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.

Keywords: granulocyte colony-stimulating factor; placental growth factor; premature infant; vascular endothelial growth factor.

Figure

Cord blood PIGF and G-CSF levels in 87 extremely preterm infants, compared according to BPD and PH status. Infants with BPD-PH disease at 36 weeks corrected age (N = 21) had significantly lower levels as compared with all infants without BPD or PH (N = 66). Levels in infants with BPD-PH were also lower when compared with the subgroups of infants with BPD only but no PH (n = 26), and infants without BPD or PH (n = 40). Median biomarker levels compared using Wilcoxon rank-sum. *P < .01 and **P ≤ .001, versus BPD-PH.