Skip to main content
NCBI home page
Archives of Disease in Childhood. Fetal and Neonatal Edition logoLink to Archives of Disease in Childhood. Fetal and Neonatal Edition
. 2003 Nov;88(6):F501–F504. doi: 10.1136/fn.88.6.F501

Increased serum levels of interleukin 6 are associated with severe intraventricular haemorrhage in extremely premature infants

A Heep, D Behrendt, P Nitsch, R Fimmers, P Bartmann, J Dembinski
PMCID: PMC1763237  PMID: 14602698

Abstract

Background: Intraventricular haemorrhage (IVH) and periventricular leucomalacia (PVL) in premature infants presumably have many causes. It has been proposed that inflammatory processes in the fetomaternal unit play an important role in the pathogenesis of these lesions.

Objective: To study the correlation of postpartum serum interleukin 6 (IL6) concentration as a marker of inflammation and neonatal cerebral morbidity in preterm infants < 28 weeks of gestational age.

Methods: A total of 88 infants were grouped according to maximum serum IL6 levels within 12 hours post partum: group A (n = 50), ⩽ 100 pg/ml; group B (n = 38), > 100 pg/ml. Ultrasound studies and clinical assessment were performed routinely.

Results: IVH was noted significantly more often in group B (24/38; 63%) than in group A (19/50; 38%) (p = 0.02). In a multiple logistic regression model, raised serum IL6 independently predicted development of severe IVH (odds ratio 8.4; 95% confidence interval 2.85 to 24.9; p = 0.0001).

Conclusions: Raised serum IL6 may serve as a marker for severe IVH in infants < 28 weeks of gestational age. Although cerebral morbidity in premature infants is determined by different variables, the identification of systemic inflammation can help to define the need for anti-inflammatory strategies to prevent cerebral morbidity.

Full Text

The Full Text of this article is available as a PDF (258.7 KB).

Figure 1 .

