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ORIGINAL RESEARCH |
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan; Section of Neonatology, Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Departments of Pathology and Obstetrics and Gynecology, University of Chicago, Chicago, Illinois; and Department of Obstetrics and Gynecology, Loyola University Medical Center, Maywood, Illinois.
Address reprint requests to: Robert Mittendorf, MD, DrPH Department of Obstetrics and Gynecology Loyola University Medical Center 2160 South First Avenue Maywood, IL 60153 E-mail: rmitten{at}luc.edu
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Abstract |
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Methods: At the time of delivery, umbilical venous cord blood samples were collected from 92 infants for whom placental pathology results were also available. Interleukin-6 concentrations in the umbilical venous cord blood plasma were measured by immunoassay. Histologic examinations of the placenta and umbilical cord were done to determine the presence or absence of funisitis and chorioamnionitis. For a power of 90% with an 
of .05, 12 subjects were required in each group.
Results: We found a significant association between the presence of histologic funisitis and elevated umbilical venous cord blood plasma IL-6 concentrations (defined as 10 pg/mL or greater). Of 15 infants whose umbilical cords showed funisitis, 93% (14 of 15) had elevated umbilical venous cord blood plasma IL-6 concentrations. Of 77 infants without funisitis, 32% (25 of 77) had elevated IL-6 concentrations in their cords (P < .001, two-sided Fisher exact test). The negative predictive value of IL-6 as a screening test for funisitis was 98%.
Conclusion: In preterm neonates, screening for funisitis by using the immunoassay for IL-6 appears to be valid. In the near future, elevated umbilical venous cord blood IL-6 concentrations at delivery could be clinically useful to identify children who might benefit from early treatment for systemic fetal inflammatory syndrome.
Interleukin-6 (IL-6), a cytokine about 26 kD,1 is a mediator of the host inflammatory response. Among the first cytokines to be secreted in response to bacterial infection, IL-6 is synthesized by mononuclear phagocytes, vascular endothelial cells, and fibroblasts, as well as the decidua, chorion, amnion, and trophoblastic cells.2–5 It is secreted in response to a variety of proinflammatory mediators, including tumor necrosis factor- and IL-1. Interleukin-6 stimulates hepatocytes to make several plasma proteins that contribute to the acute phase response, such as fibrinogen and C-reactive protein. Elevated concentrations of cytokines, including IL-6, have been found in the amniotic fluid (AF) of women in preterm labor who have intrauterine infections.5 Indeed, elevated AF concentrations of IL-6 have been shown to be sensitive and specific measures of intrauterine infection and chorioamnionitis.6 Acute histologic chorioamnionitis, thought to be a maternal rather than a fetal inflammatory response, is associated with neonatal morbidity and mortality.7 Elevated fetal plasma concentrations of IL-6 have been associated with the onset of labor and are a risk factor for adverse neonatal outcomes.
The relationships between IL-6 concentrations and histopathologic responses in the fetus, such as funisitis, are not well established. Thus, our objective in this study became twofold—to determine whether elevated concentrations of IL-6 present in umbilical venous cord blood plasma at delivery are associated with funisitis, and, if so, to determine whether IL-6 might be used as a screening test for funisitis.
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Materials and Methods |
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On initial admission, the estimated gestational lengths ranged from 24 to 34 weeks, with a mean of 32 weeks 4 days. Exclusion criteria in the MAGnet trial were preeclampsia, second stage of labor, need for emergent surgical delivery for maternal or fetal indications, and known or ultrasound-diagnosed fetal chromosomal or structural abnormalities.
At delivery, umbilical venous cord blood samples were collected aseptically in endotoxin-free glass blood collection tubes containing liquid ethylenediaminetetraacetic acid (Becton-Dickinson, Franklin Lakes, NJ) and aprotinin (Sigma A6279, Sigma Chemical Co., St. Louis, MO). The blood was then centrifuged at 1000 g for 10 minutes. The plasma was removed, aliquoted into 1.25-mL Eppendorf storage tubes, and frozen at -70C until assayed. Concentrations of IL-6 were measured by standard commercial enzyme-linked immunosorbent assay (Endogen, Cambridge, MA). The sensitivity of the assay was less than 1 pg/mL; interassay and intraassay coefficients of variation were less than 10%. We considered IL-6 values of 10 pg/mL or greater to be elevated.
