Maternal Serum Interleukin-6, C-Reactive Protein, and Matrix Metalloproteinase-9 Concentrations as Risk Factors for Preterm Birth <32 Weeks and Adverse Neonatal Outcomes

Yoram Sorokin; Roberto Romero; Lisa Mele; Ronald J Wapner; Jay D. Iams; Donald J Dudley; Catherine Y. Spong; Alan M Peaceman; Kenneth J Leveno; Margaret Harper; Steve N Caritis; Menachem Miodovnik; Brian M Mercer; John M Thorp; Mary Jo O'Sullivan; Susan M Ramin; Marshall W Carpenter; Dwight J Rouse; Baha Sibai

doi:10.1055/s-0030-1249366

American Journal of Perinatology, Table of Contents

Am J Perinatol 2010; 27(8): 631-640
DOI: 10.1055/s-0030-1249366

Maternal Serum Interleukin-6, C-Reactive Protein, and Matrix Metalloproteinase-9 Concentrations as Risk Factors for Preterm Birth <32 Weeks and Adverse Neonatal Outcomes

Yoram Sorokin¹ ^, ² , Roberto Romero³ , Lisa Mele⁴ , Ronald J. Wapner¹ ^, ⁵ , Jay D. Iams¹ ^, ⁶ , Donald J. Dudley¹ ^, ⁷ , Catherine Y. Spong⁸ , Alan M. Peaceman¹ ^, ⁹ , Kenneth J. Leveno¹ ^, ¹⁰ , Margaret Harper¹ ^, ¹¹ , Steve N. Caritis¹ ^, ¹² , Menachem Miodovnik¹ ^, ¹³ ^, ¹⁴ , Brian M. Mercer¹ ^, ¹⁵ , John M. Thorp¹ ^, ¹⁶ , Mary Jo O'Sullivan¹ ^, ¹⁷ , Susan M. Ramin¹ ^, ¹⁸ , Marshall W. Carpenter¹ ^, ¹⁹ , Dwight J. Rouse¹ ^, ²⁰ , Baha Sibai¹ ^, ²¹ for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network

¹The Departments of Obstetrics and Gynecology at Wayne State University, Detroit, Michigan
²Wayne State University, Detroit, Michigan
³The Perinatology Research Branch, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Detroit, Michigan
⁴The George Washington University Biostatistics Center, Washington, District of Columbia
⁵Drexel University College of Medicine, Philadelphia, Pennsylvania
⁶The Ohio State University, Columbus, Ohio
⁷University of Utah, Salt Lake City, Utah
⁸the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
⁹Northwestern University, Chicago, Illinois
¹⁰University of Texas Southwestern Medical Center, Dallas, Texas
¹¹Wake Forest University Health Sciences, Winston-Salem, North Carolina
¹²University of Pittsburgh, Pittsburgh, Pennsylvania
¹³Columbia University, New York, New York
¹⁴University of Cincinnati, Cincinnati, Ohio
¹⁵Case Western Reserve University, Cleveland, Ohio
¹⁶University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
¹⁷University of Miami, Miami, Florida
¹⁸The University of Texas Health Science Center at Houston, Houston, Texas
¹⁹Brown University, Providence, Rhode Island
²⁰University of Alabama at Birmingham, Birmingham, Alabama
²¹University of Tennessee, Memphis, Tennessee

Abstract

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.

KEYWORDS

Maternal serum - cytokines - preterm birth - neonatal morbidity

Full Text

References

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Yoram SorokinM.D.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology

Hutzel Women's Hospital, 3990 John R, Mailbox 163, Detroit MI, 48201

Email: ysorokin@med.wayne.edu