age (60% vs 40%, P < .001), duration of ventilation (72 IQR 30-124 vs 41 IQR 17-74 days, P < .001), and higher respiratory severity score (3.6 IQR 0.4-7.0 vs 0.8 IQR 0.3-3.3, P < .001). At discharge, pulmonary hypertension was associated with tracheostomy (27% vs 9%, P < .001), supplemental oxygen use (84% vs 61%, P < .001), and tube feeds (80% vs 46%, P < .001). Through 1 year of corrected age, pulmonary hypertension was associated with increased frequency of readmission (incidence rate ratio [IRR] = 1.38, 95% CI 1.18-1.63, P < .001). Infants with severe bronchopulmonary dysplasia-associated pulmonary hypertension have increased morbidity and mortality through 1 year of corrected age. This highlights the need for improved diagnostic practices and prospective studies evaluating treatments for this high-risk population.

NTproBNP as a surrogate biomarker for early screening of pulmonary hypertension in preterm infants with bronchopulmonary dysplasia.

Pulmonary hypertension (PH) is a known complication of bronchopulmonary dysplasia (BPD). This study aimed to determine the utility of serial N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) levels in the screening of BPD associated PH (BPD-PH) in preterm infants. Infants with birth weight <1500 g and <30 week corrected gestational age (CGA) were followed with serial NTproBNP levels and echocardiograms (ECHO). They were divided into control, BPD and BPD-PH groups. Statistical analyses included repeated measures analysis of variance and receiver operator curve (ROC) generation. Infants in the BPD-PH and BPD group had significantly elevated NTproBNP levels as compared to the control group. ROC curves for NTproBNP at 28 weeks CGA provided a cut-point of 2329 pg/ml and 578.1 pg/ml for detection of BPD-PH and BPD, respectively. NTproBNP appears to be a good screening tool to determine the onset of BPD-PH as early as 28 weeks CGA.

Bronchopulmonary dysplasia-associated pulmonary hypertension: clues from placental pathology.

Bronchopulmonary dysplasia (BPD) and the associated complication of pulmonary hypertension (PH) leads to increased mortality and a longer length of stay among survivors. Placental histopathology may give early clues of subsequent events. The objective was to evaluate the relationship of maternal vascular underperfusion (MVU) changes on placental histopathology with subsequent development of BPD-associated PH in a cohort of extremely premature infants. In a cohort of preterm infants '⩽28 weeks' gestational age (GA) and with 'severe' BPD, this retrospective study evaluated specific placental histopathological changes and assessed the relationship with subsequent development of PH. 'Severe' BPD was defined as the need for ⩾30% oxygen and/or positive pressure ventilation at 36 weeks postmenstrual age. Placental and echocardiographic assessments were done by investigators masked to the grouping and clinical outcomes. Fifty six infants with severe BPD formed the cohort; PH was noted in 22 (39.3%) infants. The GA of the infants with and without PH was comparable (25.8±1.6 vs 25.8±1.3 weeks, P=0.9). On placental histopathological examination, 13 (23%) had features of MVU. On univariate logistic regression, the presence of changes consistent with MVU increased the relative risk of subsequent BPD-associated PH by 2.75 (95% confidence interval 1.56 to 4.85, P=0.004). The significance persisted after adjustment for GA. Stratification by the presence or absence of fetal growth restriction, yielded nonsignificant associations (P=0.17). Based on the results of the present study, specific placental histopathological changes may give early clues to the subsequent development of BPD-associated PH.

Cord Blood Biomarkers of Placental Maternal Vascular Underperfusion Predict Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension

