kjp Korean Journal of Perinatology Korean J Perinatol 1229-2605 2289-0432 Korean Society of Perinatology 10.14734/kjp.2015.26.1.58 kjp-26-58 Original Article Umbilical Cord Blood Matrix Metalloproteinase-9 Levels are associated with Funisitis ShimSoon SupM.D. 1 KangHye SimM.D. 1 MaengYoung HeeM.D. 2 KimYoung DonM.D., Ph.D. 3 Department of Obstetrics and Gynecology, Jeju National University School of Medicine, Jeju, Korea Department of Pathology, Jeju National University School of Medicine, Jeju, Korea Department of Pediatrics, Jeju National University School of Medicine, Jeju, Korea Correspondence to: Young Don Kim, M.D., Ph.D., Department of Pediatrics, Jeju National University School of Medicine, Ara 1-dong 1753-3, Jeju-si, Jeju Special Self-Governing Province 690-767, South Korea, Tel: +82-64-717-2087, Fax: +82-64-717-1097, E-mail: cardios@hanmail.net 03 2015 20 03 2015 26 1 58 66 08122014 12022015 17022015 Copyright © 2015 Korean Society of Perinatology 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Purpose

Intrauterine inflammation (IUI) is a leading cause of preterm delivery. Although matrix metalloproteinase-8 (MMP-8) and intercellular adhesion molecule-1 (ICAM-1) are known to be related with IUI, it has not been fully elucidated whether MMP-9 or ICAM-3 is associated with IUI. We performed this study to determine whether the levels of tumor necrosis factor-alpha (TNF-α), MMP-9 and ICAM-3 in umbilical cord blood of preterm infants are associated with chorioamnionitis, funisitis or bronchopulmonary dysplasia.

 Methods

Eighty-two pairs of pregnant women and their preterm newborns <35 weeks gestation were enrolled. Levels of TNF-α, MMP-9 and ICAM-3 in umbilical cord blood were measured using immunoassays and compared with results of histological examination of placenta and clinical data of the study participants. Results: The level of MMP-9 in umbilical cord blood was significantly associated with the presence of funisitis (P=0.007). The level of TNF-α in umbilical cord blood was significantly associated with the development of bronchopulmonary dysplasia (P=0.030). However, presence of chorioamnionitis or funisitis was not associated with development of bronchopulmonary dysplasia. With the establishment of receiver operating characteristic (ROC) curve, the best cut-off value for umbilical blood MMP-9 was 99.42 pg/mL in identification of funisitis. The area under a constructed ROC curve for prediction of funisitis was 0.847 (standard error, 0.112; 95% confidence interval, 0.750–0.917).

 Conclusion

Measurement of MMP-9 concentration in umbilical cord blood may be an alternative way to predict whether a preterm infant has been exposed to IUI. Further study with larger numbers of subjects will be necessary to elucidate the association between the presence of IUI and neonatal adverse outcome.

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Comparison of matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-3 (ICAM-3) and tumor necrosis factor-α (TNF-α) level in umbilical cord blood according to the presence or absence of funisitis. Infants from mother with funisitis had a significantly higher level of MMP-9 than those without funisitis (P=0.007).

Comparison of matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-3 (ICAM-3) and tumor necrosis factor-α (TNF- α) level in umbilical cord blood according to the presence or absence of bronchopulmonary dysplasia (BPD). Infants with BPD had a significantly higher level of TNF-α than those without funisitis (P=0.030). Although the median level of ICAM-3 in infants with BPD was lower than those without BPD, there was no statistical significance when the gestational age was adjusted as a cofounding factor.

Receiver operating characteristic curves for identification of the presence of funisitis. Area under the curve for umbilical matrix metalloproteinase-9 level: 0.847 (95% confidence interval: 0.750–0.917, P=0.0019).

