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Clinical Chorioamnionitis and Histologic Placental Inammation

JOHN C. SMULIAN, MD, MPH, SUSAN SHEN-SCHWARZ, MD, ANTHONY M. VINTZILEOS, MD, MARIAN F. LAKE, MPH, RNC, AND CANDE V. ANANTH, PhD, MPH
Objective: To estimate the rate of histologic chorioamnionitis in the presence of diagnosed clinical chorioamnionitis and determine whether clinical markers of maternal and neonatal infection are associated with histologic chorioamnionitis. Methods: We identied singleton pregnancies from 1996 in which discharge diagnoses included clinical chorioamnionitis and reviewed maternal and neonatal records for clinical evidence of chorioamnionitis and suspected or conrmed neonatal infections. Placentas were examined for acute histologic chorioamnionitis. Results: One hundred thirty-nine pregnancies with the discharge diagnosis of maternal clinical chorioamnionitis were included. Eighty-six (61.9%) had the clinical diagnosis supported by histologic chorioamnionitis. Histologic chorioamnionitis was associated with an earlier gestational age at delivery (35.7 6.5 weeks versus 38.6 2.9 weeks, P .002), lower epidural usage (72.1% versus 92.5%, P .004), less internal monitoring (47.7% versus 75.5%, P .001), and possible neonatal sepsis (60.5% versus 35.8%, P .005). For 19 of 71 (26.8%) infants with possible neonatal sepsis, placentas did not show histologic chorioamnionitis. Conclusion: Clinical chorioamnionitis and possible neonatal infection were not supported by histologic evidence for infection in 38.1% and 26.8% of cases, respectively, suggesting other noninammatory causes of signs and symptoms. (Obstet Gynecol 1999;94:1000 5. 1999 by The American College of Obstetricians and Gynecologists.)

Clinical chorioamnionitis is diagnosed clinically in 0.9 10.5% of pregnancies and may be increasing in frequency in recent years.13 Diagnosis is important because of the associated increased risk of maternal and neonatal morbidity and mortality.4,5 The aim of reducing complications motivates physicians to be aggressive with interventions that include use of maternal antibiotics, neonatal hematologic studies, blood cultures, cerebrospinal uid sampling, and prolonged neonatal antibiotic therapy.6,7 A low threshold for these procedures and treatments potentially results in the overdiagnosis of chorioamnionitis and might account for some reported increased incidence. Histopathologic changes in the placenta can provide a record of events in utero and can be a useful measure of the accuracy of diagnoses such as clinical chorioamnionitis or early (congenital) neonatal sepsis. We designed this study to estimate the rate of acute histologic chorioamnionitis when chorioamnionitis has been diagnosed on clinical grounds. Our secondary goal was to determine whether any of the specic clinical markers of maternal or neonatal infection in women with clinically diagnosed chorioamnionitis were associated with histologic chorioamnionitis.

Materials and Methods


This was a retrospective cohort study with institutional review board approval. Study subjects were identied by review of discharge diagnoses of women who delivered at St. Peters University Hospital, New Brunswick, New Jersey, in 1996. All women with discharge diagnoses of chorioamnionitis were eligible for inclusion. Only singleton gestations delivered after 20 weeks gestation with histologic placental examinations were included. Maternal and neonatal medical records were reviewed for study variables.

From the Division of Maternal-Fetal Medicine, Division of Epidemiology and Biostatistics, Center for Perinatal Health Initiatives, Department of Obstetrics, Gynecology and Reproductive Sciences, Department of Pathology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School and Saint Peters University Hospital, New Brunswick, New Jersey. Dr. Ananth is supported, in part, by a grant from the Robert Wood Johnson Foundation, New Jersey, awarded to The Center for Perinatal Health Initiatives (Grant #-029553). The opinions, views, and conclusions expressed in this manuscript are those of the author(s) and not necessarily those of the Robert Wood Johnson Foundation.

