Maternal Serum Interleukin-6, C-Reactive Protein, and Matrix Metalloproteinase-9 Concentrations as Risk Factors for Preterm Birth <32 Weeks and Adverse Neonatal Outcomes
Open accessAbstract
Elevated concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and matrix metalloproteinase-9 (MMP-9) in fetal and neonatal compartments have been associated with an increased risk for preterm birth (PTB) and/or neonatal morbidity. The purpose of this study was to determine if the maternal serum concentration of IL-6, CRP, and MMP-9 in women at risk for PTB, who are not in labor and have intact membranes, are associated with an increased risk for PTB <32 weeks and/or neonatal morbidity. Maternal serum samples collected from 475 patients enrolled in a multicenter randomized controlled trial of single versus weekly corticosteroids for women at increased risk for preterm delivery were assayed. Serum was collected at randomization (24 to 32 weeks' gestation). Maternal serum concentrations of IL-6, CRP, and MMP-9 were subsequently determined using enzyme-linked immunoassays. Multivariate logistic regression analysis was performed to explore the relationship between maternal serum concentrations of IL-6, CRP, and MMP-9 and PTB <32 weeks, respiratory distress syndrome (RDS), chronic lung disease (CLD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and any sepsis. Maternal serum concentrations of IL-6 and CRP, but not MMP-9, above the 90th percentile at the time of randomization were associated with PTB <32 weeks. In contrast, there was no significant relationship between RDS and NEC and the maternal serum concentration of IL-6, CRP, or MMP-9 (univariate analysis). The development of CLD was associated with a high (above 90th percentile) IL-6 and CRP in maternal serum, even after adjustment for gestational age (GA) at randomization and treatment group. However, when GA at delivery was added to the model, this finding was nonsignificant. Neonatal sepsis was more frequent in neonates born to mothers with a high maternal serum concentration of CRP (>90th percentile). However, there was no significant association after adjustment for GA at randomization and treatment group. Logistic regression analysis for each analyte indicated that high maternal serum concentrations of IL-6 and CRP, but not MMP-9, were associated with an increased risk of IVH (odds ratio [OR] 4.60, 95% confidence interval [CI] 1.86 to 10.68; OR 4.07, 95% CI 1.63 to 9.50) after adjusting for GA at randomization and treatment group. Most babies (25/30) had grade I IVH. When GA at delivery was included, elevated IL-6 remained significantly associated with IVH (OR 2.77, 95% CI 1.02 to 7.09). An elevated maternal serum concentration of IL-6 and CRP are risk factors for PTB <32 weeks and subsequent development of neonatal IVH. An elevated maternal serum IL-6 appears to confer additional risk for IVH even after adjusting for GA at delivery.
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Elevated gestational CRP levels are associated with adverse infant and child brain developmental outcomes.
“Additionally, C-reactive protein (CRP), an inflammatory marker, is elevated as prenatal maternal mental distress increases [142, 143], and elevated gestational CRP levels have been associated with increased risk of preterm birth [144], adverse infant and child brain developmental outcomes [144, 145], as well as autism and schizophrenia in the offspring [146, 147].”
From Brain structural and functional outcomes in the offspring of women experiencing psychological distress during pregnancy (2024) · cites this paper as [144]
The Results (page not provided) associate high maternal CRP with neonatal intraventricular hemorrhage, a brain injury. The Neonatal data and outcomes section says infants were followed only until discharge or 120 days; the paper does not report child brain-development outcomes. The Results also indicate that CRP’s association with hemorrhage did not remain significant after adjustment for gestational age at delivery. (LLM, conf=0.86)
Experimental — accuracy not yet measuredElevated gestational CRP levels are associated with increased risk of preterm birth.
“Additionally, C-reactive protein (CRP), an inflammatory marker, is elevated as prenatal maternal mental distress increases [142, 143], and elevated gestational CRP levels have been associated with increased risk of preterm birth [144], adverse infant and child brain developmental outcomes [144, 145], as well as autism and schizophrenia in the offspring [146, 147].”
