Accuracy of Signs of Clinical Chorioamnionitis in the Term Parturient

ORIGINAL ARTICLE Accuracy of signs of clinical chorioamnionitis in the term parturient

WM Curtin1,2, PJ Katzman3, H Florescue1 and LA Metlay3

OBJECTIVE: Uniform histopathologic guidelines were applied to diagnose chorioamnionitis and estimate the accuracy of clinical signs in term parturients. STUDY DESIGN: A retrospective cohort study utilized slides from term parturient placentas with Amniotic Fluid Infection Nosology Committee guidelines as the gold standard. Sensitivity, specificity and accuracy for fever, maternal tachycardia and fetal tachycardia were calculated. RESULT: Of 641 placentas, 367 (57.3%) had histologic chorioamnionitis and 274 (42.7%) were negative. Fever had a sensitivity of 42%, specificity of 86.5% and accuracy of 61%. Fever, maternal tachycardia and fetal tachycardia had a sensitivity of 18.3%, specificity of 98.2% and accuracy of 52.4%. CONCLUSION: Histologic chorioamnionitis, frequently asymptomatic, is a common finding in placentas examined from term parturients. Clinical signs are not accurate in the diagnosis. Adoption of uniform pathologic guidelines will facilitate research into the clinical significance of these lesions in the future.

Journal of Perinatology (2013) 33, 422–428; doi:10.1038/jp.2012.135; published online 15 November 2012 Keywords: sensitivity; speciﬁcity; accuracy; clinical chorioamnionitis; histologic chorioamnionitis; guidelines

INTRODUCTION inflammation; six expert placental pathologists found Histopathology can be considered the gold standard in diagnos- approximately 90% agreement for any stage of maternal and ing chorioamnionitis.1 Some studies define clinical chorio- fetal inflammatory responses in the placenta. Using these amnionitis as fever plus two additional signs.2,3 As intrapartum guidelines as the gold standard for histologic chorioamnionitis, antibiotic treatment of chorioamnionitis improves both fetal and we retrospectively reclassified all placentas submitted from term maternal outcomes,4 in clinical obstetric practice, an intrapartum parturients in a single year to determine the sensitivity, specificity fever with appropriate risk factors5 typically prompts and accuracy for the intrapartum signs of fever, maternal administration of intravenous antibiotics. Clinical chorioa- tachycardia and fetal tachycardia. We hypothesized that fever, mnionitis has a reported incidence of 5 to 12% in the term maternal tachycardia and fetal tachycardia would have limited parturient.5–7 The individual clinical signs that are used to define sensitivity in the histopathologic diagnosis of chorioamnionitis. clinical chorioamnionitis vary among studies. An intrapartum temperature of 1001F and antibiotics administered for that indication was the only sign required in one study,6 whereas METHODS other studies required an intrapartum temperature 100 to 1011F This was a retrospective cohort study of all singleton term livebirths, X37 plus clinical signs that included one or more of the following: weeks’ gestation, that had placental examination at Strong Memorial maternal tachycardia (4100 b.p.m.), fetal tachycardia Hospital in 2005. The study was approved by the research subjects review (4160 b.p.m.), maternal leukocytosis (variably defined), uterine board at the University of Rochester Medical Center. Using the birth 2–5,7 certificate registry, all term livebirths were identified and cross-referenced tenderness and foul-smelling or purulent amniotic fluid. None with the pathology database to identify which births also had placental of these studies correlated clinical signs to placental pathology. examination. Only women admitted with singleton pregnancies in labor or Variations in the criteria for diagnosis of histopathologic undergoing induction of labor at term who had the placenta submitted for chorioamnionitis have been published.8–13 In studies reporting a pathologic examination were included as subjects of the study. Although consecutive series of all livebirths, histologic chorioamnionitis was physicians at this institution had previously received education on found in 10 to 38% of placentas.9,10,13,14,15 It is apparent that recommended indications for placental examination,17 there were no histologic chorioamnionitis occurs more frequently than clinically departmental mandates for placental submission and the decision was evident chorioamnionitis, even in the term parturient. In one ultimately that of the attending physician. We excluded patients undergoing elective primary or repeat cesarean section in the absence of labor. study, only 8.1% of patients with histologic chorioamnionitis were 17 14 Placentas had been processed according to standard guidelines. A noted to have fever. Lack of standardization in diagnostic membrane roll, two sections from the placental disc and one or two cord terminology for histologic chorioamnionitis may be one reason for sections were available for review from each placenta. The original 16 the variation in incidence. Redline et al. classified histologic histopathologic slides of the placenta were interpreted by one of two chorioamnionitis into well-defined anatomic stages and grades of perinatal pathologists (PJK and LAM) at the time of placental submission in

1Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; 2Department of Obstetrics and Gynecology and Pathology, Pennsylvania State University College of Medicine, Hershey, PA, USA and 3Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Correspondence: Dr WM Curtin, Mail Code H103, 500 University Drive, Penn State Milton Hershey Medical Center, PO Box 850, Hershey, PA 17033-0850, USA. E-mail: [email protected] Received 23 April 2012; revised 17 August 2012; accepted 10 September 2012; published online 15 November 2012 Accuracy of clinical chorioamnionitis WM Curtin et al 423 2005. All slides from subjects fulfilling the study entry criteria were retrieved in 2007 to 2008. They were rescreened by a third pathologist Table 1. Classification of histologic chorioamnionitis in the placenta (WMC) and categorized according to the absence or presence of among 367 term parturients inflammation. The inflammation was staged and graded according to the criteria of Redline et al.16 Briefly, this is a three-stage, two-grade Stage Grade Number (% total) classification for maternal and fetal inflammatory responses, the details of which are given in the Supplementary Box. Slides with placental Grade 1 Grade 2 inflammation were again reviewed concurrently with PJK for final classification, and if there was uncertainty with classification LAM was Stage 1 180 5 185 (50.4) consulted. All slides were reviewed without clinical information. Cohorts Stage 2 117 37 154 (42) were divided into two groups according to the presence or absence of Stage 3 1 27 28 (7.6) histologic chorioamnionitis. Histologic chorioamnionitis was considered to be any stage and grade of maternal inflammatory response that fulfilled the guidelines. The presence of any fetal inflammatory responses in the umbilical cord and placenta was also classified. Table 2. Classification of fetal inflammatory response in 114 (31%) of Maternal, intrapartum and neonatal data were retrieved from the 367 term parturients with histologic chorioamnionitis intrapartum electronic record (QS; GE Healthcare, Barrington, IL, USA). The hospital computerized medical records were also reviewed for discharge Stage Grade Number (% total) summaries, operative reports, placental pathology reports and discharge coding summaries. Paper charts were retrieved if additional data were needed. The following maternal data were collected: age, parity, race/ Grade 1 Grade 2 ethnicity, gestational age, group B streptococcus (GBS) status and whether Stage 1 83 4 87 (76.3) or not there was induction of labor. Intrapartum data included epidural Stage 2 23 3 26 (22.8) use, the number of vaginal examinations, use of internal monitoring and Stage 3 0 1 1 (0.9) amnioinfusion, presence of particulate meconium and severe variable decelerations (defined as X60 b.p.m. decrease from the baseline lasting X60 s), use of intrapartum antibiotics, duration of labor and ruptured membranes and mode of delivery. Placental pathology reports were placental requisitions by the delivering clinician are categorized reviewed for the original indications that lead to submission of the and summarized as follows: suspected chorioamnionitis, 158; placenta for examination. The newborn data collected included birth- medical complication of pregnancy, 110; placental abnormality or weight, Apgar scores, placental weight and whether there was observation bleeding, 83; meconium, 76; fetal growth or amniotic fluid for sepsis, the latter determined by review of the coding summary at abnormality, 58; and other, 103. Intrapartum fever or suspected newborn discharge or blood cultures taken during the newborn admission. chorioamnionitis was much more likely to be listed on the Comparisons of cohorts with and without histologic chorioamnionitis requisition as the indication for placental examination by the and with and without fetal inflammatory response (of any stage) were 2 clinician in the cohort that had histologic chorioamnionitis (134 made. Categorical data were analyzed with w tests of association and (36.5%) vs 24 (8.8%); OR 6.0; 95% CI: 3.8 to 9.5). The classification of continuous data with t-tests as appropriate. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated as appropriate. Forward the 367 placentas with histologic chorioamnionitis by stage and stepwise multiple logistic regression was used to identify independent grade is given in Table 1. Fetal inflammatory responses were clinical predictors of histologic chorioamnionitis and fetal inflammatory noted in 114 (31%) of the 367 cases with histologic chorioamnio- response at any stage. Significance was set at Pp0.05 and no corrections nitis, but in no cases among the 274 placentas without histologic were made for multiple comparisons. Statistical analysis was performed chorioamnionitis (OR 123; 95% CI: 21.4 to 705). The classification of using SPSS for Windows (SPSS, Chicago, IL, USA). the 114 cases of fetal inflammatory response by stage and grade is The clinical signs evaluated for diagnostic accuracy were fever, maternal shown in Table 2. Fetal inflammatory responses were more likely tachycardia and fetal tachycardia. Fever was defined as a maternal to occur with increasing stage of histologic chorioamnionitis: X 1 X temperature 38 C, maternal tachycardia as a pulse 120 b.p.m. and fetal stage 1, 7.6%; stage 2, 48.1%; and stage 3, 93%; P 0.001. tachycardia as a sustained (X10 min) baseline fetal heart rate of X160 b.p.m. o The sensitivity, specificity and accuracy and their 95% CI were calculated for The demographic and intrapartum characteristics of the cohorts histologic chorioamnionitis of any stage. We chose a higher cutoff for with and without histologic chorioamnionitis are given in Table 3. maternal tachycardia during labor as approximately 80% of subjects had at The frequency of intrapartum signs overall and stratified by stage least one heart rate X100 b.p.m. We did not evaluate maternal white blood of histologic chorioamnionitis is compared in Table 4. All signs cell counts as these were not uniformly available for all patients. We also did were significantly more often associated with histologic chor- not evaluate the subjective signs of uterine tenderness or foul-smelling ioamnionitis overall when compared with no histologic chorioam- amniotic fluid as these signs would only expected to be documented on nionitis. It is also noted that intrapartum fever was more often those subjects clinically suspected to have infection. 18 associated with stage 2 and stage 3 histologic chorioamnionitis We used published nomograms to estimate the necessary sample size. than stage 1. Maternal tachycardia was only significantly associated Using a data set from a previous study,19 we estimated a prevalence of histologic chorioamnionitis of 30%, a sensitivity of fever of 50% with a CI of with stage 2 and 3 histologic chorioamnionitis. Fetal tachycardia 10% and a ¼ 0.05 to give a sample size of approximately 400 subjects. The was significantly associated with all three stages of histologic specificity of fever for histologic chorioamnionitis was hypothesized to be chorioamnionitis with no significant difference noted among all 88% with a CI of 5% and a ¼ 0.05 to give an approximate sample size of three stages. The sensitivity, specificity and accuracy of clinical 200. We used the Standards for Reporting of Diagnostic Accuracy signs in prediction of histologic chorioamnionitis of any stage are guidelines for this study.20 given in Table 5. Newborn outcomes are compared in Table 6. Forward stepwise logistic regression analysis was performed with histologic chorioamnionitis as the outcome variable and the RESULTS following included as dichotomous independent variables: parity There were 713 term singleton births with placental examination X1, GBS status, induction of labor, epidural, internal monitoring, out of a total of 2700 births in 2005; 72 births were excluded as amnioinfusion, particulate meconium, fever, maternal tachycardia, the mothers were not laboring, leaving a total of 641 subjects. The fetal tachycardia, severe variable decelerations and 1 min Apgar total number of term parturients was approximately 2124; thus, p6. The following were included as continuous independent the percentage of placentas examined from term parturients was variables: gestational age, number of vaginal exams, duration 30%. They were divided into two cohorts for comparison: 367 of labor, duration of ruptured membranes and birthweight. The (57.3%) in which histologic chorioamnionitis was present and 274 results of the multiple logistic regression for independent in which (42.7%) it was absent. The indications listed on the 641 predictors of histologic chorioamnionitis are given in Table 7.