1000 0029-7844/99/$20.00
PII S0029-7844(99)00416-0

Obstetrics & Gynecology

Maternal antepartum and intrapartum records were reviewed for evidence of fever (temperature at least 100.4F), uterine tenderness, maternal tachycardia (at least 100 beats per minute), fetal tachycardia (at least 160 beats per minute), and foul-smelling amniotic uid (AF). Maximum maternal temperatures before delivery were recorded. Additional maternal variables were recorded when available such as duration of rupture of membranes, internal monitoring (scalp electrode or intrauterine pressure catheter), number of intrapartum vaginal examinations, use and duration of epidural anesthesia, whether women labored, and route of delivery (vaginal versus cesarean). Maternal group B streptococcus status also was recorded. Postpartum maternal length of stay was calculated from time of delivery to discharge. The antepartum white blood cell (WBC) counts drawn closest to time of delivery were recorded. Clinical markers of neonatal infection were identied by reviewing neonatal records. Attending Pediatricians assessments of possible neonatal sepsis were recorded when specied in charts. This diagnosis was based on the judgement of the attending physician. Specic neonatal infection markers included neonatal respiratory distress, poor feeding, poor perfusion, hypotension, lethargy, hyperthermia (rectal temperature at least 99.5F), hypothermia (rectal temperature under 96.0F), and 1- and 5-minute Apgar scores. The initial neonatal WBC count and the percentage of band cells were recorded when available. Additional neonatal variables reviewed were birth weight, infant gender, and neonatal length of stay. Placentas from each included case were examined fresh. At least two sections of placental discs were taken for microscopic examination, each of which included the center of a placental lobule, chorionic plate, and decidual oor. One of the disc sections was taken close to each site of umbilical cord insertion. Another was taken midway between cord insertion and placenta margin. At least one section of umbilical cord 2 cm from the disc insertion site and a rolled strip of extraplacental membranes were examined. Histologic ndings of all placentas were recorded by standardized protocol. Histologic chorioamnionitis was identied as inammatory inltrate of neutrophils at two or more sites in the chorionic plate and extra placental membranes in all placental sections. For purposes of this study, positive histology for chorioamnionitis was dened as greater than ten neutrophils per high-power eld in the subchorionic space and adjacent chorion based on a modication of the criteria reported by Naeye et al.8 Histopathologic examinations were done by a single perinatal pathologist (SSS). Findings that suggested maternal and neonatal infec-

tions and other clinical variables were examined for associations with histologic chorioamnionitis. Continuous variables were compared using a two-tailed t test for normally distributed data and Mann-Whitney U test for non-normally distributed continuous data. Contingency tables with Fisher exact test were used for categorical variables. Statistical signicance was P .05. All proportions are expressed as numbers and percentages with proportions accompanied by 95% condence intervals (CIs). Maternal antepartum clinical factors were examined by logistic regression to determine the best model that would predict histologic chorioamnionitis. Results from that model are presented as odds ratios (ORs) with 95% CIs.

Results
Among 6294 women who delivered in 1996, 189 (3%) had hospital discharge diagnoses of maternal chorioamnionitis. Of the identied pregnancies, 139 (73.5%) had maternal and infant records available and placental histologic examinations. Histologic evidence of chorioamnionitis was identied in 86 (61.9%, 95% CI 53.8%, 70%) of those pregnancies and was absent in 53 (38.1%, 95% CI 30%, 46.2%). Demographic features of cases with and without chorioamnionitis are presented in Table 1. Signicant associations with positive histology included nonwhite race, earlier gestational age at delivery, and lower birth weights. The OR (95% CI) for histologic chorioamnionitis for blacks was 4.2 (1.2, 14.3). Fever was identied in 86 (61.9%, 95% CI 53.8%, 70%), tender uterus in seven of 133 (5.3%, 95% CI 1.5%, 9.1%), maternal tachycardia in 63 (45.3%, 95% CI 37%, 53.6%), fetal tachycardia in 67 of 133 (50.4%, 95% CI 41.9%, 58.9%), and foul-smelling AF in 10 of 136 (7.4%, 95% CI 3%, 11.8%). The overall mean standard deviation (SD) WBC count before delivery was 12,800 4500 cells/mm3. When each variable was compared between women with and without histologic conrmation of chorioamnionitis, no signicant differences were found except higher WBC counts in women with histologic chorioamnionitis (Table 1). Among 53 cases without fever, 30 (56.6%, 95% CI 43.3%, 69.9%) had at least one clinical nding consistent with chorioamnionitis, and 72 of 86 (83.7%, 95% CI 75.9%, 91.5%) cases with fever had at least one additional clinical nding consistent with chorioamnionitis. A total of 19 cases (13.7%, 95% CI 8%, 19.4%) had no recorded objective evidence for clinical chorioamnionitis, and 11 (57.9%, 95% CI 38.7%, 80.1%) of those had histologic chorioamnionitis. Table 2 compares maternal clinical factors between those with and without histologic chorioamnionitis. Women without histologic conrmation of clinical chorioamnionitis were signicantly more likely to have