From Brain structural and functional outcomes in the offspring of women experiencing psychological distress during pregnancy (2024) · cites this paper as [144]
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Cites
Epidemiology and causes of preterm birth
Goldenberg, R. L., Culhane, J. F., Iams, J. D., & Romero, R. (2008) · The Lancet · doi:10.1016/s0140-6736(08)60074-4 · Cited by 7,801 · see citing works
Self-citationPapile, L. A., Burstein, J., Burstein, R., & Koffler, H. (1978) · The Journal of Pediatrics · doi:10.1016/s0022-3476(78)80282-0 · Cited by 6,435 · see citing works
Intrauterine infection and preterm delivery
Goldenberg, R. L., Hauth, J. C., & Andrews, W. W. (2000) · New England Journal of Medicine · doi:10.1056/nejm200005183422007 · Cited by 2,548 · see citing works
The preterm parturition syndrome
Romero, R., Espinoza, J., Kusanovic, J., Gotsch, F., Hassan, S., Erez, O., Chaiworapongsa, T., & Mazor, M. (2006) · BJOG: An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.2006.01120.x · Cited by 1,419 · see citing works
Self-citationYoon, B. H., Romero, R., Park, J. S., Kim, C. J., Kim, S. H., Choi, J.-H., & Han, T. R. (2000) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2000.104207 · Cited by 779 · see citing works
Self-citationYoon, B. H., Jun, J. K., Romero, R. J., Park, K. H., Gómez, R., Choi, J., & Kim, I.-O. (1997) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(97)70432-0 · Cited by 756 · see citing works
Self-citationYoon, B. H., Romero, R., Yang, S. H., Jun, J. K., Kim, I.-O., Choi, J.-H., & Syn, H. C. (1996) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(96)70585-9 · Cited by 584 · see citing works
Self-citationA fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition
Romero, R., Gomez, R., Ghezzi, F., Yoon, B. H., Mazor, M., Edwin, S. S., & Berry, S. M. (1998) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(98)70271-6 · Cited by 546 · see citing works
Self-citationYoon, B. H., Romero, R. J., Kim, C. J., Jun, J. K., Gómez, R., Choi, J., & Syn, H. C. (1995) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(95)90028-4 · Cited by 493 · see citing works
Self-citationYoon, B. H., Romero, R. J., Park, J. S., Kim, M., Oh, S.-Y., Kim, C. J., & Jun, J. K. (2000) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2000.109035 · Cited by 437 · see citing works
Self-citationRomero, R. J., Yoon, B. H., Mazor, M., Gómez, R., González, R., Diamond, M. P., Baumann, P. A., Araneda, H., Kenney, J. S., Cotton, D. B., et al. (1993) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(93)90014-a · Cited by 400 · see citing works
Self-citationA systemic fetal inflammatory response and the development of bronchopulmonary dysplasia
Yoon, B. H., Romero, R., Kim, K. S., Park, J. S., Ki, S. H., Kim, B. I., & Jun, J. K. (1999) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(99)70299-1 · Cited by 368 · see citing works
Self-citationSingle versus weekly courses of antenatal corticosteroids: Evaluation of safety and efficacy
Wapner, R. J., Sorokin, Y., Thom, E. A., Johnson, F. F., Dudley, D. J., Spong, C. Y., Peaceman, A. M., Leveno, K. J., Harper, M., Caritis, S. N., et al. (2006) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2006.03.087 · Cited by 292 · see citing works
Self-citationPlasma C-Reactive Protein in Early Pregnancy and Preterm Delivery
Pitiphat, W., Gillman, M. W., JOSHIPURA, K. J., Williams, P. L., Douglass, C. W., & Rich-Edwards, J. W. (2005) · American Journal of Epidemiology · doi:10.1093/aje/kwi323 · Cited by 225 · see citing works
A role for matrix metalloproteinase-9 in spontaneous rupture of the fetal membranes
Athayde, N., Edwin, S. S., Romero, R. J., Gómez, R., Maymon, E., Pacora, P., & Menon, R. (1998) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(98)70141-3 · Cited by 224 · see citing works
Self-citationThe Preterm Prediction Study: Toward a multiple-marker test for spontaneous preterm birth
