The presence of amniotic fluid leukoattractants accurately identifies histologic chorioamnionitis and predicts tocolytic efficacy in patients with idiopathic preterm labor Peter H. Cherouny, MD," Glenn A. Pankuch, BS," John J. Botti, MD," and Peter C. Appelbaum, MD, PhDb Hershey, Pennsylvania OBJECTIVES: We tested these hypotheses: (1) that amniotic fluid from patients with idiopathic preterm labor and histologic chorioamnionitis contains leukoattractants and (2) that the detection of amniotic fluid leukoattractants is an accurate predictor of tocolytic efficacy. STUDY DESIGN: Amniotic fluid from 86 patients in idiopathic preterm labor was evaluated by microbiologic tests and leukotaxis assay. The tests' ability to predict histologic chorioamnionitis and response to tocolysis (51 tocolytic candidates) is established. Statistical analysis was performed with Fisher's exact test and unpaired Student t test. RESULTS: The detection of amniotic fluid leukoattractants was a better predictor of histologic chorioamnionitis (97%) than were amniotic fluid microbiologic tests (62%) (p < 0.01). Also, in patients with detectable amniotic fluid leukoattractants tocolysis failed significantly more often than in patients without detectable leukoattractants (93% vs 7%, P < 0.01). CONCLUSION: The presence of leukoattractants in amniotic fluid detected by the leukotaxis assay accurately identifies histologic chorioamnionitis and can additionally predict tocolytic efficacy in patients with idiopathic preterm labor. (AM J OBSTET GYNECOl 1992;167:683-8.)
Key words: Pre term labor, chorioamnionitis, tocolysis Considerable research indicates that ascending infection is a significant underlying cau~e of preterm labor and may be a major factor contributing to tocolytic failure. I. 2 In the antepartum period clinical criteria supported with microbiologic testing of amniotic fluid are used to identify patients with intrauterine infection. Unfortunately, the clinical criteria for intrauterine infection are insensitive and nonspecific.'" Also, microbiologic testing of amniotic fluid (Gram stain and culture), although specific for intraamniotic infection, may fail to detect the initial stages of an ascending infection, which is believed to begin within the intact membranes and spread secondarily to the amniotic fluid.'·6 Placental membrane cultures may be a more sensitive measure of infection than are amniotic fluid studies; however, they are only available postpartaliy! The failure to exclude infection as an underlying cause of preterm labor
From the Departments of Obstetrics and Gynecology' and Pathology, b the Pennsylvania State University School of Medicine. Supported by The March of Dimes Birth Defects Foundation Grant No. 6-548. Presented at the Eleventh Annual Meeting of the Society of Perinatal Obstetricians, San Francisco, California, January 31-February 2, 1991. Received for publication October 14, 1991; revised March 9, 1992; accepted March 18, 1992. Reprint requests: Peter H. Cherouny, MD, Department of Obstetrics and Gynecology, MCHV, Burlington, VT 05401. 611137974
makes it difficult to accurately judge the efficacy of present tocolytic regimens. The association between histologic chorioamnionitis and preterm delivery has provided much of the evidence linking infection with preterm labor. 1 Further research now supports the view that histologic chorioamnionitis has an infectious cause!' 7 Unfortunately, an accurate method for the detection of histologic chorioamnionitis during the antepartum period is not available. Therefore the frequency of histologic chorioamnionitis in patients in preterm labor and its contribution to tocolytic failure remains unknown. A characteristic feature of histologic chorioamnionitis due to ascending infection is the amniotropism displayed by polymorphonuclear leukocytes in the fetal membranes. 6. 8 This suggests the presence of leukoattractants in amniotic fluid of patients with histologic chorioamnionitis. 6 Leukoattractants, other than bacterial products, that have been identified in amniotic fluid of patients with chorioamnionitis include leukotriene B.,9 platelet-activating factor,10 and interleukin-8." We have recently described the detection of amniotic fluid leukoattractants with an agarose-leukotaxis assay; we found this to be an accurate antepartum marker for histologic chorioamnionitis. 12 The assay is sensitive to a wide range and concentration of leukotactic factors. I' This is an advantage over specific leukoattractant assays (e.g., leukotriene B.) because the precise nature of the
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684 Cherouny et al.
inflammatory response of histologic chorioamnionitis and the role of individualleukoattractants is not known. The agarose-Ieukotaxis bioassay also detects biologically active forms of leukoattractants but has the disadvantage of being cumbersome to perform. The purpose of the current study is to evaluate patients with idiopathic preterm labor and intact membranes to test the following hypotheses: (1) amniotic fluid from patients with idiopathic preterm labor and histologic chorioamnionitis contains leukoattractants detected by the agarose-Ieukotaxis assay; (2) the presence or absence of amniotic fluid leukoattractants in a patient with idiopathic preterm labor can predict tocolytic efficacy.
