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Serum C-reactive protein, white blood cell count, and amniotic fluid white blood cell count in women with preterm premature rupture of membranes
Serum C-Reactive Protein, White Blood Cell Count, and Amniotic Fluid White Blood Cell Count in Women With Preterm Premature Rupture of Membranes BO HYUN YOON, MD, PhD, JONG KWAN JUN, MD, KY0 HOON PARK, MD, HEE CHUL SYN, MD, PhD, RICARDO GOMEZ, MD, AND ROBERTO ROMERO, MD Objective: To compare the diagnostic performance of maternal blood C-reactive protein, white blood cell count (WBC), and amniotic fluid (AF) WBC in the identification of positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity in women with preterm premature rupture of membranes (PROM). Methods: Maternal blood was collected for the determination of C-reactive protein and WBC at the time of amniocentesis from 90 women with preterm PROM. Amniotic fluid was cultured for aerobic and anaerobic bacteria as well as mycoplasmas. Amniotic fluid WBC was determined for research purposes. Receiver operating characteristic curve and logistic regression were used for statistical analysis. Results: The prevalence of positive AF culture was 28% (25 of 90). Women with positive AF culture and clinical chorioamnionitis had significantly higher median C-reactive protein, WBC, and AF WBC than did women without these conditions (P < .05), whereas women with histologic chorioamnionitis and significant neonatal morbidity had higher median C-reactive protein and AF WBC, but not WBC, than those without the conditions (I’ < .05). An AF WBC of at least 20 cells per mm3 had a greater sensitivity than C-reactive protein (cutoff, 0.7 mg/dL) and WBC (cutoff, 13,000 cells per mm31 in the detection of positive AF culture and histologic chorioamnionitis. Logistic regression analysis indicated that among AF WBC, C-reactive protein, and WBC, AF WBC was the best predictor of positive AF culture (odds ratio [OR] 24.2, 95% confidence interval [CI] 6.0, 97.5, P < .OOlI, histologic (OR 74.0, 95% CI 7.4, 736.3, P < .OOlI and clinical chorioamnionitis (OR 8.9,95% CI 0.9, 85.6, P = .057), and neonatal morbidity (OR 4.3, 95% CI 1.1, 16.6, P < .05).
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Conclusion: Amniotic fluid WBC performs better than C-reactive protein and maternal blood WBC in the diagnosis of positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity in women with preterm Copyright 0 2996 PROM. (Obstet GynecoZ1996;88:1034-40. by 7’he American
College
of Obstetricians
and Gynecologists.)
invasion of the amniotic cavity occurs in approximately 30% of women with preterm premature rupture of membranes (PROM) and is frequently subclinical.‘-7 Women with microbial invasion of the amniotic cavity have a shorter latency period and a higher frequency of clinical chorioamnionitis, endometritis, and perinatal morbidity than those with sterile amniotic fluid.rP7 Of major importance is that acute histologic chorioamnionitis, the histologic correlate of intrauterine infection, is a risk factor for the subsequent development of brain white matter lesions, which may lead to cerebral palsy.* The early and accurate detection of intrauterine infection is an important challenge in clinical obstetrics. Although the use of microbiological cultures of amniotic fluid (AF) obtained by amniocentesis has been the standard for the diagnosis of intrauterine infection, culture results may take several days and thus are not available for immediate patient management decisions. Consequently, other rapid AF tests such as the Gram stain,4m7 catalase activity,’ limulus amebocyte lysate,“’ leukocyte esterase,s”r leukoattractants activity,” glucose,5-7 white blood cell count ( WBC),h,7 and interleukin-6 determinations7,‘3m15 have been proposed to be of value in the rapid identification of women at risk for intrauterine infection or adverse perinatal outcome. All of these tests require amniocentesis, however, which is an invasive procedure. Several studies16”7 have indicated that an elevated Microbial
Obstetrics & Gynecology
maternal serum C-reactive protein is associated with intrauterine infection (histologic, clinical) in women with preterm PROM. Little information is available as to whether maternal serum C-reactive protein determination can replace AF analysis in the diagnosis of positive AF culture in women with preterm PROM. We have examined this question previously in women with preterm labor and intact membranes and found that AF WBC was a better predictor of AF culture results and neonatal sepsis than maternal C-reactive protein and WBC.i8 The purpose of this study is to compare the diagnostic performance of maternal serum C-reactive protein and WBC with that of AF WBC in the identification of positive AF culture, acute histologic chorioamnionitis, clinical chorioamnionitis, and neonatal complications in women with preterm PROM. We selected AF WBC as an AF test because previous studiesh,7,‘8 demonstrated the simplicity and usefulness of this test for the identification of women with positive AF culture.
