Umbilical Cord Serum Interleukin-6, C-Reactive Protein, and Myeloperoxidase Concentrations at Birth and Association with Neonatal Morbidities and Long-Term Neurodevelopmental Outcomes

Yoram Sorokin; Roberto Romero; Lisa Mele; Jay D. Iams; Alan M. Peaceman; Kenneth J. Leveno; Margaret Harper; Steve N. Caritis; 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-0033-1359723

American Journal of Perinatology, Table of Contents

Am J Perinatol 2014; 31(08): 717-726
DOI: 10.1055/s-0033-1359723

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Umbilical Cord Serum Interleukin-6, C-Reactive Protein, and Myeloperoxidase Concentrations at Birth and Association with Neonatal Morbidities and Long-Term Neurodevelopmental Outcomes

Yoram Sorokin

¹Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan

,

Roberto Romero

²Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Detroit, Michigan

,

Lisa Mele

³Biostatistics Center, The George Washington University, Washington, District of Columbia

,

Jay D. Iams

⁴Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio

,

Alan M. Peaceman

⁵Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois

,

Kenneth J. Leveno

⁶Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, Texas

,

Margaret Harper

⁷Department of Obstetrics and Gynecology, Wake Forest University Health Sciences, Winston-Salem, North Carolina

,

Steve N. Caritis

⁸Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Brian M. Mercer

⁹Department of Obstetrics and Gynecology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio

,

John M. Thorp

¹⁰Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

,

Mary Jo O'Sullivan

¹¹Department of Obstetrics and Gynecology, University of Miami, Miami, Florida

,

Susan M. Ramin

¹²Department of Obstetrics and Gynecology, The University of Texas Health Science Center at Houston, Houston, Texas

,

Marshall W. Carpenter

¹³Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island

,

Dwight J. Rouse

¹⁴Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama

,

Baha Sibai

¹⁵Department of Obstetrics and Gynecology, University of Tennessee, Memphis, Tennessee

› Author Affiliations

Abstract

Objective The aim of the study is to determine if umbilical cord serum concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and myeloperoxidase (MPO), in pregnancies at risk for preterm birth (PTB), are associated with neonatal morbidities and/or altered neurodevelopmental outcomes in the children.

Study Design Umbilical cord serum samples were collected at birth from 400 newborns delivered within a multicenter randomized controlled trial of repeated versus single course of antenatal corticosteroids (ACs), in women at increased risk for PTB. Newborns were followed through discharge and were evaluated between 36 and 42 months corrected age with neurological examination and Bayley Scales of Infant Development. Umbilical cord serum concentrations of IL-6, CRP, and MPO were determined using enzyme-linked immunoassays. Multivariate logistic regression analyses explored the relationship between umbilical cord serum IL-6, CRP, and MPO levels, adverse newborn outcomes, and PTB < 32 weeks of gestational age (GA).

Results Univariate analysis revealed that umbilical cord IL-6 above the 75th percentile was associated with increased respiratory distress syndrome (RDS) and chronic lung disease (CLD), but not with necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), or neonatal sepsis; however, this association was not significant after adjusting for GA at delivery and treatment group. No significant associations between CRP or MPO and RDS, CLD, NEC, sepsis, or IVH were evident. Regression analysis revealed that CRP above the 75th percentile was associated with a decreased risk of CLD (odds ratio, 0.10; 95% confidence interval, 0.02–0.41). No associations between umbilical cord IL-6, CRP, or MPO and MDI < 70 or PDI < 70 were evident. Umbilical cord serum concentrations of IL-6, CRP, and MPO, above the 75th percentile, were associated with more frequent PTB < 32 weeks of GA.

Conclusion Elevated umbilical cord serum concentration of CRP is associated with reduced risk for CLD even after adjusting for GA at delivery. Occurrence of levels > 75th percentile of IL-6, CRP, and MPO in umbilical cord serum was associated with PTB < 32 weeks of GA. Elevated umbilical cord serum concentrations of IL-6, CRP, and MPO at birth were not associated with poor neurodevelopmental outcomes.

Keywords

umbilical cord serum - cytokines - preterm birth - neonatal morbidity - neurodevelopmental infant outcome