Figure 1

Open in a new tab

Distribution of CRIB score in group A (IL6 ⩽ 100 pg/ml) v group B (IL6 > 100 pg/ml) (n = 88) (p = 0.063). The graphic is jittered (5%) to figure overlapping data.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Acarin L., González B., Castellano B. Neuronal, astroglial and microglial cytokine expression after an excitotoxic lesion in the immature rat brain. Eur J Neurosci. 2000 Oct;12(10):3505–3520. doi: 10.1046/j.1460-9568.2000.00226.x. [DOI] [PubMed] [Google Scholar]
  2. Bada H. S., Korones S. B., Perry E. H., Arheart K. L., Ray J. D., Pourcyrous M., Magill H. L., Runyan W., 3rd, Somes G. W., Clark F. C. Mean arterial blood pressure changes in premature infants and those at risk for intraventricular hemorrhage. J Pediatr. 1990 Oct;117(4):607–614. doi: 10.1016/s0022-3476(05)80700-0. [DOI] [PubMed] [Google Scholar]
  3. Bührer C., Grimmer I., Metze B., Obladen M. The CRIB (Clinical Risk Index for Babies) score and neurodevelopmental impairment at one year corrected age in very low birth weight infants. Intensive Care Med. 2000 Mar;26(3):325–329. doi: 10.1007/s001340051157. [DOI] [PubMed] [Google Scholar]
  4. Cai Z., Pan Z. L., Pang Y., Evans O. B., Rhodes P. G. Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatr Res. 2000 Jan;47(1):64–72. doi: 10.1203/00006450-200001000-00013. [DOI] [PubMed] [Google Scholar]
  5. Dammann O., Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res. 1997 Jul;42(1):1–8. doi: 10.1203/00006450-199707000-00001. [DOI] [PubMed] [Google Scholar]
  6. Davies J. K., Shikes R. H., Sze C. I., Leslie K. K., McDuffie R. S., Jr, Romero R., Gibbs R. S. Histologic inflammation in the maternal and fetal compartments in a rabbit model of acute intra-amniotic infection. Am J Obstet Gynecol. 2000 Nov;183(5):1088–1093. doi: 10.1067/mob.2000.108888. [DOI] [PubMed] [Google Scholar]
  7. De Felice C, Toti P., Laurini R. N., Stumpo M., Picciolini E., Todros T., Tanganelli P., Buonocore G., Bracci R. Early neonatal brain injury in histologic chorioamnionitis. J Pediatr. 2001 Jan;138(1):101–104. doi: 10.1067/mpd.2001.109605. [DOI] [PubMed] [Google Scholar]
  8. Duggan P. J., Edwards A. D. Placental inflammation and brain injury in preterm infants. Dev Med Child Neurol Suppl. 2001 Mar;86:16–17. doi: 10.1111/j.1469-8749.2001.tb04140.x. [DOI] [PubMed] [Google Scholar]
  9. Duggan P. J., Maalouf E. F., Watts T. L., Sullivan M. H., Counsell S. J., Allsop J., Al-Nakib L., Rutherford M. A., Battin M., Roberts I. Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet. 2001 Nov 17;358(9294):1699–1700. doi: 10.1016/s0140-6736(01)06723-x. [DOI] [PubMed] [Google Scholar]
  10. Eklind S., Mallard C., Leverin A. L., Gilland E., Blomgren K., Mattsby-Baltzer I., Hagberg H. Bacterial endotoxin sensitizes the immature brain to hypoxic--ischaemic injury. Eur J Neurosci. 2001 Mar;13(6):1101–1106. doi: 10.1046/j.0953-816x.2001.01474.x. [DOI] [PubMed] [Google Scholar]
  11. Gatti S., Bartfai T. Induction of tumor necrosis factor-alpha mRNA in the brain after peripheral endotoxin treatment: comparison with interleukin-1 family and interleukin-6. Brain Res. 1993 Oct 8;624(1-2):291–294. doi: 10.1016/0006-8993(93)90090-a. [DOI] [PubMed] [Google Scholar]
  12. Gomez R., Romero R., Ghezzi F., Yoon B. H., Mazor M., Berry S. M. The fetal inflammatory response syndrome. Am J Obstet Gynecol. 1998 Jul;179(1):194–202. doi: 10.1016/s0002-9378(98)70272-8. [DOI] [PubMed] [Google Scholar]
  13. Krueger M., Nauck M. S., Sang S., Hentschel R., Wieland H., Berner R. Cord blood levels of interleukin-6 and interleukin-8 for the immediate diagnosis of early-onset infection in premature infants. Biol Neonate. 2001 Aug;80(2):118–123. doi: 10.1159/000047130. [DOI] [PubMed] [Google Scholar]
  14. Kuban K., Sanocka U., Leviton A., Allred E. N., Pagano M., Dammann O., Share J., Rosenfeld D., Abiri M., DiSalvo D. White matter disorders of prematurity: association with intraventricular hemorrhage and ventriculomegaly. The Developmental Epidemiology Network. J Pediatr. 1999 May;134(5):539–546. doi: 10.1016/s0022-3476(99)70237-4. [DOI] [PubMed] [Google Scholar]
  15. Lago P., Freato F., Bettiol T., Chiandetti L., Vianello A., Zaramella P. Is the CRIB score (clinical risk index for babies) a valid tool in predicting neurodevelopmental outcome inExtremely low birth weight infants? Biol Neonate. 1999 Oct;76(4):220–227. doi: 10.1159/000014162. [DOI] [PubMed] [Google Scholar]
  16. Mark K. S., Miller D. W. Increased permeability of primary cultured brain microvessel endothelial cell monolayers following TNF-alpha exposure. Life Sci. 1999;64(21):1941–1953. doi: 10.1016/s0024-3205(99)00139-3. [DOI] [PubMed] [Google Scholar]
  17. Maskin B., Gammella D., Solari L., Videta W., Barboza M. F., Geliz L., Rondina C. Liberación precoz de la citokina antiinflamatoria IL10 en el trauma severo de cráneo. Medicina (B Aires) 2001;61(5 Pt 1):573–576. [PubMed] [Google Scholar]
  18. Messer J., Eyer D., Donato L., Gallati H., Matis J., Simeoni U. Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal infection. J Pediatr. 1996 Oct;129(4):574–580. doi: 10.1016/s0022-3476(96)70123-3. [DOI] [PubMed] [Google Scholar]
  19. Murphy B. P., Inder T. E., Rooks V., Taylor G. A., Anderson N. J., Mogridge N., Horwood L. J., Volpe J. J. Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome. Arch Dis Child Fetal Neonatal Ed. 2002 Jul;87(1):F37–F41. doi: 10.1136/fn.87.1.F37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Paneth N. Classifying brain damage in preterm infants. J Pediatr. 1999 May;134(5):527–529. doi: 10.1016/s0022-3476(99)70231-3. [DOI] [PubMed] [Google Scholar]
