Placental pathology and fetal growth outcomes in pregnancies complicated by maternal obesity.

BACKGROUND: The rising prevalence of maternal obesity presents a significant health concern because of the possible implications for obstetric complications and neonatal outcomes. Understanding the impact of obesity on placental structure and function as well as fetal growth and infant outcomes is important to improve the care of these potentially high-risk pregnancies. This study aimed to determine the effect of elevated maternal BMI on histopathologic patterns of placental injury and its consequences on fetal growth. METHODS: Data were collected from an ongoing cohort of maternal-infant dyads in the UCSD Obstetric Registry spanning 2011-2020. Maternal characteristics, including BMI, hypertensive disease and diabetes, placental gross and histopathology, and infant characteristics, including sex and birthweight, were recorded and analyzed. ANOVA and chi-square tests were used in initial analyses, followed by log-binomial and linear regression models adjusted for relevant confounders to determine associations between maternal BMI, specific patterns of placental injury, and infant birthweight percentiles. RESULTS: Among 1366 maternal-infant dyads, placentas from mothers with overweight and obesity were heavier and demonstrated higher adjusted relative risks of chronic villitis (CV), decidual vasculopathy, intervillous thrombosis, and normoblastemia. Placental efficiency, determined by fetal-placental weight ratio, was decreased with increasing BMI. Maternal obesity was associated with higher rates of preterm birth and higher birthweight percentiles. Multiple placental lesions, including maternal (MVM) and fetal vascular malperfusion (FVM), exhibited significant effects on birthweight percentiles; however, only MVM showed a differential effect based on maternal obesity. CONCLUSIONS: Presence of obesity in pregnancy is associated with increased rates of placental patterns of injury, decreased placental efficiency, and increased birthweight percentiles. While placental lesions, such as CV, have the potential to negatively impact fetal growth, the resulting birthweight percentiles demonstrate a more complex relationship between maternal obesity and fetal growth, that likely involves placental and fetal adaptation to the altered in utero environment.

Placental pathology is necessary to understand common pregnancy complications and achieve an improved taxonomy of obstetrical disease.

The importance of a fully functioning placenta for a good pregnancy outcome is unquestioned. Loss of function can lead to pregnancy complications and is often detected by a thorough placental pathologic examination. Placental pathology has advanced the science and practice of obstetrics and neonatal-perinatal medicine by classifying diseases according to underlying biology and specific patterns of injury. Many past obstacles have limited the incorporation of placental findings into both clinical studies and day-to-day practice. Limitations have included variability in the nomenclature used to describe placental lesions, a shortage of perinatal pathologists fully competent to analyze placental specimens, and a troubling lack of understanding of placental diagnoses by clinicians. However, the potential use of placental pathology for phenotypic classification, improved understanding of the biology of adverse pregnancy outcomes, the development of treatment and prevention, and patient counseling has never been greater. This review, written partly in response to a recent critique published in a major obstetrics-gynecology journal, reexamines the role of placental pathology by reviewing current concepts of biology; explaining the most recent terminology; emphasizing the usefulness of specific diagnoses for obstetrician-gynecologists, neonatologists, and patients; previewing upcoming changes in recommendations for placental submission; and suggesting future improvements. These improvements should include further consideration of overall healthcare costs, cost-effectiveness, the clinical value added of placental assessment, improvements in placental pathology education and practice, and leveraging of placental pathology to identify new biomarkers of disease and evaluate novel therapies tailored to specific clinicopathologic phenotypes of both women and infants.

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

OBJECTIVE: To assess whether cord blood biomarkers associated with placental maternal vascular underperfusion (MVU) are predictive of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH). STUDY DESIGN: 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). RESULTS: Cord blood placental growth factor (PIGF), granulocyte-colony stimulating factor (G-CSF), and vascular endothelial growth factor-A were decreased with MVU (P?

Computerized vital signs analysis and late onset infections in extremely low gestational age infants.