Material and Methods The study population consisted of women admitted to Seoul National University Hospital from April 1993 to April 1995 with the diagnosis of preterm PROM who met the following criteria: 1) singleton gestation, 2) transabdominal amniocentesis performed for microbiologic assessment of the amniotic cavity, and 3) maternal blood drawn for the determination of WBC and C-reactive protein concentration at the time of amniocentesis. Data from some of these women have been reported in our previous two papers (14 women15 and 31 women’“). The C-reactive protein concentrations, WBC, and AF WBC of these women, however, have not been reported previously. Amniocentesis is offered for microbiologic assessment of the amniotic cavity to all women admitted to our institution with a diagnosis of preterm PROM. Written informed consent was obtained from all subjects. Eighty-three percent of women with preterm PROM and singleton pregnancy admitted during the study period underwent transabdominal amniocentesis. Repeat amniocentesis was offered for routine surveillance of intraamniotic infection or fetal lung maturity every 7-10 days after the initial amniocentesis. Rupture of membranes was diagnosed by examination with sterile speculum confirming pooling of AF in the vagina, a positive nitrazine paper test result, and a positive ferning test result. Amniotic fluid obtained by transabdominal amniocentesis under ultrasonographic guidance was cultured for aerobic and anaerobic bacteria, as well as for mycoplasmas (Ureaplasma wealyticum and Mycoplasma hominis), according to methods described previously.r5 An
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1996
aliquot was examined in a hemocytometer chamber and AF WBC was determined. White blood cell count was determined with a Coulter counter (Coulter STKS, Hialeah, FL). Blood not used for WBC was centrifuged at 700 X 8 for 10 minutes at 4C, and the supernatant was stored in polypropylene tubes at -70C until C-reactive protein was determined. C-reactive protein was quantitated according to a method described previously.‘8 Samples were not subjected to freeze-thaw cycles before being assayed. Acute histologic chorioamnionitis was defined as the presence of acute inflammatory changes in any of the tissue samples (amnion, chorion-decidua, umbilical cord, or chorionic plate) using criteria published previ0us1y.‘~ Clinical chorioamnionitis was diagnosed according to the criteria of Gibbs et a1.2” Clinically significant neonatal morbidity (respiratory distress syndrome, pneumonia, congenital proven or suspected sepsis, intraventricular hemorrhage [grade II or higher], bronchopulmonary dysplasia, or necrotizing enterocolitis) was defined according to criteria described previously in detail.15,‘” Mann-Whitney U test, Student’s t test, or Wilcoxon test for censored data was used for comparison of continuous variables. Comparisons of proportions were performed with a 2 test or Fisher exact test. Receiver operating characteristic (ROC) curves were constructed to describe the relationship between the sensitivity (true-positive rate) and the false-positive rate for different values of maternal serum C-reactive protein concentration, WBC, and AF WBC in the identification of positive AF culture, acute histologic chorioamnionitis, clinical chorioamnionitis and significant neonatal morbidity. A modified t test for correlated samples, as described by Gallen and Gambino,2’ was used to compare sensitivity and specificity. Logistic regression analysis was used to explore the relationship between explanatory variables (C-reactive protein, WBC, and AF WBC) and the log odds of a number of different outcomes. Statistical significance was defined as P <
.05.