Goldenberg, R. L., Iams, J. D., Mercer, B. M., Meis, P. J., Moawad, A., Das, A., Miodovnik, M., VanDorsten, P., Caritis, S. N., Thurnau, G. R., et al. (2001) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2001.116752 · Cited by 170 · see citing works
Self-citationHYUNYOON, B., KWANJUN, J., HOONPARK, K., CHULSYN, H., Gómez, R., & Romero, R. J. (1996) · Obstetrics and Gynecology · doi:10.1016/s0029-7844(96)00339-0 · Cited by 157 · see citing works
Self-citationMaymon, E., Romero, R. J., Pacora, P., et al. (2000) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2000.108878 · Cited by 153 · see citing works
Self-citationUmbilical cord plasma interleukin-6 concentrations in preterm infants and risk of neonatal morbidity
Goepfert, A. R., Andrews, W. W., Carlo, W. A., Ramsey, P. S., Cliver, S., Goldenberg, R. L., & Hauth, J. C. (2004) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2004.06.086 · Cited by 139 · see citing works
YOON, B., YANG, S., JUN, J., PARK, K., KIM, C., & Romero, R. J. (1996) · Obstetrics and Gynecology · doi:10.1016/0029-7844(95)00380-0 · Cited by 135 · see citing works
Self-citationGoepfert, A. R., Goldenberg, R. L., Andrews, W. W., Hauth, J. C., Mercer, B. M., Iams, J. D., Meis, P. J., Moawad, A., Thom, E. A., VanDorsten, J. P., et al. (2001) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2001.109653 · Cited by 134 · see citing works
Self-citationTrochez-Martinez, R. D., Smith, P., & Lamont, R. (2007) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.2007.01385.x · Cited by 130 · see citing works
Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes
Romero, R. J., Chaiworapongsa, T., Espinoza, J., et al. (2002) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2002.127312 · Cited by 120 · see citing works
Self-citationYoon, B. H., Romero, R. J., Shim, J., Shim, S. S., Kim, C. J., & Jun, J. K. (2003) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/jmf.14.2.85.90 · Cited by 116 · see citing works
Self-citationGhezzi, F., Franchi, M. P., Raio, L., Naro, E. D., Bossi, G., d’Eril, G. V. M., & Bolis, P. (2002) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2002.119628 · Cited by 107 · see citing works
Heep, A., Behrendt, D., Nitsch, P., et al. (2003) · Archives of Disease in Childhood Fetal & Neonatal · doi:10.1136/fn.88.6.f501 · Cited by 98 · see citing works
Vogel, I., Goepfert, A. R., Thorsen, P., Skogstrand, K., Hougaard, D. M., Curry, A. E., Cliver, S., & Andrews, W. W. (2007) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2007.02.008 · Cited by 95 · see citing works
MMP-2 and MMP-9 and Their Tissue Inhibitors in the Plasma of Preterm and Term Neonates
Schulz, C., Sawicki, G., Lemke, R. P., Roeten, B., Schulz, R., & Cheung, P. (2004) · Pediatric Research · doi:10.1203/01.pdr.0000120683.68630.fb · Cited by 74 · see citing works
Martinez, E., Figueroa, R., Garry, D. J., Visintainer, P., Patel, Verma, U., Sehgal, P., & Tejani, N. (1998) · PubMed · Cited by 72 · see citing works
Umbilical cord blood interleukin-6 levels and neonatal morbidity
Weeks, J. W., Reynolds, L. P., Taylor, D. D., LEWIS, J., WAN, T., & GALL, S. (1997) · Obstetrics and Gynecology · doi:10.1016/s0029-7844(97)00421-3 · Cited by 71 · see citing works
Maternal Serum Interleukin-6 Concentration as a Marker for Impending Preterm Delivery
Murtha, A. P. (1998) · Obstetrics and Gynecology · doi:10.1016/s0029-7844(97)00602-9 · Cited by 68 · see citing works
Škrablin, S., Lovrić, H., Banović, V., Kralik, S., Dijaković, A., & Kalafatić, D. (2007) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/14767050701227877 · Cited by 52 · see citing works
Bahar, A. M., Ghalib, H. W., Moosa, R. A., et al. (2003) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.1080/j.1600-0412.2003.00156.x · Cited by 45 · see citing works
The role of matrix metalloproteinases ‐9 and ‐2 in development of neonatal chronic lung disease
Dg, S., Curley, A., Chesshyre, E. L. D., et al. (2004) · Acta Paediatrica · doi:10.1111/j.1651-2227.2004.tb03020.x · Cited by 42 · see citing works
