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Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia
Abstract
Objective Periventricular leukomalacia, a common brain white matter lesion in preterm neonates, is a major risk factor for cerebral palsy. Recently, cytokines (i.e., tumor necrosis factor and interleukin-1(beta)) have been implicated as mediators for the development of periventricular leukomalacia. The purpose of this study was to examine the relationship between umbilical cord plasma levels of tumor necrosis factor-alpha, interleukin-1(beta), interleukin-6, and interleukin-1 receptor antagonist and the occurrence of periventricular leukomalacia in preterm neonates.Study design Umbilical cord blood was collected from 172 consecutive preterm births (25 to 36 weeks). Periventricular leukomalacia-associated lesions were diagnosed by brain ultrasonography within the first 3 days of life. Tumor necrosis factor-alpha, interleukin-1(beta) interleukin-6, and interleukin-1 receptor antagonist were measured by sensitive and specific enzyme-linked immunoassay methods. Umbilical cord arterial pH was measured at birth. Statistical analysis was performed with multiple logistic regression and receiver operating characteristic curve analysis.Results Periventricular leukomalacia-associated lesions were present in 14.5% (25/172) of infants. Plasma concentrations of interleukin-6 but not of tumor necrosis factor-alpha, interleukin-1(beta), and interleukin-1 receptor antagonist were significantly higher in neonates with periventricular leukomalacia-associated lesions than in those without these lesions (median 718, range < 226 to 32,000 pg/ml vs median < 226, range < 226 to 43,670 pg/ml; p < 0.0001). An interleukin-6 value > or = 400 pg/ml had a sensitivity of 72% (18/25) and a specificity of 74% (108/147) in the identification of periventricular leukomalacia-associated lesions. Multivariate analysis showed that umbilical cord interleukin-6 was an independent risk factor for periventricular leukomalacia (odds ratio 6.2, p < 0.002) after correction for known confounding variables (i.e., gestational age at birth, umbilical artery pH, chorioamnionitis).Conclusions Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with periventricular leukomalacia-associated lesions. Our data support the hypothesis that periventricular leukomalacia may be the result of cytokine-mediated brain injury.
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“The fetal inflammatory response has been linked to the onset of preterm labour, and fetal injury and long-term handicap—including periventricular leucomalacia, cerebral palsy, and chronic lung disease.92, 93, 94”
From Epidemiology and causes of preterm birth (2008) · cites this paper as [92]
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Zmora, O., Gutzeit, O., Segal, L., Boulos, S., Millo, Z., Ginsberg, Y., Khatib, N., Fainaru, O., Ross, M. G., Weiner, Z., et al. (2020) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.1111/aogs.14054 · Cited by 14
Lutgendorf, M. A., Ippolito, D. L., Mesngon, M. T., Tinnemore, D., Dehart, M. J., Dolinsky, B. M., & Napolitano, P. G. (2013) · Reproductive Sciences · doi:10.1177/1933719113503410 · Cited by 14
Herpesvirus-infected Hofbauer cells activate endothelial cells through an IL-1β-dependent mechanism
Hendrix, P., Tang, Z., Silasi, M., Racicot, K. E., Mor, G., Abrahams, V. M., & Guller, S. M. (2020) · Placenta · doi:10.1016/j.placenta.2020.01.010 · Cited by 14
Premature Rupture of the Membranes
Mercer, B. (2011) · Clinical Obstetrics & Gynecology · doi:10.1097/grf.0b013e31821ac75d · Cited by 14
Cytokines in preterm parturition
Mazor, M., Furman, B., & Bashiri, A. (1998) · Gynecological Endocrinology · doi:10.3109/09513599809012845 · Cited by 14
Antibiotics: Treatment of preterm labor
Reimer, T., Ulfig, N., & Friese, K. (1999) · Journal of Perinatal Medicine · doi:10.1515/jpm.1999.004 · Cited by 14
Acute funisitis is associated with distinct changes in fetal hematologic profile
Kim, E. N., Kim, C. J., Park, J. W., & Yoon, B. H. (2014) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.3109/14767058.2014.927426 · Cited by 13
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MiR-29b is associated with perinatal inflammation in extremely preterm infants
Pavlek, L. R., Vudatala, S., Bartlett, C. W., Buhimschi, I. A., Buhimschi, C. S., & Rogers, L. K. (2020) · Pediatric Research · doi:10.1038/s41390-020-0943-1 · Cited by 13
Wolfsberger, C. H., Bruckner, M., Baik‐Schneditz, N., Schwaberger, B., Mileder, L. P., Avian, A., Urlesberger, B., & Pichler, G. (2020) · Frontiers in Pediatrics · doi:10.3389/fped.2020.00401 · Cited by 13
Neonatal Brain Damage Following Prolonged Latency after Preterm Premature Rupture of Membranes
Park, S. H., Kim, H. J., Yang, J. H., Choi, J. S., Lim, J. E., Oh, M., & Na, J. Y. (2006) · Journal of Korean Medical Science · doi:10.3346/jkms.2006.21.3.485 · Cited by 13
Self-citationPremature Rupture of the Membranes
Mercer, B. M. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-4224-2.50034-x · Cited by 12
Rapid evaluation of the absence of inflammation after rupture of membranes
Berthiaume, M., Rousseau, É., Rola‐Pleszczynski, M., & Pasquier, J. (2013) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.3109/14767058.2013.829814 · Cited by 12
Interleukin‐6 polymorphism and bronchopulmonary dysplasia risk in very low‐birthweight infants
Usuda, T., Kobayashi, T., Sakakibara, S., Kobayashi, A., Kaneko, T., Wada, M., Onozuka, J., Numata, O., Torigoe, K., Yamazaki, H., et al. (2012) · Pediatrics International · doi:10.1111/j.1442-200x.2012.03625.x · Cited by 12
Metadata
- Authors
- Yoon, B. H., Romero, R., Yang, S. H., Jun, J. K., Kim, I.-O., Choi, J.-H., & Syn, H. C.
- Affiliations
- Seoul National University (KR)
- Venue
- American Journal of Obstetrics and Gynecology
- Publisher
- Elsevier BV
- Published
- 1996-05
- Volume
- 174
- Issue
- 5
- Pages
- 1433-1440
- ISSN
- 0002-9378 (ISSN-L)
- OpenAlex
- W1964039180
- Cited by
- 584
- References
- 31
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 13 · 2021: 8 · 2020: 8 · 2019: 9 · 2018: 9 · 2017: 22 · 2016: 14 · 2015: 19 · 2014: 22 · 2013: 22 · 2012: 25
- FWCI
- 21.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Obstetrics and Gynecology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Health Sciences › Medicine › Obstetrics and Gynecology › Preterm Birth and Chorioamnionitis
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and Maternal Infections
- Keywords
- periventricular leukomalacia, interleukin-6, umbilical cord plasma, preterm infants, white matter lesions, TNF-α, IL-1β, interleukin-1 receptor antagonist, cytokines, cerebral palsy risk, umbilical artery pH, biomarkers, risk factors, brain ultrasonography, gestational age
- MeSH terms
- Adult, C-Reactive Protein, Female, Fetal Blood, Humans, Immunoenzyme Techniques, Infant, Newborn, Infant, Premature, Interleukin-1, Leukomalacia, Periventricular, Osmolar Concentration, Pregnancy, ROC Curve, Sensitivity and Specificity, Tumor Necrosis Factor-alpha, Interleukin-6, Receptors, Interleukin-1
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