AIM: Current clinical and laboratory diagnostics for neonatal infection are inadequate. An infant's systemic inflammatory response may be identified earlier than clinical suspicion by a computerized algorithm (RALIS) incorporating multiple vital signs (VS). We tested the ability of RALIS to detect late onset infection (LOI) earlier than clinically suspected. METHODS: We conducted a retrospective review of infants enrolled in a birth cohort study at Prentice Women's Hospital. VS data (heart rate, respirations, temperature, desaturation, bradycardia) were extracted from electronic records of 73 premature infants (born ≤28 weeks' gestation; survived first month). RALIS generated a continuous output for the first 28 days of life. A score ≥5 for 6 h triggered an alert. The time of RALIS alert to time of clinical suspicion of infection (time culture sent) was measured for each episode of suspected and/or confirmed LOI. RESULTS: Among the 73 infants followed with RALIS, there were 34 episodes of culture-positive LOI, seven culture-negative but treated episodes, and 13 false-positive culture (untreated) episodes. Twenty-five infants had no culture-positive or treated sepsis events during the observation period. There was a positive linear association between alert and culture (ß=0.88, P<0.001). Mean absolute time difference between alert and culture was 59.4 h before culture. Sensitivity and specificity of RALIS for LOI were 0.82 and 0.44. CONCLUSION: The RALIS algorithm is a sensitive indicator for early detection of infection in preterm infants. Further modifications to improve the specificity of the algorithm are needed prior to application of VS modeling to patient antibiotic treatment decisions.

Cord Blood Adductomics Reveals Oxidative Stress Exposure Pathways of Bronchopulmonary Dysplasia.

Fetal and neonatal exposures to perinatal oxidative stress (OS) are key mediators of bronchopulmonary dysplasia (BPD). To characterize these exposures, adductomics is an exposure science approach that captures electrophilic addition products (adducts) in blood protein. Adducts are bound to the nucleophilic cysteine loci of human serum albumin (HSA), which has a prolonged half-life. We conducted targeted and untargeted adductomics to test the hypothesis that adducts of OS vary with BPD. We studied 205 preterm infants (≤28 weeks) and 51 full-term infants from an ongoing birth cohort. Infant plasma was collected at birth (cord blood), 1-week, 1-month, and 36-weeks postmenstrual age. HSA was isolated from plasma, trypsin digested, and analyzed using high-performance liquid chromatography-mass spectrometry to quantify previously annotated (known) and unknown adducts. We identified 105 adducts in cord and postnatal blood. A total of 51 known adducts (small thiols, direct oxidation products, and reactive aldehydes) were increased with BPD. Postnatally, serial concentrations of several known OS adducts correlated directly with supplemental oxygen exposure. The application of large-scale adductomics elucidated OS-mediated pathways of BPD. This is the first study to investigate the "neonatal-perinatal exposome" and to identify oxidative stress-related exposure biomarkers that may inform antioxidant strategies to protect the health of future generations of infants.

Macrophage Polarizations in the Placenta and Lung are Associated with Bronchopulmonary Dysplasia.

The intricate interplay between macrophage polarization and placenta vascular dysfunction has garnered increasing attention in the context of placental inflammatory diseases. This study delves into the complex relationship between macrophage polarization within the placenta and its potential impact on the development of vascular dysfunction and inflammatory conditions. The placenta, a crucial organ in fetal development, relies on a finely tuned balance of immune responses for proper functioning. Disruptions in this delicate equilibrium can lead to pathological conditions, including inflammatory diseases affecting the fetus and newborn infant. We explored the interconnectedness between placental macrophage polarization and its relevance to lung macrophages, particularly in the context of early life lung development. Bronchopulmonary dysplasia (BPD), the most common chronic lung disease of prematurity, has been associated with abnormal immune responses, and understanding the role of macrophages in this context is pivotal. The investigation aims to shed light on how alterations in placental macrophage polarization may contribute to lung macrophage behavior and, consequently, influence the development of BPD. By unraveling the intricate mechanisms linking macrophage polarization, placental dysfunction and BPD, this research seeks to provide insights that could pave the way for targeted therapeutic interventions. The findings may offer novel perspectives on preventing and managing placental and lung-related pathologies, ultimately contributing to improved maternal and neonatal health outcomes.

Universal Digital High-Resolution Melt Analysis for the Diagnosis of Bacteremia.