& 2013 Nature America, Inc. Journal of Perinatology (2013), 422 – 428 Accuracy of clinical chorioamnionitis WM Curtin et al 424 Table 3. Demographic and intrapartum data among cohorts with and without histologic chorioamnionitis

Variablea Histologic chorioamnionitis OR (95% CI) P-value

Present (n ¼ 367) Absent (n ¼ 274)

Maternal age (years) 28.3±6.4 28.3±6.5 0.92 Race/ethnicity 0.63 Caucasian 218 (59.4) 173 (63.1) African-American 97 (26.4) 71 (25.9) Hispanic 24 (6.5) 15 (5.5) Asian 28 (7.5) 15 (5.5) Parity X1 156 (42.5) 163 (59.5) 0.50 (0.37–0.69) o0.001 Gest. age (weeks) 39.5±1.14 39.0±1.3 o0.001 GBS positive 80 (21.8) 75 (27.4) 0.74 (0.52–1.1) 0.103 Induction of labor 126 (34.3) 137 (50.0) 0.52 (0.38–0.72) o0.001 Epidural 302 (82.3) 185 (67.5) 2.24 (1.55–3.23) o0.001 Internal monitoring 223 (60.8) 121 (44.2) 1.96 (1.43–2.69) o0.001 X6 Vaginal exams 204 (55.6) 100 (36.5) 2.18 (1.58–3.0) o0.001 Severe variables 141 (38.4) 77 (28.1) 1.60 (1.14–2.24) 0.006 Particulate meconium 37 (10.1) 21 (7.7) 1.42 (0.81–2.5) 0.221 Amnioinfusion 64 (17.4) 36 (13.1) 1.4 (0.9–2.2) 0.138 Intrapartum antibiotics 176 (48.0) 87 (31.8) 1.98 (1.41–2.8) o0.001 Intrapartum amp/gent 125 (34.1) 25 (9.1) 5.15 (3.16–8.42) o0.001 Duration of labor (h) 15.3±11.7 11.9±12.1 o0.001 Duration of ROM (h) 11.5 (0–129) 7.3 (0–144) o0.001 Cesarean section 118 (32.2) 85 (31) 1.05 (0.75–1.48) 0.761 Abbreviations: CI, conﬁdence intervals; GBS, group B streptococcus; OR, odds ratio; ROM, rupture of membranes. aResults expressed as mean±s.d., median (minimum–maximum), or number (%).

