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ORIGINAL RESEARCH |
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 Peter’s University Hospital, New Brunswick, New Jersey.
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Abstract |
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Methods: We identified 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 confirmed 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 noninflammatory causes of signs and symptoms.
Clinical chorioamnionitis is diagnosed clinically in 0.9–10.5% of pregnancies and may be increasing in frequency in recent years.1–3 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 fluid 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 specific clinical markers of maternal or neonatal infection in women with clinically diagnosed chorioamnionitis were associated with histologic chorioamnionitis.
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Materials and Methods |
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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 fluid (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 identified by reviewing neonatal records. Attending Pediatricians’ assessments of possible neonatal sepsis were recorded when specified in charts. This diagnosis was based on the judgement of the attending physician. Specific 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 floor. 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 extra-placental membranes were examined.
Histologic findings of all placentas were recorded by standardized protocol. Histologic chorioamnionitis was identified as inflammatory infiltrate 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 defined as greater than ten neutrophils per high-power field in the subchorionic space and adjacent chorion based on a modification 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 infections 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 significance was P < .05. All proportions are expressed as numbers and percentages with proportions accompanied by 95% confidence 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.
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Results |
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. Significant 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).
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). Among 53 cases without fever, 30 (56.6%, 95% CI 43.3%, 69.9%) had at least one clinical finding consistent with chorioamnionitis, and 72 of 86 (83.7%, 95% CI 75.9%, 91.5%) cases with fever had at least one additional clinical finding 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 confirmation of clinical chorioamnionitis were significantly more likely to have epidurals, more likely to have internal fetal monitoring, and had more vaginal examinations.
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). 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 1–138], P = .05).
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and 2, potentially predictive of chorioamnionitis, based on univariable analysis, were entered in a logistic regression model to determine the best predictors of histologic confirmation (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.
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Discussion |
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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 findings. Despite the variable degree of objective diagnostic support, our institution’s overall 3% rate of clinical chorioamnionitis is consistent with other reports.4,10
Although it is difficult 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 significantly 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.
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 confirmation of chorioamnionitis in 38.1% of our cases was disappointing. We also recognize the limitations of retrospective study design. Specific clinical findings 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 significantly more likely to have had an epidural in labor (91.6%) than those who had placental inflammation (72.1%). In the univariable analysis we found that internal monitoring and increased vaginal examinations were associated with negative histology. Those findings 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 nonsignificant.
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 influence neonatal management. That agrees with findings 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 inflammation, suggesting a group at low risk for infection, whereas 50% (34 of 68) of neonates without possible sepsis had placental inflammation. This confirms the difficulty in using a clinical diagnosis of maternal chorioamnionitis to correctly predict those infants likely to have significant infections.
The issue of a gold standard for chorioamnionitis diagnosis has not been settled. When there is no placental histologic inflammation, it is reasonable to conclude that significant 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 significant area of inflammation has not been missed.19 Placental cultures also might be positive without histologic chorioamnionitis.20 Histologic inflammation does not by itself guarantee the presence of a significant infectious process. Microorganisms are isolated in only 70% of placentas with histologic chorioamnionitis.20,21 Some cases of histologic inflammation can be due to a variety of noninfectious causes, including fetal hypoxia, amniotic fluid pH changes, immunologic responses to fetal tissues, meconium, and other nonspecific reactive responses.19 It is possible that there are subgroups of placental inflammation that are more likely to be associated with significant infections. Those higher risk groups might be detectable by identification of circulating inflammatory 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.
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Footnotes |
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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.
Received February 8, 1999. Received in revised form May 7, 1999. Accepted June 3, 1999.
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References |
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2. Soper DE, Mayhall CG, Frogatt JW. Characterization and control of intraamniotic infection in an urban teaching hospital. Am J Obstet Gynecol 1996;175:304–9.[Medline]
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6. Gilstrap III LC, Leveno KJ, Cox SM, Burris JS, Mashburn M, Rosenfeld CR. Intrapartum treatment of acute chorioamnionitis: Impact on neonatal sepsis. Am J Obstet Gynecol 1988;159:579–83.[Medline]
7. Gibbs RS, Dinsmoor MJ, Newton ER, Ramamurthy RS. A randomized trial of intrapartum versus immediate postpartum treatment of women with intra-amniotic infection. Obstet Gynecol 1988;72: 823–8.
8. Naeye RL, Maisels MJ, Lorenz RP, Bottie JJ. The clinical significance of placental villous edema. Pediatrics 1983;71:588–94.
9. Yoder PR, Gibbs RS, Blanco JD, Castaneda YS, St Clair PJ. A prospective, controlled study of maternal and perinatal outcome after intra-amniotic infection at term. Am J Obstet Gynecol 1983; 145:695–701.[Medline]
10. Newton ER, Prihoda TJ, Gibbs RS. Logistic regression analysis of risk factors for intra-amniotic infection. Obstet Gynecol 1989;73: 571–5.
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16. Herbst A, Wolner-Hanssen P, Ingemarsson I. Risk factors for fever in labor. Obstet Gynecol 1995;86:790–4.[Abstract]
17. Krohn MA, Hitti J. Characteristics of women with clinical intra-amniotic infection who deliver preterm compared with term. Am J Epidemiol 1998;258:111–6.
18. Wiswell TE, Stoll BJ, Tuggle JM. Management of asymptomatic, term gestation neonates born to mothers treated with intrapartum antibiotics. Pediatr Infect Dis J 1990;9:826–31.[Medline]
19. Salafia CM, Weigl C, Silberman L. The prevalence and distribution of acute placental inflammation in uncomplicated term pregnancies. Obstet Gynecol 1989;73:383–9.
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.[Abstract]
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