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Table 1. Demographic Characteristics and Individual Markers of Clinical Chorioamnionitis With and Without Histologic Chorioamnionitis
Histologic chorioamnionitis Present (n Maternal age (y) Gravidity Parity Male infant White Gestational age (wk) Birth weight (g) Fever Tender uterus Maternal tachycardia Fetal tachycardia Foul-smelling amniotic uid WBC ( 1000) before delivery Maximum temperature (F) 86) 95% CI Absent (n 53) 95% CI P .96 .29 .64 .63 .01 .002 .001 .25 .26 .66 .42 .09 .001 .15

28.6 6.1 2 (17) 0 (0 6) 49 (57.0%) 39 (45.3%) 35.7 6.5 2719 1131 50 (58.1%) 6/84 (7.1%) 38 (44.2%) 38/80 (47.5%) 9/83 (10.8%) 13.9 4.8 100.4 1.4

46.5, 67.5 34.8, 55.8

47.7, 68.5 1.6, 12.6 33.7, 54.7 36.6, 58.4 4.1, 17.5

28.6 5.8 2 (15) 0 (0 2) 28 (52.8%) 36 (67.9%) 38.6 2.9 3371 755 36 (67.9%) 1/49 (2%) 25 (47.2%) 29 (54.7%) 1 (1.9%) 11.0 3.4 100.7 1.4

39.4, 66.2 55.3, 80.5

55.3, 80.5 0, 5.9 33.8, 60.6 41.3, 68.1 0, 5.6

CI condence intervals for proportions reported as percentages; WBC white blood cell count in cells per mm3. Results expressed as n (%), mean standard deviation, or median (range) unless otherwise indicated.

epidurals, more likely to have internal fetal monitoring, and had more vaginal examinations. Nineteen of 71 infants with possible sepsis (26.8%, 95% CI 16.5%, 37.1%) had negative placental histologic examinations. There was a signicantly higher proportion (P .005) of possible neonatal sepsis with histologic chorioamnionitis (52 of 86 [60.5%, 95% CI 50.2%, 70.8%] versus 19 of 53 [35.8%, 95% CI 22.9%, 48.7%]); however, other than 1- and 5-minute Apgar scores and band cell counts, positive histology was not signicantly associated with any of the specic neonatal clinical infection variables (Table 3). The range of neonatal hospital stays was slightly smaller when there was no histologic chorioamnionitis, (median of 4 days [range 1 85] versus median of 4 days [range 1138], P .05). Demographic information and clinical antepartum

variables from Tables 1 and 2, potentially predictive of chorioamnionitis, based on univariable analysis, were entered in a logistic regression model to determine the best predictors of histologic conrmation (Table 4). Because of suspected importance of epidural usage on diagnosing clinical chorioamnionitis, we forced that variable in the model. White blood cell count and gestational age were the other important variables in the models. Increasing WBC count was linearly associated with a 20% increased risk of histologic chorioamnionitis (OR [95% CI] 1.2 [1.1, 1.3]). The lowest rate of histologic chorioamnionitis (28.6%) occurred at 35 weeks. The overall relationship between gestational age at delivery and histologic chorioamnionitis was nonlinear (Figure 1) with the OR highest at lower gestational ages, decreasing to a nadir at 35 weeks (referent OR of 1.0) and gradually increasing thereafter.

Table 2. Maternal Clinical Variables With and Without Histologic Chorioamnionitis


Histologic chorioamnionitis Present (n Group B streptococcus Labor Induction of labor Vaginal delivery Epidural Hours of epidural Hours of membrane rupture Internal monitoring Number of vaginal examinations Intrapartum antibiotics Postpartum LOS (d) 86) 95% CI 7.2, 24.2 92.6, 100 11.4, 28.2 45.3, 66.3 62.6, 81.6 Absent (n 53) 95% CI 1.7, 18.7 94.4, 100 21.2, 46.8 30.1, 56.7 85.4, 99.6 P .39 .99 .06 .15 .004 .86 .32 .001 .006 .48 .51

11/70 (15.7%) 83 (96.5%) 17 (19.8%) 48 (55.8%) 62 (72.1%) 7 (0.535) 12 (0 493) 41 (47.7%) 5 (0 16) 55 (64%) 3 (120)

37.1, 58.3 53.9, 74.1

5/49 (10.2%) 52 (98.1%) 18 (34%) 23 (43.4%) 49 (92.5%) 7 (1 41) 10 (0 58) 40 (75.5%) 7 (0 14) 37 (69.8%) 3 (0 16)

63.9, 87.1 57.4, 82.2

CI condence intervals for proportions reported as percentages; LOS length of stay. Results expressed as n (%) or median (range) unless otherwise indicated.