Table 4. Frequency of clinical signs of chorioamnionitis among cohorts with and without histologic chorioamnionitis, overall and stratiﬁed by stage

Signa Histologic chorioamnionitis OR (95% CI) P-value

Present (n ¼ 367) Absent (n ¼ 274)

Fever 154 (42) 37 (13.5) 4.63 (3.09–6.9) o0.001 Stage 1 55 (29.7) 2.71 (1.7–4.4) o0.001 Stage 2 82 (53.2) 7.3 (4.4–12.0) o0.001 Stage 3 17 (60.7) 9.9 (4.0–24.8) o0.001

Maternal tachycardia 173 (47.1) 83 (30.3) 2.05 (1.48–2.85) o0.001 Stage 1 71 (38.4) 1.43 (0.9–2.2) 0.07 Stage 2 87 (56.5) 3.03 (1.97–4.66) o0.001 Stage 3 15 (53.6) 2.7 (1.1–6.2) 0.02

Fetal tachycardia 133 (36.2) 45 (16.4) 2.89 (1.97–4.25) o0.001 Stage 1 56 (30.3) 2.21 (1.38–3.5) 0.001 Stage 2 63 (40.9) 3.52 (2.19–5.69) o0.001 Stage 3 14 (50) 5.1 (2.1–12.2) o0.001 Abbreviations: CI, conﬁdence intervals; OR, odds ratio. aResults expressed as number (%).

Table 5. Performance of clinical signs in prediction of histologic chorioamnionitis

Signa Sensitivity Speciﬁcity Accuracy

Fever 42 (36.9–47.2) 86.5 (82–90.3) 61.0 (57.7–63.9) Maternal tachycardia 47.4 (42.2–52.7) 69.7 (63.9–75.1) 56.8 (52.9–60.5) Fetal tachycardia 36.2 (31.3–41.4) 83.7 (78.7–87.8) 56.5 (53.1–59.6) Any one sign 67.6 (62.5–72.3) 54.0 (47.9–60.0) 61.8 (57.9–65.6) X2 signs 40.6 (35.5–45.8) 88.0 (83.5–91.6) 60.8 (57.6–63.6) All signs 18.3 (14.4–22.6) 98.2 (95.8–99.4) 52.4 (50.4–53.4) Abbreviation: CI, conﬁdence intervals. aResults expressed as % (95% CI).

Cohorts were compared with (n ¼ 114) and without fetal frequency of intrapartum signs overall and stratified by stage of inflammatory responses (n ¼ 527) and the maternal demographic fetal inflammatory response is compared in Table 9. All signs were and intrapartum characterisitcs results are given in Table 8. The significantly more often associated with fetal inflammatory

Journal of Perinatology (2013), 422 – 428 & 2013 Nature America, Inc. Accuracy of clinical chorioamnionitis WM Curtin et al 425 Table 6. Newborn outcomes among cohorts with and without histologic chorioamnionitis

Variablea Histologic chorioamnionitis OR (95% CI) P-value

Present (n ¼ 367) Absent (n ¼ 274)

Birthweight (g) 3418±460 3282±568 0.001 Apgar, 1 min, p6 60 (16.3) 31 (11.3) 1.53 (0.94–2.1) 0.071 Apgar, 5 min, p6 9 (2.5) 6 (2.2) 1.12 (0.36–3.6) 0.82 Observation for sepsis 157 (42.8) 48 (17.5) 3.52 (2.42–5.11) o0.001 Placental weight (g) 482±109 467.9±112 0.101 Abbreviations: CI, conﬁdence intervals; OR, odds ratio. aResults expressed as mean±s.d., or number (%).