To determine the possible bacterial correlates of funisitis, chorioamnionitis, and cerebral palsy, placental cultures were obtained aseptically by surgically separating the amnion from the chorion and swabbing the inner sides of the membranes. Selective media included those specific for aerobes, anaerobes, Mycoplasma, Urea-plasma, and Chlamydia. Cultures were not done in seven women.
Preliminary examinations of all but eight umbilical cords and placentas (six from singleton gestations and two from one twin gestation [seven unique pregnancies]) were done by a hospital staff pathologist. However, all essential pathologic findings, including chorioamnionitis and funisitis, were confirmed on secondary review by a perinatal pathologist (A.M.). Both pathologists were masked to the umbilical venous cord blood plasma IL-6 concentrations in the specimens being evaluated. The patients with the eight unreviewed cords and placentas were excluded from the study. Placentas were examined after fixation in 10% buffered formalin. After gross examination and measurement of membranes and umbilical cord, the trimmed placental disc was weighed and sectioned. Standard sections included the membranes nearest to the point of rupture; if identified, a cross section of umbilical cord; and a full thickness section of placental parenchyma. Acute chorioamnionitis was defined as neutrophils present within the amnionic layer or its basement membrane. Funisitis was defined as recognizable neutrophils infiltrating the wall of one or more umbilical vessels.
In addition, demographic, maternal, and obstetric data were abstracted from the maternal records. Charts were available for 12 of the pregnancies in which funisitis was diagnosed and 69 of the pregnancies without funisitis. Univariate analyses were done on all variables to determine whether significant differences existed between patients with funisitis and those without funisitis. Fisher exact tests were used for dichotomous variables, and Mann-Whitney U tests for continuous variables. To control for possible confounding, we performed a multivariable logistic regression analysis that included gestational age, an important predictor for most adverse outcomes.
For a study in which 90% of neonates with funisitis would have an elevated umbilical venous cord blood plasma IL-6 level, 30% of children without funisitis would have elevated umbilical cord IL-6 levels ( . = 05, and 1 - ß[power] = 90%), so 12 subjects would be required in each group (24 total subjects). Permission to conduct this study was given by the Institutional Review Board, Biological Sciences Division, University of Chicago.
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Results |
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). Further, by multivariable regression analysis in which possible confounding by gestational age (usually an important predictor of adverse outcome) was controlled for, elevated IL-6 levels in umbilical venous cord blood plasma remained statistically significant and was the only independent predictor of funisitis (adjusted odds ratio [OR] 15.3; 95% confidence interval [CI] 3.0, 156.4).
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Among the 86 placentas for which we obtained cultures, 34% (29 of 86) had no growth, 41% (35 of 86) grew pure isolates of one species, and 26% (22 of 86) grew mixed isolates of more than one species. Coagulase-negative staphylococci were the most numerous bacteria cultured at delivery, with an overall prevalence of 28% (24 of 86). Escherichia coli, 14% (12 of 86); Mycoplasma, 14% (12 of 86); species of Bacteroides, 10% (nine of 86); and Ureaplasma, 9% (eight of 86) were the next most prevalent bacteria. We recently reported our finding from the MAGnet trial of an association between cerebral palsy and the presence of coagulase-negative staphylococci in the chorioamnion space.9
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Discussion |
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Although funisitis was highly correlated with elevated concentrations of IL-6 in umbilical venous cord blood, the positive predictive value of an elevated cord blood IL-6 level for funisitis was 36% in this population of preterm infants, in which funisitis was more prevalent than in term infants. Although 36% is a seemingly low value, it is good to keep in mind that the population-based positive predictive value of the most highly regarded and widely used screening test in obstetrics and gynecology, the Papanicolaou smear, is only 14.5%.18,19 Further, the high negative predictive value (98%) increases the usefulness of cord blood IL-6 as a screening tool, because it is unlikely that an infant with a normal IL-6 level would have funisitis. This is an important consideration as new pediatric therapies to prevent adverse neonatal outcomes that require early neonatal intervention evolve.