Full Text

References

References
1 Romero R, Espinoza J, Kusanovic JP , et al. The preterm parturition syndrome. BJOG 2006; 113 (3) (Suppl. 03) 17-42
2 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371 (9606) 75-84
3 Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998; 179 (1) 194-202
4 Yoon BH, Romero R, Jun JK , et al. Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 β, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1997; 177 (4) 825-830
5 Ghezzi F, Gomez R, Romero R , et al. Elevated interleukin-8 concentrations in amniotic fluid of mothers whose neonates subsequently develop bronchopulmonary dysplasia. Eur J Obstet Gynecol Reprod Biol 1998; 78 (1) 5-10
6 Yoon BH, Romero R, Kim KS , et al. A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1999; 181 (4) 773-779
7 Weeks JW, Reynolds L, Taylor D, Lewis J, Wan T, Gall SA. Umbilical cord blood interleukin-6 levels and neonatal morbidity. Obstet Gynecol 1997; 90 (5) 815-818
8 Smulian JC, Bhandari V, Campbell WA, Rodis JF, Vintzileos AM. Value of umbilical artery and vein levels of interleukin-6 and soluble intracellular adhesion molecule-1 as predictors of neonatal hematologic indices and suspected early sepsis. J Matern Fetal Med 1997; 6 (5) 254-259
9 Goepfert AR, Andrews WW, Carlo W , et al. Umbilical cord plasma interleukin-6 concentrations in preterm infants and risk of neonatal morbidity. Am J Obstet Gynecol 2004; 191 (4) 1375-1381
10 Martinez E, Figueroa R, Garry D , et al. Elevated amniotic fluid interleukin-6 as a predictor of neonatal periventricular leukomalacia and intraventricular hemorrhage. J Matern Fetal Investig 1998; 8 (3) 101-107
11 Kassal R, Anwar M, Kashlan F, Smulian J, Hiatt M, Hegyi T. Umbilical vein interleukin-6 levels in very low birth weight infants developing intraventricular hemorrhage. Brain Dev 2005; 27 (7) 483-487
12 Yoon BH, Romero R, Yang SH , et al. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 1996; 174 (5) 1433-1440
13 Yoon BH, Romero R, Kim CJ , et al. High expression of tumor necrosis factor-α and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 1997; 177 (2) 406-411
14 Yoon BH, Romero R, Park JS , et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000; 182 (3) 675-681
15 Pacora P, Chaiworapongsa T, Maymon E , et al. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med 2002; 11 (1) 18-25
16 Yoon BH, Romero R, Park JS , et al. 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; 183 (5) 1124-1129
17 Goodman RB, Pugin J, Lee JS, Matthay MA. Cytokine-mediated inflammation in acute lung injury. Cytokine Growth Factor Rev 2003; 14 (6) 523-535
18 Belperio JA, Keane MP, Lynch III JP, Strieter RM. The role of cytokines during the pathogenesis of ventilator-associated and ventilator-induced lung injury. . Semin Respir Crit Care Med 2006; 27 (4) 350-364
19 Strieter RM, Belperio JA, Keane MP. Cytokines in innate host defense in the lung. J Clin Invest 2002; 109 (6) 699-705
20 Kotecha S, Wilson L, Wangoo A, Silverman M, Shaw RJ. Increase in interleukin (IL)-1 beta and IL-6 in bronchoalveolar lavage fluid obtained from infants with chronic lung disease of prematurity. Pediatr Res 1996; 40 (2) 250-256
21 Baier RJ, Majid A, Parupia H, Loggins J, Kruger TE. CC chemokine concentrations increase in respiratory distress syndrome and correlate with development of bronchopulmonary dysplasia. Pediatr Pulmonol 2004; 37 (2) 137-148
22 Vento G, Capoluongo E, Matassa PG , et al. Serum levels of seven cytokines in premature ventilated newborns: correlations with old and new forms of bronchopulmonary dysplasia. Intensive Care Med 2006; 32 (5) 723-730
23 Viscardi RM, Muhumuza CK, Rodriguez A , et al. Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants. Pediatr Res 2004; 55 (6) 1009-1017
24 Leviton A. Preterm birth and cerebral palsy: is tumor necrosis factor the missing link?. Dev Med Child Neurol 1993; 35 (6) 553-558
25 Yoon BH, Park C-W, Chaiworapongsa T. Intrauterine infection and the development of cerebral palsy. BJOG 2003; 110 (Suppl. 20) 124-127
26 Minagawa K, Tsuji Y, Ueda H , et al. Possible correlation between high levels of IL-18 in the cord blood of pre-term infants and neonatal development of periventricular leukomalacia and cerebral palsy. Cytokine 2002; 17 (3) 164-170
27 Wapner RJ, Sorokin Y, Thom EA , et al; National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network. Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. Am J Obstet Gynecol 2006; 195 (3) 633-642
28 Wapner RJ, Sorokin Y, Mele L , et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 2007; 357 (12) 1190-1198
29 Liang KY, Zeger SL. Regression analysis for correlated data. Annu Rev Public Health 1993; 14: 43-68
30 Watts DH, Krohn MA, Hillier SL, Eschenbach DA. The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol 1992; 79 (3) 351-357
31 Andrews WW, Hauth JC, Goldenberg RL, Gomez R, Romero R, Cassell GH. Amniotic fluid interleukin-6: correlation with upper genital tract microbial colonization and gestational age in women delivered after spontaneous labor versus indicated delivery. Am J Obstet Gynecol 1995; 173 (2) 606-612