examination and the clinician was more likely to submit the a Table 7. Multiple logistic regression for independent predictors of placenta when there was a clinical suspicion for chorioamnionitis. histologic chorioamnionitis Of 2124 term parturient placentas, 30% were submitted for examination. While this is a sizable portion of placentas, it is not a Variable OR (95% CI) P-value random sample and therefore subject to bias. Clinicians are more Gestational age (weeks) 1.26 (1.09–1.45) 0.002 likely to submit the placenta for examination when chorioamnio- Number of vaginal exams 1.17 (1.08–1.26) o0.001 nitis is suspected and this may be an explanation for the high rate Duration of ruptured membranes 1.02 (1.0002–1.04) 0.048 of histologic chorioamnionitis and fever in our study. We do not (h) know our true population prevalence of histologic chorioamnio- Fever 2.83 (1.76–4.55) o0.001 nitis from our term parturients, and thus could not offer reliable Induction of labor 0.29 (0.20–0.43) o0.001 estimates of positive predictive value and negative predictive Fetal tachycardia 1.66 (1.05–2.63) 0.03 value for clinical signs. The sensitivity, specificity and accuracy of Parity X1 0.65 (0.45–0.94) 0.021 clinical signs are not affected by prevalence, and thus these Abbreviations: CI, confidence intervals; OR, odds ratio. calculated values are valid estimates. The prevalence of histologic aGoodness-of-fit test, P ¼ 0.485; Nagelkerke R2 ¼ 0.266, Model w2, Po0.001. chorioamnionitis and funisitis in one prospective study of term parturients was reported as 23.6% and 6.7%, respectively.21 A response overall in comparison to no fetal inflammatory response. hypothetical positive predictive value and negative predictive It is also noted that maternal tachycardia was more often value for fever in our total population of 2124 term parturients is associated with stage 2 or greater fetal inflammatory response calculated as follows: a hypothesized prevalence of disease when compared with stage 1. Newborns in the cohort with fetal (histologic chorioamnionitis) of 24% for the remaining 1483 inflammatory response were more likely to have 1-min Apgar term parturients who did not have the placenta examined with a 13.5% false-positive rate and a 58% false-negative rate added to scores p6, a higher frequency of observation for sepsis and all placentas also showed histologic chorioamnionitis (Table 10). the existing data for our 641 term parturients with placental Forward stepwise logistic regression analysis was performed with examination would give a positive predictive value of 61.7% (95% fetal inflammatory response as the outcome variable and the CI: 57.2 to 66.0) and a negative predictive value of 74.3% (95% CI: following included as dichotomous independent variables: parity 72.1 to 76.4). If we had chosen a cutoff for histologic X X1, GBS status, induction of labor, epidural, internal monitoring, chorioamnionitis that was more severe (for example, stage 2) particulate meconium, amnioinfusion, fever, maternal tachycardia, in this study, minor changes in sensitivity and specificity would be fetal tachycardia, severe variable decelerations and 1-min Apgar expected with a decline in prevalence of disease and a concomitant decrease in the positive predictive value and an p6. The following were included as continuous independent variables: gestational age, number of vaginal exams, duration of increase in the negative predictive value. labor, duration of ruptured membranes and birthweight. The This study included only term pregnancies in labor to assess the results of the multiple logistic regression for independent accuracy of clinical signs using histologic chorioamnionitis as the gold predictors of fetal inflammatory response are given in Table 11. standard and may be unique in that respect. One study that included both term and preterm deliveries with a discharge diagnosis of clinical chorioamnionitis did not find a difference in intrapartum DISCUSSION fever, or maternal tachycardia and fetal tachycardia between groups 22 23 Histologic chorioamnionitis was a common finding, present in with and without histologic chorioamnionitis. Heller et al. also 57% of term placentas submitted for examination. Approximately studied term and preterm deliveries with and without histologic one-third of these placentas also had a fetal inflammatory chorioamnionitis and found no significant differences in the response. Only 42% of women had an intrapartum fever. The proportion with intrapartum fever. In our study, the overall clinical signs (fever, maternal tachycardia, fetal tachycardia) were incidence of intrapartum fever was approximately 30%. Intrapartum strongly associated with histologic chorioamnionitis but were fever does not necessarily mean infection from chorioamnionitis, but diagnostically insensitive. there is currently no way to distinguish between infectious and The strength of this study was the large numbers of term noninfectious fever in labor. Epidural anesthesia is associated with parturients and their placentas included in the analysis and the fever and there was a high rate of epidural use in this study. The uniform application of standard histopathologic staging and incidence of fever in women receiving intrapartum epidural 24 grading criteria. The results of this study would be expected anesthesia ranges from approximately 2 to 46%. to be generalizable to similar populations of patients. The Of note in our study is that fetal inflammatory responses did not retrospective nature of the study would be a weakness. The occur in the absence of histologic chorioamnionitis. This finding is prevalence of histologic chorioamnionitis was high in this study as in agreement with the view that a fetal inflammatory response is a the study was predicated on the submission of the placenta for sequela to maternal histologic chorioamnionitis and seldom seen

& 2013 Nature America, Inc. Journal of Perinatology (2013), 422 – 428 Accuracy of clinical chorioamnionitis WM Curtin et al 426 Table 8. Demographic and intrapartum data among cohorts with and without fetal inﬂammatory responses