Clinical characteristics of the study participants∗

  CA (+) n=22 CA (–) n=60 P value † FN (+) n=5 FN (–) n=77 P value † BPD (+) n=4 BPD (–) n=78 P value †
Mother
 Cesarean section 16 (72.7) 55 (9.7) NS 2 (40) 69 (89.6) 0.016 3 (75) 68 (87.2) NS
 Age (yr) 32.5±4.4 31.6. ±4.3 NS 30.4±5.0 31.9±4.3 NS 29.5±4.7 31.9±4.3 NS
 Serum WBC 10,850.0±3,535.2 9,113.3±2,717.1 1 0.040 1 14,740.0±4,844 9,244.2±2,592. 8 0.000 1 11,625.0±499.2 9,473.4±3,075. 4 NS
 Maternal tachycardia 10 (45.5) 25 (41.7) NS 5 (100) 30 (39.0) 0.012 2 (50) 33 (42.3) NS
 Fetal tachycardia 12 (54.5) 20 (33.3) NS 4 (80) 28 (36.4) NS 2 (50) 30 (38.5) NS
 Funisitis 5 (22.7) 0 (0) 0.001 – – – 1 (25) 4 (5.1) NS
 Chorioamnionitis – – – 5 (100) 17 (22.1) 0.001 1 (25) 21 (26.9) NS
 Antibiotics use 11 (50.0) 11 (18.3) 0.010 4 (80) 18 (23.4) 0.017 1 (25) 21 (26.9) NS
 Dexamethasone use 12 (54.5) 19 (31.7) NS 5 (100) 26 (33.8) 0.006 3 (75) 28 (35.9) NS
 PPROM 11 (50.0) 8 (13.3) 0.001 4 (80) 15 (19.5) 0.009 1 (25) 18 (23.1) NS
 PTL with intact membrane 7 (31.8) 16 (26.7) NS 1 (20) 22 (28.6) NS 1 (25) 22 (28.2) NS
 PIH & others 3 (13.6) 13 (21.7) NS 0 (0) 1 (1.3) NS 1 (25) 14 (17.9) NS
Preterm Infant
 Gestational age (week) 31.3±3.1 33.1±2.3 0.012 29.6±3.4 32.8±2.5 0.010 26.3±1.7 32.9±2.3 0.001
 Birth weight (g) 1,670.0±419.8 1,852.7±517.1 NS 1 1,634.0±546.6 1,814.7±495.6 NS 840.0±209.9 1853.1±455.5 0.001
 Male 11 (50.0) 27 (45.0) NS 3 (60) 35 (45.5) NS 2 (50) 36 (46.2) NS
 SGA 13 (92.9) 24 (54.5) 0.020 5 (100) 32 (60.4) NS 1 (33.3) 19 (34.5) NS
 Apgar score at 1 min 6.6±1.6 7.0±1.6 NS 6.7±1.6 7.0±1.7 NS 5.0±0.8 6.8±1.6 0.016
 Apgar score at 5 min 8.2±1.1 8.5±0.9 NS 8.2±1.0 8.8±0.4 NS 7.8±0.5 8.3±1.0 NS
 RDS 9 (40.9) 8 (13.3) 0.012 2 (40) 15 (19.5) NS 4 (100) 13 (16.7) 0.001
 BPD36 (+) 1 (4.5) 3 (5.0) NS 1 (20) 3 (3.9) NS 4 (100) 3 (3.8) 0.001
 PDA 4 (18.2) 4 (6.7) NS 2 (40) 6 (7.8) NS 1 (25) 7 (9.0) NS
 PVL 2 (9.1) 1 (1.7) NS 0 (0) 3 (3.9) NS 0 (0) 3 (3.8) NS

Abbreviation: CA, chorioamnionitis; FN, funisitis; BPD, bronchopulmonary dysplasia

No NEC, sepsis, pneumothorax, pulmonary hemorrhage, severe intraventricular hemorrhage (grade III or IV) and PDA requiring an operative correction were reported.

Mann-WhitneyU test or Fisher's exact test.