Maternal serum interleukin 6 levels in preterm labor: prediction of admission-to-delivery interval
Turhan, N. Ö., Karabulut, A. B., & Adam, B. (2000) · Journal of Perinatal Medicine · doi:10.1515/jpm.2000.018 · Cited by 39 · see citing works
Kassal, R., Anwar, M., Kashlan, F. T., Smulian, J. C., Hiatt, M., & Hegyi, T. (2005) · Brain and Development · doi:10.1016/j.braindev.2004.12.003 · Cited by 28 · see citing works
Pfeiffer, K. A., REINSBERG, J., Rahmun, A., et al. (1999) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.1034/j.1600-0412.1999.780906.x · Cited by 27 · see citing works
Lewis, D. F., Barrilleaux, P. S., Wang, Y., et al. (2001) · American Journal of Perinatology · doi:10.1055/s-2001-18694 · Cited by 21 · see citing works
Predictive Value of Maternal Serum and Vaginal Interleukin-6 Levels in Preterm Labor
Sözmen, Ş. Ç., Mungan, T., MICOZKADIOGLU, S., et al. (2005) · Journal of the Society for Gynecologic Investigation · doi:10.1016/j.jsgi.2005.02.006 · Cited by 12 · see citing works
Trochez-Martinez, R. D., Smith, P. G., & Lamont, R. (2008) · Obstetric Anesthesia Digest · doi:10.1097/01.aoa.0000308284.37919.1c · Cited by 8 · see citing works
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- Authors
- Sorokin, Y., Romero, R., Mele, L., Wapner, R., Iams, J., Dudley, D., Spong, C., Peaceman, A., Leveno, K., Harper, M., Caritis, S., Miodovnik, M., Mercer, B., Thorp, J., O'Sullivan, M., Ramin, S., Carpenter, M., Rouse, D., & Sibai, B.
- Affiliations
- Wayne State University (US)
- National Institutes of Health (US)
- George Washington University (US)
- Northwestern University (US)
- The University of Texas at Dallas (US)
- University of Pittsburgh (US)
- University of North Carolina at Chapel Hill (US)
- University of Tennessee Health Science Center (US)
- ORCID
- Venue
- American Journal of Perinatology
- Publisher
- Georg Thieme Verlag KG
- Published
- 2010-03-01
- Volume
- 27
- Issue
- 08
- Pages
- 631-640
- ISSN
- 0735-1631 (ISSN-L)
- 1098-8785
- PMC
- PMC2976602
- OpenAlex
- W1999422044
- Cited by
- 154
- References
- 40
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 10 · 2019: 11 · 2018: 11 · 2017: 8 · 2016: 17 · 2015: 9 · 2014: 13 · 2013: 11 · 2012: 14
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Perinatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2r24hd050924-06, UL1TR000005)
- National Center for Research Resources (M01RR000080)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD40512, U01HD036801, R24 HD-050924, HD27917, U10HD040544, U10HD034208, U10HD027861, HD-27915, U10HD040512, HD34116, UG1HD034116, HD40545, HD34136, (HD40500, U10HD027915, HD-21414, U10HD040545, U10HD040560, HD 40544, HD-27860, HD40560, HD27861, U10HD027917, U10HD036801, U10HD027905, U10HD027860, U10HD021410, HD 34208, HD 36801, U10HD034116, HD27869, [HD21410, U10HD040500, U10HD034122, U10HD040485, U10HD027869, U10HD034136, UG1HD034208, U24HD036801, UG1HD040500, UG1HD040512, UG1HD027869, UG1HD040544, UG1HD040485, UG1HD027915, UG1HD040560, UG1HD040545, HD 40485)
- Topics
- Health Sciences › Medicine › Epidemiology › Preterm Birth and Chorioamnionitis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Neonatal and Maternal Infections
- Keywords
- preterm birth, interleukin-6, C-reactive protein, MMP-9, maternal serum biomarkers, preterm birth risk factors, neonatal morbidity, intraventricular hemorrhage, chronic lung disease of prematurity, neonatal sepsis, necrotizing enterocolitis, respiratory distress syndrome, corticosteroid therapy, gestational age
- MeSH terms
- C-Reactive Protein, Female, Humans, Infant, Newborn, Infant, Newborn, Diseases, Lung Diseases, Maternal-Fetal Exchange, Pregnancy, Pregnancy Outcome, Pregnancy Trimester, Second, Pregnancy Trimester, Third, Respiratory Distress Syndrome, Newborn, Risk Factors, Biomarkers, Interleukin-6, Sepsis, Intracranial Hemorrhages, Enterocolitis, Necrotizing, Matrix Metalloproteinase 9, Premature Birth
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