Variablea Fetal inﬂammatory response OR (95% CI) P-value

Present (n ¼ 114) Absent (n ¼ 527)

Maternal age (years) 27.6±6.6 28.4±6.3 0.23 Parity X1 44 (38.6) 275 (52.2) 0.58 (0.37–0.89) 0.009 Gestational age (weeks) 39.5±1.13 39.2±1.2 0.004 GBS positive 33 (28.9) 122 (23.1) 1.34 (0.86–2.12) 0.190 Induction 31 (27.2) 232 (44.0) 0.47 (0.31–0.74) 0.001 Epidural 95 (83.3) 232 (44.0) 1.72 (1.02–2.91) 0.001 Internal monitors 79 (69.3) 265 (50.3) 2.32 (1.45–3.43) o0.001 X6 vag. exams 63 (55.3) 241 (45.7) 1.47 (0.96–2.25) 0.065 Severe variables 46 (40.4) 175 (33.2) 1.4 (0.92–1.13) 0.115 Particulate meconium 8 (7.0) 50 (9.5) 0.72 (0.34–1.54) 0.004 Amnioinfusion 28 (25.4) 72 (13.7) 2.06 (1.26–3.36) 0.115 Intrapartum antibiotics 72 (63.2) 191 (36.2) 3.02 (1.94–4.7) o0.001 Intrapartum amp/gent 56 (49.1) 94 (17.8) 4.45 (2.83–7.0) o0.001 Duration of labor (h) 14.7±8.6 13.7±12.6 0.291 Duration of ROM (h) 10.6 (0.03–93.55) 5.77 (0–144) 0.002 Cesarean section 47 (41.2) 156 (29.6) 1.67 (1.10–2.52) 0.016 Abbreviations: CI, conﬁdence intervals; GBS, group B streptococcus; OR, odds ratio; ROM, rupture of membranes. aResults expressed as mean±s.d., median (minimum–maximum) or number (%).

Table 9. Frequency of clinical signs of chorioamnionitis among cohorts with and without fetal inﬂammatory response, overall and stratiﬁed by stage

Signa Fetal inﬂammatory response OR (95% CI) P-value

Present (n ¼ 114) Absent (n ¼ 527)

Fever 64 (56) 127 (24.1) 4.03 (2.59–6.28) o0.001 Stage 1 48 (55.2) 3.88 (2.37–6.35) o0.001 Stage X2 16 (59.3) 4.58 (1.95–10.87) o0.001

Maternal tachycardia 64 (56) 192 (36.4) 2.23 (1.45–3.44) o0.001 Stage 1 42 (48.3) 1.63 (1.01–2.63) 0.035 Stage X2 22 (81.5) 7.68 (2.70–23.53) o0.001

Fetal tachycardia 53 (46.5) 125 (23.7) 2.79 (1.79–4.34) o0.001 Stage 1 38 (43.7) 2.49 (1.52–4.09) o0.001 Stage X2 15 (55.6) 4.02 (1.72–9.44) o0.001 Abbreviations: CI, conﬁdence intervals; OR, odds ratio. aResults expressed as number (%).

Table 10. Newborn outcomes among cohorts with and without fetal inﬂammatory responses

Variablea Fetal inﬂammatory response OR (95% CI) P-value

Present (n ¼ 114) Absent (n ¼ 527)

Birthweight (g) 3369±410 3358±553 0.818 Apgar, 1 min, p6 24 (21.0) 67 (12.7) 1.83 (1.1–3.06) 0.021 Apgar, 5 min, p6 4 (3.5) 11 (2.1) 1.71 (0.56–5.18) 0.363 Observation for sepsis 70 (61.2) 135 (25.6) 4.62 (3.03–7.05) o0.001 Placental weight (g) 481±85 475±114 0.558 Histologic chorioamnionitis 114 (100) 253 (48) 122 (18.38–2380) o0.001 Abbreviations: CI, conﬁdence intervals; OR, odds ratio. aResults expressed as mean±s.d., or number (%).

in isolation.8 Detection of histologic chorioamnionitis may be other authors have found.26–28 We also did not find any significant improved with increasing samples of extraplacental membranes.25 association with histologic chorioamnionitis when meconium We did not find an association by multivariate analysis between staining was listed as an indication on the requisition nor was particulate meconium or severe variable decelerations and there any significant association between the histologic presence histologic chorioamnionitis and fetal inflammatory responses as of meconium and histologic chorioamnionitis (data not shown).