Fast and accurate diagnosis of bloodstream infection is necessary to inform treatment decisions for septic patients, who face hourly increases in mortality risk. Blood culture remains the gold standard test but typically requires approximately 15 hours to detect the presence of a pathogen. We, therefore, assessed the potential for universal digital high-resolution melt (U-dHRM) analysis to accomplish faster broad-based bacterial detection, load quantification, and species-level identification directly from whole blood. Analytical validation studies demonstrated strong agreement between U-dHRM load measurement and quantitative blood culture, indicating that U-dHRM detection is highly specific to intact organisms. In a pilot clinical study of 17 whole blood samples from pediatric patients undergoing simultaneous blood culture testing, U-dHRM achieved 100% concordance when compared with blood culture and 88% concordance when compared with clinical adjudication. Moreover, U-dHRM identified the causative pathogen to the species level in all cases where the organism was represented in the melt curve database. These results were achieved with a 1-mL sample input and sample-to-answer time of 6 hours. Overall, this pilot study suggests that U-dHRM may be a promising method to address the challenges of quickly and accurately diagnosing a bloodstream infection.

Leveraging the placenta to advance neonatal care.

The impact of placental dysfunction and placental injury on the fetus and newborn infant has become a topic of growing interest in neonatal disease research. However, the use of placental pathology in directing or influencing neonatal clinical management continues to be limited for a wide range of reasons, some of which are historical and thus easily overcome today. In this review, we summarize the most recent literature linking placental function to neonatal outcomes, focusing on clinical placental pathology findings and the most common neonatal diagnoses that have been associated with placental dysfunction. We discuss how recent technological advances in neonatal and perinatal medicine may allow us to make a paradigm shift, in which valuable information provided by the placenta could be used to guide neonatal management more effectively, and to ultimately enhance neonatal care in order to improve our patient outcomes. We propose new avenues of clinical management in which the placenta could serve as a diagnostic tool toward more personalized neonatal intensive care unit management.

Development of a novel humanized mouse model to study bronchopulmonary dysplasia.

Rationale: The role of circulating fetal monocytes in bronchopulmonary dysplasia is not known. We utilized a humanized mouse model that supports human progenitor cell engraftment (MISTRG) to test the hypothesis that prenatal monocyte programming alters early lung development and response to hyperoxia. Methods: Cord blood-derived monocytes from 10 human infants were adoptively transferred into newborn MISTRG mice at p0 (1 × 106 cells/mouse, intrahepatic injection) followed by normoxia versus hyperoxia (85% oxygen × 14 days). Lungs were harvested at p14 for alveolar histology (alveolar count, perimeter and area) and vascular parameters (vWF staining for microvessel density, Fulton's index). Human CD45 staining was conducted to compare presence of hematopoietic cells. Murine lung parameters were compared among placebo and monocyte-injected groups. The individual profiles of the 10 patients were further considered, including gestational age (GA; n = 2 term, n = 3 moderate/late preterm, and n = 5 very preterm infants) and preeclampsia (n = 4 patients). To explore the monocyte microenvironment of these patients, 30 cytokines/chemokines were measured in corresponding human plasma by multiplex immunoassay. Results: Across the majority of patients and corresponding mice, MISTRG alveolarization was simplified and microvessel density was decreased following hyperoxia. Hyperoxia-induced changes were seen in both placebo (PBS) and monocyte-injected mice. Under normoxic conditions, alveolar development was altered modestly by monocytes as compared with placebo (P < 0.05). Monocyte injection was associated with increased microvessel density at P14 as compared with placebo (26.7 ± 0.73 vs. 18.8 ± 1.7 vessels per lung field; P < 0.001). Pooled analysis of patients revealed that injection of monocytes from births complicated by lower GA and preeclampsia was associated with changes in alveolarization and vascularization under normoxic conditions. These differences were modified by hyperoxia. CD45+ cell count was positively correlated with plasma monocyte chemoattractant protein-1 (P < 0.001) and macrophage inflammatory protein-1ß (P < 0.01). Immunohistochemical staining for human CD206 and mouse F4/80 confirmed absence of macrophages in MISTRG lungs at P14. Conclusions: Despite the inherent absence of macrophages in early stages of lung development, immunodeficient MISTRG mice revealed changes in alveolar and microvascular development induced by human monocytes. MISTRG mice exposed to neonatal hyperoxia may serve as a novel model to study isolated effects of human monocytes on alveolar and pulmonary vascular development.