To assess whether cord blood biomarkers associated with placental maternal vascular underperfusion (MVU) are predictive of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH). Premature infants enrolled in a longitudinal cohort study were randomly sampled from 4 gestational age strata (n?=?190, range 23-36 weeks). Fifteen factors from a human angiogenesis panel were measured in cord blood using multiplex immunoassay. Multivariate linear regression was used to compare biomarker levels according to placental histologic MVU, taking into account acute/chronic inflammation and fetal vascular pathology. Biomarkers associated with MVU were further evaluated in the subgroup of extremely low gestational age infants (gestational age ? 28 weeks; n?=?48), and measured by enzyme-linked immunoassay in an additional 39 infants to determine associations with BPD (defined using the National Institutes of Health workshop criteria) and PH (identified by echocardiogram at 36 weeks of gestation). Cord blood placental growth factor (PIGF), granulocyte-colony stimulating factor (G-CSF), and vascular endothelial growth factor-A were decreased with MVU (P?<?.003), and decreased with BPD-PH (P?<?.05). The findings were validated for PIGF and G-CSF in 39 additional extremely low gestational age infants. In the combined group (n?=?87), PIGF was decreased in infants with BPD-PH (n?=?21) versus controls without PH (median 3 pg/mL [IQR 2-7] vs median 15 pg/mL [IQR 6-30], respectively; P?<?.001). G-CSF was similarly decreased with BPD-PH (median, 55 pg/mL [IQR 38-85] vs median 243 pg/mL [IQR 48-1593], respectively; P?=?.001). Receiver operator curve analysis revealed that decreased PIGF and G-CSF were predictive of BPD-PH (area under the curve 0.83 and 0.76, respectively). Cord blood angiogenic factors that are decreased with placental MVU may serve as predictors of BPD-PH.

Placental Villous Vascularity Is Decreased in Premature Infants with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension.

The development of pulmonary hypertension (PH) is a serious complication of bronchopulmonary dysplasia (BPD) among infants born at extremely low gestational ages. Bronchopulmonary dysplasia-associated PH is characterized by persistent pulmonary vasoconstriction, progressive right heart dysfunction, and an increased risk of death. We have shown previously that certain placental vascular lesions are associated with BPD-associated PH. Further evaluation of the villous and vascular morphometry of these placentas is warranted. Using digital image analysis (DIA), we compared villous and vascular morphometric parameters of placentas from infants with and without BPD-associated PH. We conducted a case-control study of placentas from 14 infants born at ≤28 weeks' gestational age (GA). Cases with PH (N=7) and non-PH controls (N=7) were identified using echocardiogram screening at 36 weeks' corrected GA. Central parenchymal sections from each placenta were stained for CD31. Digital image analysis was used to measure vessel and villous capillary number, perimeter, diameter, and area. Mean villous vascularity (number of vessels per villus) was calculated for each patient. Mean vessel and villous number as well as area were similar between the two groups. Villous vascularity was decreased in placentas from infants who ultimately had PH disease compared to non-PH controls (5.5±1.0 vs 7.1±1.6; P<0.05). Placental villous vascularity is decreased in infants with BPD-associated PH. Further studies should assess whether placental morphometric markers may allow clinicians to better predict BPD and provide earlier and more targeted management.

Sildenafil therapy in bronchopulmonary dysplasia-associated pulmonary hypertension: a retrospective study of efficacy and safety.

Bronchopulmonary dysplasia (BPD) is associated with a high incidence of pulmonary artery hypertension (PAH) and is frequently treated with sildenafil. The objective was to investigate the echocardiographic and clinical efficacy and safety of sildenafil in this setting. The hypothesis was that treatment would result in significant echocardiographic and clinical improvements. This was a retrospective study of the cohort of infants who were born between 2004 and 2012 and administered sildenafil as in-patients for BPD-associated PAH. Medical records and archived echocardiographic data were reviewed. Twenty-two infants fulfilled the inclusion criteria and had a mean (±SD) gestation age and birth weight of 25.6 (±1.3) weeks and 631 (±181) g, respectively. Six (27 %) infants died before discharge (predominantly due to respiratory failure; in three of them, a concomitant viral respiratory infection was thought to be an aggravating factor). Amongst survivors, no mortality was noted up to 1 year follow-up. Significant improvement in echocardiographic markers of pulmonary hypertension was noted in the echocardiogram performed 27.5 days (interquartile range 24, 31) post-initiation of therapy, two thirds showing ≥20 % decline in the right ventricular systolic pressure. Left ventricular fractional shortening did not alter significantly. At initiation, all infants had 'severe' BPD. The fraction of inspired oxygen (FiO2) decreased significantly from 0.57 (SE ± 0.05) to 0.42 (SE ± 0.03) (p = 0.02), and no significant alteration was noted over the timeframe in mean pCO2 (64.4 ± 3.3 to 63.2 ± 3.3 mmHg). The number of infants needing endotracheal intubation and mechanical ventilation decreased (from 3 to 1) over the same time. No serious adverse effects were noted. Sildenafil therapy was associated with a significant improvement in the echocardiographic markers of PAH and a reduction in FiO2. The medication was well tolerated.