Journal of Perinatology (2013), 422 – 428 & 2013 Nature America, Inc. Accuracy of clinical chorioamnionitis WM Curtin et al 427 Table 11. Multiple logistic regressiona for independent predictors of 2 Newton ER, Prihoda TJ, Gibbs RS. Logistic regression analysis of risk factors of fetal inflammatory responses intra-amniotic infection. Obstet Gynecol 1989; 73: 571–575. 3 Sperling RS, Ramamurthy RS, Gibbs RS. A comparison of intrapartum versus postpartum treatment of intrapartum infection. Obstet Gynecol 1987; 70: Variable OR (95% CI) P-value 861–865. 4 Gibbs RS, Dinsmoor MJ, Newton ER, Ramamurthy RS. A randomized trial of Histologic chorioamnionitis 88.3 (12.2–641) o0.001 intrapartum versus immediate postpartum treatment of women with intra- Fever 2.54 (1.59–4.06) o0.001 Amnioinfusion 1.91 (1.08–3.39) 0.026 amniotic infection. Obstet Gynecol 1988; 72: 823–828. Induction of labor 0.52 (0.31–0.86) 0.011 5 Soper DE, Mayhall CG, Dalton HP. Risk factors for intraamniotic infection: a prospective epidemiologic study. Am J Obstet Gynecol 1989; 161: 562–568. Abbreviations: CI, confidence intervals; OR, odds ratio. 6 Rouse DJ, Landon M, Leveno KJ, Leindecker S, Varner MW, Caritis SN et al. National aGoodness-of-fit test, P ¼ 0.686; Nagelkerke R2 ¼ 0.364; Model w2, Po0.001. Institute of Child Health and Human Development, Maternal–Fetal Medicine Units Network. The Maternal–Fetal Medicine Units cesarean registry: chorioamnionitis at term and its duration-relationship to outcomes. Am J Obstet Gynecol 2004; 191: 211–216. The reason why advancing gestational age and induction of 7 Alexander JM, McIntire DM, Leveno KJ. Chorioamnionitis and the prognosis for labor are independent, positive and negative predictors, respec- term infants. Obstet Gynecol 1999; 94: 274–278. 29 8 Blanc WA. Pathways of fetal and early neonatal infection: viral placentitis, bacterial tively, of histologic chorioamnionitis is unclear. Park et al. also and fungal chorioamnionitis. J Pediatr 1961; 59: 473–496. reported these findings in their study of term parturients. An 9 Fox H, Langley FA. Leukocytic infiltration of the placenta and umbilical cord. A explanation in the case of advancing gestational age may be that clinicopathologic study. Obstet Gynecol 1971; 37: 451–458. the physical barrier to ascending infection may be decreased 10 Pryse-Davies J, Beazley JM, Leach G. A study of placental size and chor- through loss of the mucus plug or cervical dilation. The association ioamnionitis in a consecutive series of hospital deliveries. J Obstet Gynaecol Br with induction of labor may be related to an unripe cervix as an Commonw 1973; 80: 246–251. effective barrier, qualitative differences in labor or the possibility 11 Blanc WA. Pathology of the placenta, membranes and umbilical cord in bacterial, that some cases of term spontaneous labor are initiated by fungal, and viral infections in man. In: Naeye RL, Kissane JM, Kaufman N (eds). Perinatal Diseases. Williams & Wilkins: Baltimore, MD, 1981, pp 67–132. intrauterine infection. 12 Naeye RL, Maisels MJ, Lorenz RP, Botti JJ. The clinical significance of placental In summary, while intrapartum clinical signs are significantly villous edema. Pediatrics 1983; 71: 588–594. associated with histopathologic chorioamnionitis and fetal inflam- 13 Salafia CM, Weigl C, Silberman L. The prevalence and distribution of acute pla- matory responses, they lack diagnostic accuracy. It is therefore cental inflammation in uncomplicated term pregnancies. Obstet Gynecol 1989; 73: possible to have pathologically significant inflammatory lesions in 383–389. the placenta with no intrapartum signs, as well as an asympto- 14 Guzick DS, Winn K. The association of chorioamnionitis with preterm delivery. matic newborn. The short- and long-term consequences of this Obstet Gynecol 1985; 65: 11–16. discrepancy are not clear. Chorioamnionitis at term has been 15 Beebe LA, Cowan LD, Altshuler G. The epidemiology of placental features: associated with cerebral palsy. Cerebral palsy had a prevalence of associations with gestational age and neonatal outcomes. Obstet Gynecol 1996; 87: 771–778. 