

* Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
Department of Medical Genetics, National Taiwan University College of Medicine, Taipei, Taiwan
|| Department of Obstetrics and Gynecology, National Taiwan University Hospital, National Taiwan University College of Medicine
| ABSTRACT |
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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 assigned a BPD status and were excluded. PlGF levels in cord blood were measured using enzyme-linked immunosorbent assay. Mann-Whitney rank sum test, Spearman correlation coefficients, and multivariable linear or logistic regression 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 negatively with gestational age and BW. However, multivariable 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 correlated 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 sensitivity 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 intervention.
Key Words: bronchopulmonary dysplasia cord blood placenta growth factor
Abbreviations: BPD, bronchopulmonary dysplasia PlGF, placenta growth factor VEGF, vascular endothelial growth factor GA, gestational age RDS, respiratory distress syndrome BW, birth weight
With the widespread use of antenatal steroids, exogenous surfactant therapy, and improvements in neonatal care, the survival rate of very low birth weight infants has increased, but bronchopulmonary dysplasia (BPD) remains 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, infection, and antioxidant/oxidant imbalance.3,4 In premature infants with BPD, the pathologic findings include alveolar hypoplasia, vascular arrest, adaptive dysmorphic changes, and variable interstitial proliferation.5,6 However, only a few candidate biological makers might be able to predict which infants are at greater risk for developing BPD.7,8 Consequently, early therapeutic intervention is difficult.
Placenta growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, is a 132amino acid, 50-kDa dimeric glycoprotein. Present in normal tissues, especially the placenta, thyroid, and lungs, it is an important mediator of angiogenesis and hematopoiesis.913 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 |
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Collection of Cord Blood and PlGF Measurement
Cord blood was collected in heparinized syringes on delivery and centrifuged within 15 minutes of collection. The plasma was kept at 70°C until analysis by a technician who was blinded to the patients' condition. The level of PlGF in the cord blood was assayed by a standardized sandwich enzyme-linked immunosorbent assay method (R&D Systems, Minneapolis, MN) in duplicate according to the manufacturer's protocol.
Data Analysis
Comparisons between unpaired groups were performed by Mann-Whitney rank sum test. The relationships between PlGF and GA, birth weight (BW), and ventilator days were analyzed by Spearman correlation coefficients. Multivariable analyses were conducted using logistic and linear regression. P < .05 was considered statistically significant.
| RESULTS |
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More and more evidence shows that duration of oxygen therapy is a less accurate surrogate to predict long-term pulmonary outcome because the criteria for the use of oxygen is rarely defined.15,16 Therefore, we used the duration of ventilation as another pulmonary outcome. The duration of intubation negatively correlated with GA (P < .001) and BW (P < .001) but positively correlated with the PlGF levels in cord blood (P < .001; Fig 3). Multivariable linear regression with intubation days as the dependent variable revealed that only PlGF level (P = .033) was independently correlated (Table 3).
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A receiver operating characteristics curve was used to determine the best cutoff point of cord blood PlGF to discriminate between infants with and without BPD. The specificity of cord blood PlGF >17 pg/mL for BPD was 95%, the sensitivity was 53%, the positive predictive value was 83%, and the negative predictive value was 82%.
| DISCUSSION |
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The VEGF family includes PlGF. It binds to the VEGF-1 receptor but not to the VEGF-2 receptor; the latter is thought to mediate the angiogenic and proliferative effects of VEGF. PlGF mRNA is present in normal tissues such as the placenta, thyroid, and lungs.10 Previously, we demonstrated that PlGF mRNA was detected in lungs during saccular division. It was downregulated rapidly after alveolarization was completed in mice.14 However, little is known about PlGF expression in human lungs during the last trimester of pregnancy. In this study, we demonstrated that PlGF levels in human cord blood declined with increasing GA, suggesting that PlGF may play a role during human lung development as a synergistic agent with VEGF to promote vasculogenesis.9 It should be downregulated after lung maturation.
In our previous report, we found that overexpression of PlGF in mice caused air space enlargement similar to BPD. Furthermore, we demonstrated that exogenous PlGF inhibited proliferation and promoted death of mouse type II pneumocytes in vitro.14 On the basis of these data, PlGF may exert a key influence on pulmonary remodeling by regulating type II pneumocyte proliferation or death. In this study, we showed that PlGF levels in cord blood were significantly elevated in the BPD group. Although PlGF levels were significantly and negatively correlated with GA, which is smaller in infants with BPD, PlGF still was a significant risk factor of BPD after multivariable logistic regression analysis. Furthermore, the PlGF levels in cord blood were independently correlated with the severity of BPD, as represented by the duration of intubation. These data revealed that PlGF might play a role, via its action on type II pneumocytes, in the pathogenesis of BPD.
The mechanisms that lead to increase PlGF in cord blood of infants with BPD remain unknown. Some suggested that there may be a genetic susceptibility to BPD.1820 In our previous report, we found that maternal PlGF concentration was elevated in Down syndrome pregnancies during the early second trimester.21 We postulate that the additional copy of chromosome 21 might in some way upregulate the expression of PlGF gene or downregulate its degradation. In this study, we demonstrated that elevated cord blood PlGF level was an independent risk factor to develop BPD; it preceded clinical evidence of BPD. Overproduction of PlGF during alveolarization, which may have a genetic predisposition, might be responsible for the subsequently impaired saccular division and BPD.
Recently, 2 reports showed evidence that measuring bombesin-like peptide and keratinocyte growth factor concentrations during the early postnatal course could predict BPD. Cullen et al7 found that elevated urine bombesin-like peptide levels at 1 to 4 days after birth in preterm infants who were born before 28 weeks' gestation increased the risk of developing BPD. Danan et al8 showed that keratinocyte growth factor concentration within 5 days after birth was significantly higher in survivors without BPD than in those with BPD. However, using these 2 markers to predict BPD will be possible until 4 to 5 days after birth. Here, we demonstrated that using cord blood PlGF levels might predict BPD at birth.
In conclusion, the PlGF levels in cord blood correlated significantly and negatively with GA and BW. The cord blood PlGF elevation preceded BPD and was an independent risk factor. High PlGF levels in cord blood were significantly correlated with the clinical severity of BPD, indicating that PlGF might play a role in the pathogenesis of BPD. The measurement of cord blood PlGF level at birth might be a biological marker to permit early intervention and might provide a new therapeutic target to prevent BPD.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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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{at}ha.mc.ntu.edu.tw
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K. A. Mohammed, N. Nasreen, R. S. Tepper, and V. B. Antony Cyclic stretch induces PlGF expression in bronchial airway epithelial cells via nitric oxide release Am J Physiol Lung Cell Mol Physiol, February 1, 2007; 292(2): L559 - L566. [Abstract] [Full Text] [PDF] |
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