The fetal inflammatory response syndrome,☆☆,

Presented in part at the Seventeenth Annual Meeting of the Society of Perinatal Obstetricians, Anaheim, California, January 20-25, 1997.
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Abstract

OBJECTIVE: The objective of this study was to determine the frequency and clinical significance of a systemic inflammatory response as defined by an elevated plasma interleukin-6 concentration in fetuses with preterm labor or preterm premature rupture of membranes.

STUDY DESIGN: Amniocenteses and cordocenteses were performed in 157 patients with preterm labor and preterm premature rupture of membranes. Written informed consent and multi-institutional review board approvals were obtained. Amniotic fluid was cultured for aerobic and anaerobic bacteria, as well as mycoplasmas. Amniotic fluid and fetal plasma interleukin-6 concentrations were measured with a sensitive and specific immunoassay. Statistical analyses included contingency tables, receiver operating characteristic curve analysis, and multiple logistic regression.

RESULTS: One hundred five patients with preterm labor and 52 patients with preterm premature rupture of membranes were included in this study. The overall prevalence of severe neonatal morbidity (defined as the presence of respiratory distress syndrome, suspected or proved neonatal sepsis, pneumonia, bronchopulmonary dysplasia. intraventricular hemorrhage, periventricular leukomalacia, or necrotizing enterocolitis) among survivors was 34.8% (54/155). Neonates in whom severe neonatal morbidity developed had higher concentrations of fetal plasma interleukin-6 than fetuses without development of severe neonatal morbidity (median 14.0 pg/mL, range 0.5 to 900 vs median 5.2 pg/mL, range 0.3 to 900, respectively; P < .005). Multivariate analysis was performed to explore the relationship between the presence of a systemic fetal inflammatory response and subsequent neonatal outcome. To preserve a meaningful temporal relationship between the results of fetal plasma interleukin-6 concentrations and the occurrence of severe neonatal morbidity, the analysis was restricted to 73 fetuses delivered within 7 days of cordocentesis who survived. The prevalence of severe neonatal morbidity in this subset of patients was 53.4% (39/73). A fetal plasma interleukin-6 cutoff value of 11 pg/mL was used to define the presence of a systemic inflammatory response. The prevalence of a fetal plasma interleukin-6 level >11 pg/mL was 49.3% (36/73). Fetuses with fetal plasma interleukin-6 concentrations >11 pg/mL had a higher rate of severe neonatal morbidity than did those with fetal plasma interleukin-6 levels ≤11 pg/mL (77.8% [28/36] vs 29.7% [11/37], respectively; P < .001). Stepwise logistic regression analysis demonstrated that the fetal plasma interleukin-6 concentration was an independent predictor of the occurrence of severe neonatal morbidity (odds ratio 4.3, 95% confidence interval 1 to 18.5) when adjusted for gestational age at delivery, the cause of preterm delivery (preterm labor or preterm premature rupture of membranes), clinical chorioamnionitis, the cordocentesis-to-delivery interval, amniotic fluid culture, and anmiotic fluid interleukin-6 results.

CONCLUSION: A systemic fetal inflammatory response, as determined by an elevated fetal plasma interleukin-6 value, is an independent risk factor for the occurrence of severe neonatal morbidity. (Am J Obstet Gynecol 1998;179:194-202.)

Section snippets

Patients and eligibility

Women who were examined at Hutzel Hospital with preterm labor and intact membranes or with preterm premature rupture of membranes, over a 4-year period of time, were offered amniocentesis for the diagnosis of microbial invasion of the amniotic cavity and the assessment of fetal lung maturity. Patients who consented to have an amniocentesis were asked to participate in a research management protocol that included the aspiration of additional amniotic fluid for research purposes and

Study population

One hundred five patients with preterm labor and 52 patients with preterm premature rupture of membranes were included in this study. There were two perinatal deaths. In both cases the infants were delivered before 24 weeks of gestation and were excluded from analysis. The overall prevalence of preterm delivery <37 weeks was 80% (124/155). Severe neonatal morbidity developed in 54 neonates (34.8%). Table I displays the clinical characteristics of patients according to the presence or absence of

Comment

Our results demonstrate that a fetal plasma IL-6 level above 11 pg/mL is a major independent risk factor for the subsequent development of severe neonatal morbidity. The prevalence of an elevated fetal plasma IL-6 value in patients with preterm labor or premature rupture of membranes delivered within 1 week of cordocentesis was about 50% for either condition.

Microbial invasion of the amniotic cavity was associated wiith a fetal plasma IL-6 value >11 pg/mL (63.4% [26/41] vs 14.9% [17/114], for

Acknowledgements

We acknowledge the contribution of Dr Robert Sokol, Dr David Cotton, Dr Ruben Quintero, Dr Mark Evans, Dr Mitchell Dombrowski, Dr Yoram Sorokin, Dr Maurizio Galasso, Dr Karoline Puder, Sandy Field, RN, Carolyn Sudz, RN, Adriana Soto, RDMS, Mary King, RDMS, Tess Tagle, RN, and Elisa Walsh, RN, of Wayne State University/the Detroit Medical Center; Dr John C. Hobbins, Dr E. Albert Reece, Dr Alan H. DeCherney, Dr Maurice H. Mahoney, Dr Frederick Naftolin, and Virginia Sabo, RN, of Yale University;

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From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Wayne State University/Hutzel Hospital,a the Perinatology Research Branch, National Institute of Child Health and Human Development,b the Department of Obstetrics and Gynecology, Sotero del Rio Hospital,c the Department of Obstetrics and Gynecology, Seoul National University,d and the Department of Obstetrics and Gynecology, Ben-Gurion University.e

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Reprint requests: Roberto Romero, MD, Department of Obstetrics and Gynecology, Hutzel Hospital, Perinatology Research Branch, NICHD, 4707 St. Antoine Blvd, Detroit, MI 48201.

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