0.67 per 1000 singleton births of normal birth weight surviving to 30 16 Redline RW, Faye-Peterson O, Heller D, Quereshi F, Savell V, Vogler C. Society for age 3 in one study. Maternal infection was found to be a risk Pediatric Pathology, Perinatal Section, Amniotic Fluid Infection Nosology Com- factor for cerebral palsy overall and histologic chorioamnionitis, as mittee. Amniotic infection syndrome: nosology and reproducibility of placental a subcategory of maternal infection, was associated with an reaction patterns. Pediatr Dev Pathol 2003; 6: 435–448. increased risk of unexplained spastic cerebral palsy (OR 8.9; 95% 17 Langston C, Kaplan C, Macpherson T, Manci E, Peevy K, Clark B et al. Practice CI: 1.9 to 40). Of particular note in this study was the fact that most guideline for examination of the placenta: developed by the Placental Pathology infants born to infected women did not have recognized neonatal Practice Guideline Development Task Force of the College of American Pathol- infection in the newborn period. The authors estimated that the ogists. Arch Pathol Lab Med 1997; 121: 449–476. attributable risk of infection to total spastic cerebral palsy was 12% 18 Carley S, Dosman S, Jones SR, Harison M. Simple nomograms to calculate sample 31 size in diagnostic studies. Emerg Med J 2005; 22: 180–181. in children of normal birth weight. Wu and Colford reported that 19 Curtin WM, Kraus S, Metlay LA, Katzman PJ. Pathologic examination of the pla- clinical chorioamnionitis was associated with an increased risk of centa and observed practice. Obstet Gynecol 2007; 109: 35–41. cerebral palsy in preterm and term infants; they pointed out the 20 Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM et al. crucial need to develop consensus definitions for histologic Towards complete and accurate reporting of studies of diagnostic accuracy: the chorioamniontis as uniform definitions would likely strengthen STARD initiative. BMJ 2003; 326: 41–44. the relationship. The stage and grade of histologic chorio- 21 Lee SM, Romero R, Lee KA, Yang HJ, Oh KJ, Park CW et al. The frequency and risk amnionitis and fetal inflammatory responses associated with factors of funisitis and histologic chorioamnionitis in pregnant women at term cerebral palsy is an area in need of further study. One case–control who delivered after the spontaneous onset of labor. J Matern Fetal Neonatal Med study noted that only severe fetal responses to maternal infection 2011; 24:37–42. 22 Smulian JC, Shen-Schwarz S, Vintzileos AM, Lake MF, Ananth CV. Clinical chor- were statistically associated with neurologic impairment following 32 ioamnionitis and histologic placental inflammation. Obstet Gynecol 1999; 94: term birth. Elucidation of the relationship between stage and 1000–1005. grade of histologic chorioamnionitis and fetal inflammatory 23 Heller DS, Rimpel LH, Skurnick JH. Does histologic chorioamnionitis correspond to responses and short-term neonatal outcomes, for example, clinical chorioamnionitis? J Reprod Med 2008; 53: 25–28. readmission for neonatal sepsis and long-term outcomes, such 24 Segal S. Labor epidural analgesia and maternal fever. Anesth Analg 2010; 111: as cerebral palsy, will necessarily rest on a firm foundation of 1467–1475. standard and uniform histopathologic diagnosis. 25 Winters R, Waters BL. What is adequate sampling of extraplacental membranes?: a randomized, prospective analysis. Arch Pathol Lab Med 2008; 132: 1920–1923. CONFLICT OF INTEREST 26 Rao S, Pavlova Z, Incerpi MH, Ramanthan R. Meconium-stained amniotic fluid and morbidity in near-term and term deliveries with acute histologic chorioamnionitis The authors declare no conflict of interest. and/or funisitis. J Perinatol 2001; 21: 537–540. 27 Burgess AM, Hutchins GM. Inflammation of the lungs, umbilical cord and placenta associated with meconium passage in utero. Review of 123 autopsied cases. REFERENCES Pathol Res Pract 1996; 192: 1121–1128. 1 Pankuch GA, Appelbaum PC, Lorenz RP, Botti JJ, Schachter J, Naeye RL. Placental 28 Salafia CM, Ghidini A, Sherer DM, Pezullo JC. Abnormalities of the fetal heart rate microbiology and histology and the pathogenesis of chorioamnionitis. Obstet in preterm deliveries are associated with acute intra-amniotic infection. JSoc Gynecol 1984; 64: 802–806. Gynecol Invest 1998; 5: 188–191.

& 2013 Nature America, Inc. Journal of Perinatology (2013), 422 – 428 Accuracy of clinical chorioamnionitis WM Curtin et al 428 29 Park HS, Romero R, Lee SM, Jun JK, Yoon BH. Histologic chorioamnionitis is more 31 Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: a meta- common after spontaneous labor than after induced labor at term. Placenta 2010; analysis. JAMA 2000; 284: 1417–1424. 31: 792–795. 32 Redline RW, O’Riordan MA. Placental lesions associated with cerebral palsy and 30 Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal neurologic impairment following term birth. Arch Pathol Lab Med 2000; 124: birth weight. JAMA 1997; 278: 207–211. 1785–1791.

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Journal of Perinatology (2013), 422 – 428 & 2013 Nature America, Inc.