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

Abstract

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 < .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). Conclusions Cord blood angiogenic factors that are decreased with placental MVU may serve as predictors of BPD-PH.

Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia

“…Similarly, endostatin (ES): angiopoietin‐1 (Ang‐1) ratio on day of life 7 may also be useful as a biomarker for early PH‐risk prediction in patients with severe BPD . Lastly, placental growth factor (PIGF) and NT‐proBNP have also shown potential as biomarkers for PH in BPD . Furthermore, there are likely biomarkers that have not yet been identified, so there is a place for unbiased evaluation of genome wide associations for PH in BPD patients.…”

Fetal Vascular Origins of Bronchopulmonary Dysplasia

“…Mestan et al also convincingly demonstrate that cord blood biomarkers, including placental growth factor, granulocyte colony stimulating factor, and VEGF factor A are decreased in association with striking placental findings of MVU and were further associated with subsequent diagnoses of BPD and PH. 21 Most importantly, placental growth factor and granulocyte colony stimulating factor were markedly decreased in a second validation cohort as well, further supporting the concept that cord blood angiogenic factors are decreased with placental MVU and may be very early predictors of BPD-PH risk. In addition, the authors speculate that disruption of placentation and vascular perfusion represents failed angiogenesis, as reflected by these biomarkers, and that abnormal developmental angiogenesis may reflect abnormalities of vascular signaling that contribute to postnatal disease.…”

“…In this volume of The Journal, Mestan et al 21 provide exciting new information that extends past observations and links abnormalities of placental structure with high risk for BPD and BPD with pulmonary hypertension (PH). This team and others have established the concept that placental vascular structural abnormalities related to hypertensive disorders of pregnancy and preeclampsia are strongly associated with fetal growth restriction and that examination of placental tissue for vascular lesions that reflect maternal underperfusion (MVU) after preterm birth provides a unique and very solid approach to predict the subsequent risk for BPD and PH.…”

Differential Secretion of Angiopoietic Factors and Expression of MicroRNA in Umbilical Cord Blood from Healthy Appropriate-For-Gestational-Age Preterm and Term Newborns—in Search of Biomarkers of Angiogenesis-Related Processes in Preterm Birth

“…VEGF is expressed in villous and extravillous trophoblasts and its expression level alters with adverse pregnancy outcomes [43]. It has been observed that pregnancies with placenta that demonstrated severe vascular under-perfusion were strongly associated with lower levels of proangiogenic factors in UCB, such as VEGF and its soluble receptor sVEGFR-2 [44]. It was found that resident placental endothelial cells from pregnancies characterized by fetal growth restriction resulting in preterm delivery, demonstrated decreased angiogenesis with impaired signaling in different VEGF pathways, including activation of the VEGF-NO signaling [45].…”