Placenta Growth Factor Elevation in the Cord Blood of Premature Neonates Predicts Poor Pulmonary Outcome Po-Nien Tsao, MD*; Shu-Chen Wei, MD‡; Yi-Ning Su, MD§; Chien-Nan Lee, MD, MPH; Hung-Chieh Chou, MD*; Wu-Shiun Hsieh, MD*; and Fon-Jou Hsieh, MD ABSTRACT. Objective. To determine whether an ele- vated placenta growth factor (PlGF) level in cord blood is associated with increased risk for preterm infants to de- velop bronchopulmonary dysplasia (BPD). Methods. Sixty-three preterm infants who were born at 34 weeks’ gestation or earlier were enrolled. Two infants who died before 28 days’ postnatal age could not be as- signed a BPD status and were excluded. PlGF levels in cord blood were measured using enzyme-linked immunosor- bent assay. Mann-Whitney rank sum test, Spearman corre- lation coefficients, and multivariable linear or logistic re- gression analyses were used for statistical analysis. Results. The BPD group had a higher PlGF level, lower gestational age, lower birth weight (BW), higher incidence of endotracheal tube intubation, and longer duration of intubation. The PlGF levels in cord blood correlated nega- tively with gestational age and BW. However, multivari- able logistic regression analyses revealed that only elevated cord blood PlGF levels and BW were associated with BPD after adjusting for all contributing factors. Furthermore, an increased PlGF level in cord blood was significantly corre- lated with the clinical severity of BPD, as measured by duration of intubation. At 17 mg/dL, the specificity of cord blood PlGF level in predicting BPD was 95%, the sensitiv- ity was 53%, the positive predictive value was 83%, and the negative predictive value was 82%. Conclusions. Measuring cord blood PlGF level at birth might be a biological marker for predicting the occurrence of BPD and allowing early therapeutic inter- vention. Pediatrics 2004;113:1348 –1351; bronchopulmo- nary dysplasia, cord blood, placenta growth factor. ABBREVIATIONS. BPD, bronchopulmonary dysplasia; PlGF, pla- centa growth factor; VEGF, vascular endothelial growth factor; GA, gestational age; RDS, respiratory distress syndrome; BW, birth weight. W ith the widespread use of antenatal ste- roids, exogenous surfactant therapy, and improvements in neonatal care, the sur- vival rate of very low birth weight infants has in- creased, but bronchopulmonary dysplasia (BPD) re- mains 1 of the major complications in premature infants who need prolonged ventilator support. The incidence of BPD ranges from 7.5% to 20% in infants who are born before 34 weeks. 1,2 The cause of BPD includes immaturity, prolonged oxygen therapy, barotrauma, volume trauma, infec- tion, and antioxidant/oxidant imbalance. 3,4 In pre- mature infants with BPD, the pathologic findings include alveolar hypoplasia, vascular arrest, adap- tive dysmorphic changes, and variable interstitial proliferation. 5,6 However, only a few candidate bio- logical makers might be able to predict which infants are at greater risk for developing BPD. 7,8 Conse- quently, early therapeutic intervention is difficult. Placenta growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, is a 132–amino acid, 50-kDa dimeric glycoprotein. Present in normal tissues, especially the placenta, thyroid, and lungs, it is an important mediator of angiogenesis and hematopoiesis. 9–13 In our previous study, we demonstrated that PlGF overexpression transgenic mice have enlarged airspace, similar to the pathologic findings of infants with BPD. 14 The aim of this study was to determine whether PlGF levels in the cord blood could predict increased risk for subsequent BPD in preterm infants. METHODS Study Group This study was performed at the National Taiwan University Hospital with the approval of the internal review board. All infants who were born at 34 weeks’ gestation or earlier were enrolled in this study. Infants were excluded when there was evidence of prenatal maternal infection or infection within the first 3 days of life. We determined gestational age (GA) by the last menstrual date or prenatal ultrasound. Weekly prenatal steroids were routinely used when preterm labor occurred from 24 to 34 weeks of gestation. Respiratory distress syndrome (RDS) was defined as acute respiratory failure at birth with characteristic chest radiograph changes in the absence of sepsis, pneumonia, or other causes of respiratory distress. Exogenous surfactant was administered within 2 hours after birth to infants who had RDS and remained ventilator dependent and required a fraction of inspired oxygen 0.4 to maintain pulse oximeter saturation 90%. Infants, ventilated, requiring 40% oxygen and ventilator rate 18/min, were considered by the clinical management team to be ready for extubation. BPD was defined as the need for supplemental oxygen or mechanical ventilation at 28 days’ post- natal age, in association with radiologic changes consistent with BPD. Demographic information and perinatal history were ob- tained from medical records. From the *Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; ‡Depart- ment of Internal Medicine, National Taiwan University College of Medi- cine, Taipei, Taiwan; §Department of Medical Genetics, National Taiwan University College of Medicine, Taipei, Taiwan; and Department of Ob- stetrics and Gynecology, National Taiwan University Hospital, National Taiwan University College of Medicine. Received for publication May 23, 2003; accepted Sep 19, 2003. Reprint requests to (F.J.H.) Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University Hospital, No. 7, Chung- Shan South Road, Taipei, Taiwan. E-mail: fjhsieh@ha.mc.ntu.edu.tw PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- emy of Pediatrics. 1348 PEDIATRICS Vol. 113 No. 5 May 2004