Results One of the 91 women who met the entry criteria had a bloody tap with AF WBC of 101 cells per mm3 and was excluded in the final analysis because the WBC of this sample might have been from maternal blood. The prevalence of positive AF culture was 28% (25 of 90). Microorganisms isolated from the amniotic cavity included U urealyticum (n = 22), Escherickia coli (II = 2), Candida sp (n = 2), and one isolate each of Acinetobacter baumanii, Streptococcus mitis, and coagulase negative Staphylococcus. The coagulase negative Staphylococcus
Yoon
et al
Diapostic
M&hods
it7
PROM
1035
Table
1. Characteristics
of Women
According
to Amniotic
Fluid
Negative Maternal age (years, mean ? SD) Nulliparous Gestation at admission (wk, median and range) Gestation at delivery (wk, median and range) Clinical chorioamnionitis Significant neonatal morbidity*+ RDS+ Pneumonia+ Proven neonatal sepsis’ Neonatal sepsis (proven/suspected)’ Intraventricular hemorrhage (grade II or higher)’ Bronchopulmonary dysplasia? Necrotizing enterocolitis’ Perinatal death C-reactive protein (mg/ dL, median and range) WBC (cells per mm3, median and range) AF WBC (cells per mm3, median and range)
Culture
amniotic fluid (n = 65)
28.4 I 3.9 40 (62%) 34.3 (20-36.7) 35.3 (24.3-41.4) 2 (3%) IS/ 61 (30%) 2/61 (3%) l/61 (2%) 3/61 (5%) S/61 (13%) 14161 (23%) 1/ 61(2%) 3/61(5%) 5/65 (8%) 0.2 (O-8.9) 9400 (3300-19,000) 2 (O-1000 or greater)
Results culture
Positive
amniotic fluid (n = 25) 29.4 + 5.1 11 (44%) 32.7 (23.1-36.4) 33.0 (23.3-36.3) 6 (24%) 16/23 (70%) 5123 (22%) 2/23 (9%) 0 4123 (17%) 12123 (52%) 2123 (9%) 2123 (9%) 3125 (12%) 0.8 (0.1-13.0) 11300 (4500-23,800) 268 (O-2800)
culture P NS NS NS i ,001 < .Ol < ,005 < .05 NS NS NS < .05 NS NS NS i ,005 < .02 i ,001
SD = standard deviation; NS = not significant; RDS = respiratory distress syndrome; WBC = white blood cell count; AF = amniotic fluid. * Significant neonatal morbidity was defined as the presence of RDS, pneumonia, congenital proven or suspected sepsis, intraventricular hemorrhage (grade II or higher), bronchopulmonary dysplasia, or necrotizing enterocolitis. ‘Six neonates who either were not activelv resuscitated at birth or died in the delivery room despite intensive resuscitative efforts, because of either extreme prematurity (n = 2) or congenital anomaly (11 = 4) and, thus, could not be evaluated about the presence or absence of complications, were excluded from the analysis.
