title: Maternal serum interleukin-6, C-reactive protein, and matrix metalloproteinase-9 concentrations as risk factors for preterm birth <32 weeks and adverse neonatal outcomes.
abstract: 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.
authors.affiliation: The Departments of Obstetrics and Gynecology at Wayne State University, Detroit, MI 48201, USA. ysorokin@med.wayne.edu
authors.forename: Yoram
authors.initials: Y
authors.lastname: Sorokin
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Lisa
authors.initials: L
authors.lastname: Mele
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wapner
authors.forename: Jay D
authors.initials: JD
authors.lastname: Iams
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Dudley
authors.forename: Catherine Y
authors.initials: CY
authors.lastname: Spong
authors.forename: Alan M
authors.initials: AM
authors.lastname: Peaceman
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Leveno
authors.forename: Margaret
authors.initials: M
authors.lastname: Harper
authors.forename: Steve N
authors.initials: SN
authors.lastname: Caritis
authors.forename: Menachem
authors.initials: M
authors.lastname: Miodovnik
authors.forename: Brian M
authors.initials: BM
authors.lastname: Mercer
authors.forename: John M
authors.initials: JM
authors.lastname: Thorp
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: O'Sullivan
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ramin
authors.forename: Marshall W
authors.initials: MW
authors.lastname: Carpenter
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Rouse
authors.forename: Baha
authors.initials: B
authors.lastname: Sibai
mesh_terms: D015415:Biomarkers / Q000097:blood*; D002097:C-Reactive Protein / Q000378:metabolism*; D020345:Enterocolitis, Necrotizing / Q000151:congenital / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism / Q000628:therapy; D015850:Interleukin-6 / Q000097:blood*; D020300:Intracranial Hemorrhages / Q000151:congenital / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D008171:Lung Diseases / Q000151:congenital / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D008431:Maternal-Fetal Exchange; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000453:epidemiology; D011262:Pregnancy Trimester, Second / Q000097:blood*; D011263:Pregnancy Trimester, Third / Q000097:blood*; D047928:Premature Birth / Q000097:blood* / Q000401:mortality / Q000503:physiopathology; D012127:Respiratory Distress Syndrome, Newborn / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D012307:Risk Factors; D018805:Sepsis / Q000151:congenital / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D002097:C-Reactive Protein; D020780:Matrix Metalloproteinase 9