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Table 3. Clinical Criteria for Possible Neonatal Infection With and Without Histologic Chorioamnionitis
Histologic chorioamnionitis Present (n Possible sepsis Respiratory distress Poor feeding Poor perfusion Hypotension Lethargy Hyperthermia Hypothermia Apgar score at 1 min Apgar score at 5 min WBC ( 1000) Band cell count (%) 86) 95% CI 50.2, 70.8 26.9, 47.7 0, 10.4 0, 7.6 0, 7.6 0, 5.7 1.6, 12.8 0, 3.5 Absent (n 53) 95% CI 22.9, 48.7 12.9, 36.1 0, 17.9 0, 5.6 0, 5.6 0, 5.6 5.5, 24.7 P .005 .12 .62 .99 .99 .99 .14 .99 .01 .006 .50 .001

52 (60.5%) 31/83 (37.3%) 2/45 (4.4%) 3/83 (3.6%) 3/83 (3.6%) 2/83 (2.4%) 6/83 (7.2%) 1/83 (1.2%) 8 (19) 9 (19) 19.5 11.9 11.7 8.7

19 (35.8%) 13 (24.5%) 2/26 (7.7%) 1 (1.9%) 1 (1.9%) 1 (1.9%) 8 (15.1%) 0 9 (37) 9 (59) 17.9 6.2 4.7 4

Abbreviations as in Table 1. Results expressed as n (%), median (range), or mean

standard deviation unless otherwise indicated.

Discussion
True clinical chorioamnionitis is a difcult diagnosis. Standardized clinical criteria have been suggested, including maternal temperature of at least 100.4F, with or without additional features such as maternal tachycardia, fetal tachycardia, uterine tenderness, foul-smelling AF, and maternal leukocytosis (more than 15,000 cells/mm3).9,10 Unfortunately, a variety of clinical management practices can alter the reliability of some of those features, especially in preterm gestations.1114 For all gestational ages, epidural anesthesia might alter the assessibility of uterine tenderness, cause intrapartum fevers, and induce maternal and fetal tachycardias.15,16 Antipyretics, such as acetaminophen, can be used before a rising temperature reaches 100.4F to prevent fever.17 In our study, 19 cases (13.7%) lacked any criteria consistent with clinical chorioamnionitis and 34.5% of those given clinical diagnoses of chorioamnionitis had maternal temperatures of less than 100.4F. Newton et al10 reported that 16% of women diagnosed with clinical chorioamnionitis in their series had temperatures under 100.4F. Therefore, in many cases the diagnosis of chorioamnionitis is determined by clinical judgement based on varying degrees of objective ndings. Despite the variable degree of objective diagnostic support, our
Table 4. Multivariable Logistic Regression Model of Histologic Conrmation of Chorioamnionitis
Odds ratio (95% condence interval) Gestational age (Gestational age)2 Epidural White blood cell count (See Figure 1) (See Figure 1) 0.3 (0.1, 1.2) 1.2 (1.1, 1.3) P .066 .072 .095 .004

institutions overall 3% rate of clinical chorioamnionitis is consistent with other reports.4,10 Although it is difcult to know if clinical chorioamnionitis is associated with intra-amniotic infection in a given case, it is important to try to make the diagnosis. Intrapartum antibiotic treatment for clinical chorioamnionitis has signicantly reduced the incidence of postpartum maternal complications and neonatal sepsis.6,7 The perceived need to administer timely intrapartum antibiotics might have had the unanticipated effect of promoting early anticipation of chorioamnionitis by clinicians before actual diagnostic criteria were met in our population, which might account for some cases without histologic evidence of infection.

Figure 1. Odds ratios (OR) and 95% condence intervals for histologic chorioamnionitis based on gestational age. The gestational age with the lowest histologic chorioamnionitis rate (35 weeks) was used as the referent OR of 1.0.