Our study also showed a specific fetal, rather than maternal, response to intrauterine inflammatory events. Several studies found an association between elevated IL-6 concentrations in AF or cord blood and adverse neonatal outcomes,14–17 but there are few that directly showed cytokine production by fetal or neonatal tissues.20 Many cells are capable of secreting or being acted on by IL-6. Thus, there can be significant IL-6 secretion in the uterus, but fetal secretion of IL-6 might be less frequent. Moreover, it is difficult to use extrafetal intrauterine samples to derive information about intrafetal events. IL-6 screening for funisitis could offer a practical opportunity for the immediate, direct evaluation of fetal inflammation at birth, which might be helpful in hospitals where experience with perinatal histopathology is limited and where the diagnosis of funisitis based on histopathology alone might be delayed a day or more while the placental specimen is being prepared and evaluated microscopically. In contrast, the determination of IL-6 concentrations in umbilical venous cord blood is a rapid and inexpensive assay which any clinical laboratory can do within a few hours of delivery.
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Footnotes |
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Received June 5, 2000. Received in revised form August 16, 2000. Accepted August 31, 2000.
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References |
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2. Dudley DJ, Trautman MS, Araneo BA, Edwin SS, Mitchell MD. Decidual cell biosynthesis of interleukin-6: Regulation by inflammatory cytokines. J Clin Endocrinol Metab 1992;74:884–9.[Abstract]
3. Kameda T, Matsuzaki N, Sawai K, Okada T, Saji F, Matsuda T, et al. Production of interleukin-6 by normal human trophoblast. Placenta 1990;11:205–13.[Medline]
4. Liechty KW, Koenig JM, Mitchell MD, Romero R, Christensen RD. Production of interleukin-6 by fetal and maternal cells in vivo during intraamniotic infection and in vitro after stimulation with interleukin-1. Pediatr Res 1990;29:1–4.
5. Romero R, Avila C, Santhanaum U, Sehgal PB. Amniotic fluid interleukin-6 in preterm labor. J Clin Invest 1990;85:1392–400.
6. Greig PC, Ernest JM, Teot L, Erikson M, Talley R. Amniotic fluid interleukin-6 levels correlate with histologic chorioamnionitis and amniotic fluid cultures in patients in premature labor with intact membranes. Am J Obstet Gynecol 1993;169:1035–44.[Medline]
7. Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi JH, et al. Amniotic fluid interleukin-6: A sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 1995;172:960–70.[Medline]
8. Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is tocolytic magnesium sulphate associated with increased total paediatric mortality? Lancet 1997;350:1517–8.[Medline]
9. Mittendorf R, Roizen N, Moawad AH, Khoshnood B, Lee KS. Association between cerebral palsy and coagulase negative staphylococci. Lancet 1999;354:1875–6.[Medline]
10. Van Hoeven KH, Anyaegbunam A, Hochster H, Whitty JE, Distant J, Crawford C, et al. Clinical significance of increasing histologic severity of acute inflammation in the fetal membranes and umbilical cord. Pediatr Pathol Lab Med 1996;16:731–44.[Medline]
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12. Matsuda T, Nakajima T, Hattori S, Hanatani K, Fukazawa Y, Kobayashi K, et al. Necrotizing funisitis: Clinical significance and association with chronic lung disease in premature infants. Am J Obstet Gynecol 1997;177:1402–7.[Medline]
13. Grafe M. The correlation of prenatal brain damage with placental pathology. J Neuropathol Exp Neurol 1994;53:407–15.[Medline]
14. Figueroa-Damian R, Arredondo-Garcia JL, Mancilla-Ramirez J. Amniotic fluid interleukin-6 and the risk of early-onset sepsis among preterm infants. Arch Med Res 1999;30:198–202.[Medline]
15. Martinez E, Figueroa R, Garry D, Visintainer P, Patel K, Verma U, et al. Elevated amniotic fluid interleukin-6 as a predictor of neonatal periventricular leukomalacia and intraventricular hemorrhage. J Matern Fetal Investig 1998;8:101–7.[Medline]
16. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998;179:194–202.[Medline]
17. Yoon BH, Romero R, Kim KS, Park JS, Ki SH, Kim BI, et al. A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1999;181: 773–9.[Medline]
18. Sadeghi SB, Sadeghi A, Robboy SJ. Prevalence of dysplasia and cancer of the cervix in a nationwide Planned Parenthood population. Cancer 1988;61:2359–61.[Medline]
19. Mittendorf R, Pryde P, Herschel M, Williams MA. Is routine antenatal toxoplasmosis screening justified in the United States? Statistical considerations in the application of medical screening tests. Clin Obstet Gynecol 1999;42:163–73.[Medline]
20. Yoon BH, Roberto R, Kim CJ, Koo JN, Chee G, Syn HC, et al. High expression of tumor necrosis factor- and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 1997;177:406–11.[Medline]
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