Methods Amniotic fluid was collected by amniocentesis from 86 patients admitted to University Hospital of The Pennsylvania State University School of Medicine with idiopathic preterm labor and intact membranes without clinical evidence of infection, after informed consent was obtained. The amniocentesis protocol was approved by the Clinical Investigation Committee of Un iversity Hospital. Patients are derived from a >90% white referral population in which 16% have annual family incomes
Key words: Pre term labor, chorioamnionitis, tocolysis Considerable research indicates that ascending infection is a significant underlying cau~e of preterm labor and may be a major factor contributing to tocolytic failure. I. 2 In the antepartum period clinical criteria supported with microbiologic testing of amniotic fluid are used to identify patients with intrauterine infection. Unfortunately, the clinical criteria for intrauterine infection are insensitive and nonspecific.'" Also, microbiologic testing of amniotic fluid (Gram stain and culture), although specific for intraamniotic infection, may fail to detect the initial stages of an ascending infection, which is believed to begin within the intact membranes and spread secondarily to the amniotic fluid.'·6 Placental membrane cultures may be a more sensitive measure of infection than are amniotic fluid studies; however, they are only available postpartaliy! The failure to exclude infection as an underlying cause of preterm labor
From the Departments of Obstetrics and Gynecology' and Pathology, b the Pennsylvania State University School of Medicine. Supported by The March of Dimes Birth Defects Foundation Grant No. 6-548. Presented at the Eleventh Annual Meeting of the Society of Perinatal Obstetricians, San Francisco, California, January 31-February 2, 1991. Received for publication October 14, 1991; revised March 9, 1992; accepted March 18, 1992. Reprint requests: Peter H. Cherouny, MD, Department of Obstetrics and Gynecology, MCHV, Burlington, VT 05401. 611137974
makes it difficult to accurately judge the efficacy of present tocolytic regimens. The association between histologic chorioamnionitis and preterm delivery has provided much of the evidence linking infection with preterm labor. 1 Further research now supports the view that histologic chorioamnionitis has an infectious cause!' 7 Unfortunately, an accurate method for the detection of histologic chorioamnionitis during the antepartum period is not available. Therefore the frequency of histologic chorioamnionitis in patients in preterm labor and its contribution to tocolytic failure remains unknown. A characteristic feature of histologic chorioamnionitis due to ascending infection is the amniotropism displayed by polymorphonuclear leukocytes in the fetal membranes. 6. 8 This suggests the presence of leukoattractants in amniotic fluid of patients with histologic chorioamnionitis. 6 Leukoattractants, other than bacterial products, that have been identified in amniotic fluid of patients with chorioamnionitis include leukotriene B.,9 platelet-activating factor,10 and interleukin-8." We have recently described the detection of amniotic fluid leukoattractants with an agarose-leukotaxis assay; we found this to be an accurate antepartum marker for histologic chorioamnionitis. 12 The assay is sensitive to a wide range and concentration of leukotactic factors. I' This is an advantage over specific leukoattractant assays (e.g., leukotriene B.) because the precise nature of the
683
684 Cherouny et al.
inflammatory response of histologic chorioamnionitis and the role of individualleukoattractants is not known. The agarose-Ieukotaxis bioassay also detects biologically active forms of leukoattractants but has the disadvantage of being cumbersome to perform. The purpose of the current study is to evaluate patients with idiopathic preterm labor and intact membranes to test the following hypotheses: (1) amniotic fluid from patients with idiopathic preterm labor and histologic chorioamnionitis contains leukoattractants detected by the agarose-Ieukotaxis assay; (2) the presence or absence of amniotic fluid leukoattractants in a patient with idiopathic preterm labor can predict tocolytic efficacy.
Methods Amniotic fluid was collected by amniocentesis from 86 patients admitted to University Hospital of The Pennsylvania State University School of Medicine with idiopathic preterm labor and intact membranes without clinical evidence of infection, after informed consent was obtained. The amniocentesis protocol was approved by the Clinical Investigation Committee of Un iversity Hospital. Patients are derived from a >90% white referral population in which 16% have annual family incomes