Placental dysfunction influences fetal monocyte subpopulation gene expression in preterm birth.

The placenta is the primary organ for immune regulation, nutrient delivery, gas exchange, protection against environmental toxins, and physiologic perturbations during pregnancy. Placental inflammation and vascular dysfunction during pregnancy are associated with a growing list of prematurity-related complications. The goal of this study was to identify differences in gene expression profiles in fetal monocytes - cells that persist and differentiate postnatally - according to distinct placental histologic domains. Here, by using bulk RNA-Seq, we report that placental lesions are associated with gene expression changes in fetal monocyte subsets. Specifically, we found that fetal monocytes exposed to acute placental inflammation upregulate biological processes related to monocyte activation, monocyte chemotaxis, and platelet function, while monocytes exposed to maternal vascular malperfusion lesions downregulate these processes. Additionally, we show that intermediate monocytes might be a source of mitogens, such as HBEGF, NRG1, and VEGFA, implicated in different outcomes related to prematurity. This is the first study to our knowledge to show that placental lesions are associated with unique changes in fetal monocytes and monocyte subsets. As fetal monocytes persist and differentiate into various phagocytic cells following birth, our study may provide insight into morbidity related to prematurity and ultimately potential therapeutic targets.

Genomic sequencing in clinical trials.

Human genome sequencing is the process by which the exact order of nucleic acid base pairs in the 24 human chromosomes is determined. Since the completion of the Human Genome Project in 2003, genomic sequencing is rapidly becoming a major part of our translational research efforts to understand and improve human health and disease. This article reviews the current and future directions of clinical research with respect to genomic sequencing, a technology that is just beginning to find its way into clinical trials both nationally and worldwide. We highlight the currently available types of genomic sequencing platforms, outline the advantages and disadvantages of each, and compare first- and next-generation techniques with respect to capabilities, quality, and cost. We describe the current geographical distributions and types of disease conditions in which these technologies are used, and how next-generation sequencing is strategically being incorporated into new and existing studies. Lastly, recent major breakthroughs and the ongoing challenges of using genomic sequencing in clinical research are discussed.

Understanding Racial Disparities of Preterm Birth Through the Placenta.

The racial disparity associated with preterm birth is a public health concern in the United States. The placenta is the principal metabolic, respiratory, and endocrine organ of the fetus and a key route by which environmental exposures are transmitted from mother to offspring. Available at every delivery, it may serve as a marker of differences in prenatal exposures that manifest differently by race. Recently, we described differences in placental pathology between African-American and White preterm births: the prevalence of chronic inflammation was higher among African-American women's placentas compared with those of White women. Similarly, racial differences have been shown in placental malperfusion and placental weight. Social determinants such as poverty and stress from discrimination have been implicated in racial disparities in preterm birth. To date, however, the underlying biological mechanisms, whether through inflammatory, oxidative stress, or other pathways involving epigenetic programming, remain largely unknown. The placenta, complemented by maternal and umbilical cord blood biomarkers, may provide important information on the perinatal environment that explains the origins of racial disparities in preterm birth rates and subsequent health outcomes. This article reviews existing literature and current research gaps. Opportunities are discussed for future placental research that may reveal novel mechanisms leading to the development of new approaches in the prevention and management of preterm birth and its outcomes.

Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants.

Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O2) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function. Together, these findings have important implications as they suggest that perinatal Klotho deficiency contributes to BPD-PH risk and strategies that preserve Klotho levels, may improve long-term cardiopulmonary outcomes in preterm infants.

Variations in Umbilical Cord Hematopoietic and Mesenchymal Stem Cells With Bronchopulmonary Dysplasia.