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This study population represented only cases of clinical chorioamnionitis for which placental histology was obtained, so our results might represent an optimistic assessment of histologic chorioamnionitis rates because placentas might have been preferentially sent when an abnormality was expected. Assuming that was a best-case scenario, the absence of histologic conrmation of chorioamnionitis in 38.1% of our cases was disappointing. We also recognize the limitations of retrospective study design. Specic clinical ndings supportive of clinical diagnoses of chorioamnionitis might not have been recorded in medical records. Several investigators have reported associations of intrapartum fever with epidural anesthesia.15,16 Although the mechanism of hyperpyrexia from epidural anesthesia is unclear, the pathophysiology is most likely unrelated to infection. In our present study, women without histologic chorioamnionitis were signicantly more likely to have had an epidural in labor (91.6%) than those who had placental inammation (72.1%). In the univariable analysis we found that internal monitoring and increased vaginal examinations were associated with negative histology. Those ndings might be related to epidural anesthesia, which is associated with longer labors that are likely to result in more vaginal examinations and internal fetal monitoring. We were unable to address the effect of length of labor because it was not consistently available. Our logistic regression analysis indicated that when epidural was placed in the model, the effects of internal monitoring and number of vaginal examinations became nonsignicant. About half our women with clinical chorioamnionitis had infants assessed with possible sepsis. None of the clinical features of early neonatal sepsis were consistently present in those infants, which underscores the subjectivity of many newborn sepsis evaluations. It is possible that having a clinical diagnosis of maternal chorioamnionitis can inuence neonatal management. That agrees with ndings of Wiswell et al18 who surveyed directors of fellowships in neonatology and pediatric infectious diseases and found that for women who received antibiotics for presumed chorioamnionitis, the percentages of directors who recommended complete blood cell counts, blood cultures, and lumbar punctures were 78%, 71%, and 28%, respectively. Thirty-nine percent reported they would begin empiric treatment of all infants. In our study, 26.8% of placentas from infants with possible sepsis were without inammation, suggesting a group at low risk for infection, whereas 50% (34 of 68) of neonates without possible sepsis had placental inammation. This conrms the difculty in using a clinical diagnosis of maternal chorioamnionitis to correctly predict those infants likely to have signicant infections.

The issue of a gold standard for chorioamnionitis diagnosis has not been settled. When there is no placental histologic inammation, it is reasonable to conclude that signicant infectious causes of maternal or infant symptomatology are less likely. However, such a conclusion assumes adequate sampling of the placenta, membranes, and umbilical cord have been done to be sure that a signicant area of inammation has not been missed.19 Placental cultures also might be positive without histologic chorioamnionitis.20 Histologic inammation does not by itself guarantee the presence of a signicant infectious process. Microorganisms are isolated in only 70% of placentas with histologic chorioamnionitis.20,21 Some cases of histologic inammation can be due to a variety of noninfectious causes, including fetal hypoxia, amniotic uid pH changes, immunologic responses to fetal tissues, meconium, and other nonspecic reactive responses.19 It is possible that there are subgroups of placental inammation that are more likely to be associated with signicant infections. Those higher risk groups might be detectable by identication of circulating inammatory cytokines, which mediate maternal and infant clinical responses to infection.22,23 There is a need for better understanding of the clinical manifestations of intra-amniotic infection and associated placental histology to improve management for mothers and neonates.

References
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20. Hillier SL, Martus J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319: 972 8. 21. Svensson L, Ingemarsson I, Mardh PA. Chorioamnionitis and the isolation of microorganisms from the placenta. Obstet Gynecol 1986;67:4039. 22. Smulian JC, Vintzileos AM, Lai YL, Santiago J, Shen-Schwarz S, Campbell WA. Maternal chorioamnionitis and umbilical vein interleukin-6 levels for identifying early neonatal sepsis. J Matern Fetal Med 1999;8:88 94. 23. Shimoya K, Matsuzaki N, Taniguchi T, Okada T, Saji F, Murata Y. Interleukin-8 level in maternal serum as a marker for screening of histologic chorioamnionitis at term. Int J Gynaecol Obstet 1997;57: 1539.

Reprints are not available.

Received February 8, 1999. Received in revised form May 7, 1999. Accepted June 3, 1999.
Copyright 1999 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.

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