  21. Papile L. A., Burstein J., Burstein R., Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978 Apr;92(4):529–534. doi: 10.1016/s0022-3476(78)80282-0. [DOI] [PubMed] [Google Scholar]
  22. Protonotariou E., Malamitsi-Puchner A., Giannaki G., Rizos D., Phocas I., Sarandakou A. Patterns of inflammatory cytokine serum concentrations during the perinatal period. Early Hum Dev. 1999 Sep;56(1):31–38. doi: 10.1016/s0378-3782(99)00029-8. [DOI] [PubMed] [Google Scholar]
  23. Raivich G., Jones L. L., Werner A., Blüthmann H., Doetschmann T., Kreutzberg G. W. Molecular signals for glial activation: pro- and anti-inflammatory cytokines in the injured brain. Acta Neurochir Suppl. 1999;73:21–30. doi: 10.1007/978-3-7091-6391-7_4. [DOI] [PubMed] [Google Scholar]
  24. Schultz Christian, Rott Christina, Temming Petra, Schlenke Peter, Möller Jens C., Bucsky Peter. Enhanced interleukin-6 and interleukin-8 synthesis in term and preterm infants. Pediatr Res. 2002 Mar;51(3):317–322. doi: 10.1203/00006450-200203000-00009. [DOI] [PubMed] [Google Scholar]
  25. Stanimirovic D., Satoh K. Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol. 2000 Jan;10(1):113–126. doi: 10.1111/j.1750-3639.2000.tb00248.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Suzuki S., Tanaka K., Nogawa S., Nagata E., Ito D., Dembo T., Fukuuchi Y. Temporal profile and cellular localization of interleukin-6 protein after focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 1999 Nov;19(11):1256–1262. doi: 10.1097/00004647-199911000-00010. [DOI] [PubMed] [Google Scholar]
  27. Synnes A. R., Chien L. Y., Peliowski A., Baboolal R., Lee S. K., Canadian NICU Network Variations in intraventricular hemorrhage incidence rates among Canadian neonatal intensive care units. J Pediatr. 2001 Apr;138(4):525–531. doi: 10.1067/mpd.2001.111822. [DOI] [PubMed] [Google Scholar]
  28. Sävman K., Blennow M., Gustafson K., Tarkowski E., Hagberg H. Cytokine response in cerebrospinal fluid after birth asphyxia. Pediatr Res. 1998 Jun;43(6):746–751. doi: 10.1203/00006450-199806000-00006. [DOI] [PubMed] [Google Scholar]
  29. Tortorolo G., Luciano R., Papacci P., Tonelli T. Intraventricular hemorrhage: past, present and future, focusing on classification, pathogenesis and prevention. Childs Nerv Syst. 1999 Nov;15(11-12):652–661. doi: 10.1007/s003810050454. [DOI] [PubMed] [Google Scholar]
  30. Van Dam A. M., Bauer J., Tilders F. J., Berkenbosch F. Endotoxin-induced appearance of immunoreactive interleukin-1 beta in ramified microglia in rat brain: a light and electron microscopic study. Neuroscience. 1995 Apr;65(3):815–826. doi: 10.1016/0306-4522(94)00549-k. [DOI] [PubMed] [Google Scholar]
  31. Volpe J. J. Intraventricular hemorrhage and brain injury in the premature infant. Diagnosis, prognosis, and prevention. Clin Perinatol. 1989 Jun;16(2):387–411. [PubMed] [Google Scholar]
  32. Weeks J. W., Reynolds L., Taylor D., Lewis J., Wan T., Gall S. A. Umbilical cord blood interleukin-6 levels and neonatal morbidity. Obstet Gynecol. 1997 Nov;90(5):815–818. doi: 10.1016/S0029-7844(97)00421-3. [DOI] [PubMed] [Google Scholar]
  33. Winkler M., Rath W., Fischer D. C., van de Leur E., Haubeck H. Regulation of interleukin-8 synthesis in human lower uterine segment fibroblasts by cytokines and growth factors. Obstet Gynecol. 2000 Apr;95(4):584–588. doi: 10.1016/s0029-7844(99)00614-6. [DOI] [PubMed] [Google Scholar]
  34. Yanowitz Toby Debra, Jordan Jeanne Ann, Gilmour Carol Huntress, Towbin Richard, Bowen A'Delbert, Roberts James Michael, Brozanski Beverly Sobchak. Hemodynamic disturbances in premature infants born after chorioamnionitis: association with cord blood cytokine concentrations. Pediatr Res. 2002 Mar;51(3):310–316. doi: 10.1203/00006450-200203000-00008. [DOI] [PubMed] [Google Scholar]
  35. Yoon B. H., Jun J. K., Romero R., Park K. H., Gomez R., Choi J. H., Kim I. O. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol. 1997 Jul;177(1):19–26. doi: 10.1016/s0002-9378(97)70432-0. [DOI] [PubMed] [Google Scholar]
  36. Yoon B. H., Kim C. J., Romero R., Jun J. K., Park K. H., Choi S. T., Chi J. G. Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits. Am J Obstet Gynecol. 1997 Oct;177(4):797–802. doi: 10.1016/s0002-9378(97)70271-0. [DOI] [PubMed] [Google Scholar]
  37. Yoon B. H., Romero R., Kim C. J., Koo J. N., Choe G., Syn H. C., Chi J. G. High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol. 1997 Aug;177(2):406–411. doi: 10.1016/s0002-9378(97)70206-0. [DOI] [PubMed] [Google Scholar]
  38. Yoon B. H., Romero R., Park J. S., Kim M., Oh S. Y., Kim C. J., Jun J. K. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. Am J Obstet Gynecol. 2000 Nov;183(5):1124–1129. doi: 10.1067/mob.2000.109035. [DOI] [PubMed] [Google Scholar]
  39. de Vries H. E., Blom-Roosemalen M. C., van Oosten M., de Boer A. G., van Berkel T. J., Breimer D. D., Kuiper J. The influence of cytokines on the integrity of the blood-brain barrier in vitro. J Neuroimmunol. 1996 Jan;64(1):37–43. doi: 10.1016/0165-5728(95)00148-4. [DOI] [PubMed] [Google Scholar]

Articles from Archives of Disease in Childhood Fetal and Neonatal Edition are provided here courtesy of BMJ Publishing Group

RESOURCES