Objective: To test the hypothesis that umbilical cord blood-derived CD34+ hematopoietic stem cells (HPSC), cord tissue-derived CD90+ and CD105+ mesenchymal stem cells (MSC) vary with bronchopulmonary dysplasia (BPD). Methods: We conducted a prospective longitudinal study at a large birth center (Prentice Women's Hospital in Chicago, IL). Premature infants (N = 200) were enrolled in 2:1:1 ratio based on gestational age (GA): mildly preterm (31-32 weeks), moderately preterm (29-30 weeks), and extremely preterm (23-28 weeks). Cord blood (CB) and cord tissues (CT) were collected at birth using commercial banking kits, and analyzed for collection blood volume, tissue mass, CD34+, CD90+, CD105+ counts, and concentrations. Multiplex immunoassay was used to measure 12 cytokines and growth factors in CB plasma of 74 patients. BPD severity was defined according to NIH consensus definitions. Univariate and multivariate regression models were used to identify perinatal covariates and assess associations between stem cell concentrations, cytokines, and BPD outcomes. Results: Of 200 patients enrolled (mean GA = 30 ± 2 weeks), 30 developed mild, 24 moderate, and 19 severe BPD. Concentrations of HPSC and MSC, as measured by %CD34+, %CD90+, and %CD105+ of total cells, increased with degree of prematurity. Collection parameters varied with GA, birth weight (BW), gender, prolonged rupture of membranes, mode of delivery, chorioamnionitis, and multiple gestation. Moderate-severe BPD or death was increased with lower GA, BW, Apgar scores, and documented delayed cord clamping. %CD34+ and %CD90+ were increased with BPD and directly correlated with BPD severity. Severe BPD was positively associated with %CD34+ (beta-coefficient = 0.9; 95% CI = 0.4-1.5; P < 0.01) and %CD90+ (beta-coefficient = 0.4; 95% CI = 0.2-0.6; P < 0.001) after adjustment for covariates. CB plasma granulocyte-colony stimulating factor (G-CSF) was inversely associated with %CD90+, and decreased with BPD. Below median G-CSF combined with elevated %CD90+ predicted BPD (positive predictive value = 100%). Conclusions: CB and CT collections yielded high concentrations of HPSCs and MSCs in BPD infants, accompanied by low circulating G-CSF. These variations suggest possible mechanisms by which stem cell differentiation and function predict BPD.

Racial differences in placental pathology among very preterm births.

INTRODUCTION: African American women are at higher risk for preterm birth compared to white women, but no placental pathology has characterized this disparity. The objective of this study was to examine the association of race with placental pathology among very preterm births. METHODS: We conducted an eight-year retrospective cohort study of very preterm infants born at ≤32 weeks at Northwestern Prentice Women's Hospital in Chicago, Illinois. Archived placental slides underwent standardized masked histopathologic review. Logistic regression was performed for placental pathology, adjusting for available relevant covariates and stratified by infant sex and gestational age. RESULTS: Placentas were available for 296 white and 224 African American mother-infant pairs among births at ≤32 weeks gestation. Compared to placentas from white births, the adjusted OR (aOR) for acute inflammation in placentas from African American births was 1.95 (95% CI 0.87-4.37), the aOR for chronic inflammation was 3.35 (1.49-7.54), the aOR for fetal vascular pathology was 0.82 (0.29-2.32), and the aOR for maternal vascular pathology was 1.01 (0.51-1.99). Stratified analysis showed associations between all placental pathologies and race among male births. Across gestational age groups (<28 and ≥ 28 weeks), the association between race and placental pathology was present for chronic inflammation and fetal vascular pathology. DISCUSSION: Race is associated with placental pathology, and in particular, with chronic inflammation among very preterm births. The effect is modified by infant sex and gestational age. Placental histopathology may be useful markers for understanding the biological processes that shape disparities in pregnancy outcomes.

Cord blood alpha klotho is decreased in small for gestational age preterm infants with placental lesions of accelerated aging.