32 Hillier SL, Witkin SS, Krohn MA, Watts DH, Kiviat NB, Eschenbach DA. The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection. Obstet Gynecol 1993; 81 (6) 941-948
33 Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel L, Hassan S. The role of inflammation and infection in preterm birth. Semin Reprod Med 2007; 25 (1) 21-39
34 Romero R, Gomez R, Ghezzi F , et al. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 1998; 179 (1) 186-193
35 Nishimaki S, Sato M, An H , et al. Comparison of markers for fetal inflammatory response syndrome: fetal blood interleukin-6 and neonatal urinary β(2)-microglobulin. J Obstet Gynaecol Res 2009; 35 (3) 472-476
36 Hatzidaki E, Gourgiotis D, Manoura A , et al. Interleukin-6 in preterm premature rupture of membranes as an indicator of neonatal outcome. Acta Obstet Gynecol Scand 2005; 84 (7) 632-638
37 Santana C, Guindeo MC, González G, García-Muñoz F, Saavedra P, Doménech E. Cord blood levels of cytokines as predictors of early neonatal sepsis. Acta Paediatr 2001; 90 (10) 1176-1181
38 Kaukola T, Herva R, Perhomaa M , et al. Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurologic outcome in very preterm, extremely low birth weight infants. Pediatr Res 2006; 59 (3) 478-483
39 Mittendorf R, Montag AG, MacMillan W , et al. Components of the systemic fetal inflammatory response syndrome as predictors of impaired neurologic outcomes in children. Am J Obstet Gynecol 2003; 188 (6) 1438-4 , discussion 1444–1446
40 Hansen-Pupp I, Hallin AL, Hellström-Westas L , et al. Inflammation at birth is associated with subnormal development in very preterm infants. Pediatr Res 2008; 64 (2) 183-188
41 Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347 (20) 1557-1565
42 Yoon BH, Romero R, Shim JY, Shim SS, Kim CJ, Jun JK. C-reactive protein in umbilical cord blood: a simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis. J Matern Fetal Neonatal Med 2003; 14 (2) 85-90
43 An H, Nishimaki S, Ohyama M , et al. Interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-I in the cord blood as predictors of chronic lung disease in premature infants. Am J Obstet Gynecol 2004; 191 (5) 1649-1654
44 Ambalavanan N, Carlo WA, D'Angio CT , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Cytokines associated with bronchopulmonary dysplasia or death in extremely low birth weight infants. Pediatrics 2009; 123 (4) 1132-1141
45 Kramer BW, Kallapur S, Newnham J, Jobe AH. Prenatal inflammation and lung development. Semin Fetal Neonatal Med 2009; 14 (1) 2-7
46 Jobe AH. The new bronchopulmonary dysplasia. Curr Opin Pediatr 2011; 23 (2) 167-172
47 Van Marter LJ, Dammann O, Allred EN , et al; Developmental Epidemiology Network Investigators. Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002; 140 (2) 171-176
48 Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996; 97 (2) 210-215
49 Shimoya K, Taniguchi T, Matsuzaki N , et al. Chorioamnionitis decreased incidence of respiratory distress syndrome by elevating fetal interleukin-6 serum concentration. Hum Reprod 2000; 15 (10) 2234-2240
50 Hannaford K, Todd DA, Jeffery H, John E, Byth K, Gilbert GL. Role of ureaplasma urealyticum in lung disease of prematurity. Arch Dis Child Fetal Neonatal Ed 1999; 81: F162-F167
51 Laughon M, Allred EN, Bose C , et al; ELGAN Study Investigators. Patterns of respiratory disease during the first 2 postnatal weeks in extremely premature infants. Pediatrics 2009; 123 (4) 1124-1131
52 Been JV, Rours GIJG, Kornelisse RF , et al. Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants. Am J Obstet Gynecol 2009; 201 (6) 587.e1-587.e8
53 Soraisham AS, Singhal N, McMillan DD, Sauve RS, Lee SK ; Canadian Neonatal Network. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 2009; 200 (4) 372.e1-372.e6
54 Andrews WW, Goldenberg RL, Faye-Petersen O, Cliver S, Goepfert AR, Hauth JC. The Alabama Preterm Birth study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants. Am J Obstet Gynecol 2006; 195 (3) 803-808
55 Goldenberg RL, Andrews WW, Goepfert AR , et al. The Alabama Preterm Birth Study: Umbilical cord blood ureaplasma urealyticum and mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol 2008; 198: 43.e1-43.e5
56 Eiserich JP, Baldus S, Brennan M-L , et al. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 2002; 296 (5577) 2391-2394
57 Segura RM, Alegre J, Varela E , et al. Interleukin-8 and markers of neutrophil degranulation in pleural effusions. Am J Respir Crit Care Med 1998; 157 (5, Pt 1) 1565-1572
58 Zhang R, Brennan M-L, Fu X , et al. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 2001; 286 (17) 2136-2142
59 Sharma J, Rastogi P, Creer MH, McHowat J. Polymorphonuclear leukocytes isolated from umbilical cord blood as a useful research tool to study adherence to cell monolayers. J Immunol Methods 2009; 351 (1–2) 30-35
60 Yang KD, Wang CL, Huang LT , et al. Implication of cord blood myeloperoxidase but not of soluble p-selectin levels in preterm deliveries. J Perinat Med 2004; 32 (1) 49-52
61 Huang HC, Wang CL, Huang LT , et al. Association of cord blood cytokines with prematurity and cerebral palsy. Early Hum Dev 2004; 77 (1–2) 29-36