BACKGROUND: Intrauterine growth restriction is often accompanied by placental vascular disease, of which histologic maternal vascular malperfusion is prominent. Maternal vascular malperfusion is characterized by accelerated villous maturation consistent with placental aging. Alpha klotho is an anti-aging protein produced by the placenta. We hypothesize that cord blood alpha klotho varies with maternal vascular malperfusion and small for gestational age infants through dysregulated angiogenesis. METHODS: Nested case-control study of 54 preterm infants (N = 22 small for gestational age infants, 32 appropriate for gestational age infants, mean gestational age = 33.7 ±â€¯2.7 weeks) and validation sample (N = 39) from a longitudinal birth cohort at Prentice Women's Hospital, Chicago, IL. Cord blood alpha klotho was measured via enzyme-linked immunoassay; concentrations were linked to multiplex data of cord blood angiogenic growth factors. RESULTS: Median cord blood alpha klotho was decreased in small for gestational age infants (1200 [859, 2083] pg/mL) versus controls (3193 [1703, 3963] pg/mL; p < 0.01) and with severe maternal vascular malperfusion (1170 [760, 2645] pg/mL; P < 0.01), consistent with validation sample. Alpha klotho was decreased with maternal vascular malperfusion sublesions signifying accelerated villous maturation, including increased syncytial knots (1230 [805, 3606] pg/mL; p < 0.05) and distal villous hypoplasia (1170 [770, 3390] pg/mL; p < 0.05). Among 15 angiogenic markers, alpha klotho correlated directly with angiopoietin-2 (beta-coefficient = 2.6, p = 0.01). CONCLUSIONS: Cord blood alpha klotho is decreased with small for gestational infants and maternal vascular malperfusion sublesions of accelerated placental villous maturation, and correlated with angiopoietin-2. Alpha klotho may play a role in vascular-mediated accelerated placental aging leading to intrauterine growth restriction.

Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide.

BACKGROUND: Chronic lung disease and severe intraventricular hemorrhage or periventricular leukomalacia in premature infants are associated with abnormal neurodevelopmental outcomes. In a previous randomized, controlled, single-center trial of premature infants with the respiratory distress syndrome, inhaled nitric oxide decreased the risk of death or chronic lung disease as well as severe intraventricular hemorrhage and periventricular leukomalacia. We hypothesized that infants treated with inhaled nitric oxide would also have improved neurodevelopmental outcomes. METHODS: We conducted a prospective, longitudinal follow-up study of premature infants who had received inhaled nitric oxide or placebo to investigate neurodevelopmental outcomes at two years of corrected age. Neurologic examination, neurodevelopmental assessment, and anthropometric measurements were made by examiners who were unaware of the children's original treatment assignment. RESULTS: A total of 138 children (82 percent of survivors) were evaluated. In the group given inhaled nitric oxide, 17 of 70 children (24 percent) had abnormal neurodevelopmental outcomes, defined as either disability (cerebral palsy, bilateral blindness, or bilateral hearing loss) or delay (no disability, but one score of less than 70 on the Bayley Scales of Infant Development II), as compared with 31 of 68 children (46 percent) in the placebo group (relative risk, 0.53; 95 percent confidence interval, 0.33 to 0.87; P=0.01). This effect persisted after adjustment for birth weight and sex, as well as for the presence or absence of chronic lung disease and severe intraventricular hemorrhage or periventricular leukomalacia. The improvement in neurodevelopmental outcome in the group given inhaled nitric oxide was primarily due to a 47 percent decrease in the risk of cognitive impairment (defined by a score of less than 70 on the Bayley Mental Developmental Index) (P=0.03). CONCLUSIONS: Premature infants treated with inhaled nitric oxide have improved neurodevelopmental outcomes at two years of age.

An update on the diagnosis and management of bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension.

The past decade of neonatal care has been highlighted by increased survival rates in smaller and more premature infants. Despite reduction in mortality associated with extreme prematurity, long term pulmonary morbidities remain a concern, with growing recognition of the clinical burden attributable to infants with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH). Recent publications shed light on the critical contributions of maternal placental pathology and compromised intrauterine growth to fetal pulmonary vascular development. A body of literature has further clarified postnatal risk factors for PH, most notably the severity of BPD but surprisingly the additional presence of non-pulmonary morbidities including necrotizing enterocolitis (NEC). Limitations of current diagnostics persist with growing consideration of novel echocardiographic approaches as well as complementary non-invasive biomarkers to better identify infants at risk. In 2015, a joint report published by the American Heart Association and American Thoracic Society provided the first guidelines for the care of children with PH with limited content to address BPD-associated PH. These guidelines were expanded upon in an expert consensus report produced by the Pediatric Pulmonary Hypertension Network (PPHNet). These recommendations encouraged the use of standardized screening protocols and emphasized the importance of evaluation and treatment of comorbidities when PH is identified. Cardiac catheterization was recommended prior to initiation of therapy for more accurate quantification of pulmonary pressures, clarification of anatomy and guidance in the use of pharmacotherapy. Despite these guidelines, significant practice variation persists and gaps remain with respect to optimal evaluation and management of BPD-associated PH.