was isolated from one woman with an AF culture positive for multiple microorganisms. Table 1 compares the clinical characteristics of women according to AF culture results. There were no differences between the women in these two groups in mean maternal age, distribution of parous and nonparous women, and median gestational age at admission. Women with positive AF cultures, however, had a statistically significant lower median gestational age at delivery (P < .OOl), higher rate of clinical chorioamnionitis (P < .Ol), significant neonatal morbidity (P < .005), and higher median maternal plasma C-reactive protein concentration, WBC, and AF WBC (P < ,005, P < .02, and P < .OOl, respectively) than did women with a negative AF culture (Table 1). The relationship between histologic chorioamnionitis and the results of various tests was examined in women who delivered within 72 hours of amniocentesis. This time was selected to preserve a meaningful temporal relationship between the results of various amniotic fluid and maternal blood tests and those of placental histology. Fifty-six women met this criteria; seven of the remaining 34 patients delivered within 72 hours of repeat amniocentesis, the results of which were included in this analysis to examine the relationship with placental histology. The prevalence of acute histologic chorioamnionitis was 56% (35 of 63). Women with acute
1036
Yoon et al
Diagnostic
Methods
in PROM
histologic chorioamnionitis had significantly higher median C-reactive protein concentration and AF WBC (but not WBC) than did women without histologic chorioamnionitis (Figure 1) (C-reactive protein: median 0.9 [range O-13.01mg/dL versus median 0.25 [range O-3.91 mg/dL; P < .05, WBC: median 11,400 [range 420023,800] cells per mm3 versus median 11,000 [range 6300-14,700] cells per mm3; P > .l, AF WBC: median 198 [range O-2800] cells per mm3 versus median 2 [range O-561 cells per mm3; P < .OOl, respectively). Figure 2 displays ROC curves describing the performance of maternal serum C-reactive protein, WBC, and AF WBC in the identification of acute histologic chorioamnionitis (area under the curve: C-reactive protein, 0.67, z = 2.49, P < .Ol; WBC, 0.61, z = 1.58, P = .058; AF WBC, 0.84, z = 6.54, P < .OOl, respectively). The following cutoffs were chosen: 20 cells per mm3 for AF WBC, 0.7 mg / dL for maternal serum C-reactive protein, and 13,000 cells per mm3 for WBC (seeFigure 2). Table 2 describes the diagnostic indices and predictive values of different laboratory tests in the identification of histologic chorioamnionitis and positive amniotic fluid culture. An AF WBC of at least 20 cells per mm3 had the highest sensitivity (P < .05 compared with C-reactive protein or WBC) and specificity in the identification of acute histologic chorioamnionitis and positive amniotic fluid culture. Furthermore, logistic re-
Obstetrics t? Gynecology
PC05 6 T 9 2
4
9 0 2
&
0
.
.. .
t
aA
t-1
(+I
Histologic
67 E’
chorioamnionitis
.
24000 20000
g k
16000
8000
t-1 Histologic
(4 chorioamnionitis 0 2800
4
P<.OOi
. . .
(positive AF culture), only AF WBC retained a significant relationship (Table 3). Clinical chorioamnionitis occurred in eight of 90 women (8.9%). Six patients had positive AF cultures for microorganisms. All delivered preterm neonates and their placentas had histologic evidence of acute inflammation. Patients with clinical chorioamnionitis had a significantly higher median C-reactive protein concentration, WBC, and AF WBC than did those without clinical chorioamnionitis (C-reactive protein: median 3.4 [range O.l-13.01 mg/dL versus median 0.3 [range O-8.91 mg/dL; P < .05, WBC: median 12,550 [range 6600-16,700] cells per mm3 versus median 9650 [range 3300-23,800] cells per mm3; P < .Ol, AF WBC: median 103.5 [range 3-4051 cells per mm3 versus median 3 [range O-28801 cells per mm3; P < .Ol, respectively). Logistic regression analysis using AF WBC, C-reactive protein, and WBC as explanatory variables indicated, however, that AF WBC had the best relationship with the log odds of clinical chorioamnionitis (Table 3). Mothers delivering newborns with significant morbidity had significantly higher median C-reactive protein concentration and AF WBC than mothers delivering newborns without significant complications (C-reactive protein: median 0.65 [range O-12.21 mg/dL versus median 0.2 [range O-4.01 mg/dL; P < .005, WBC: median 10,950 [range 4200-19,000] cells per mm3 versus median 9450 [range 3300-23,800] cells per mm3; P = .08, AF WBC: median 79.5 [range O-1000 or greater] cells per mm3 versus median 2 [range 0 -28801 cells per mm3; P < ,001, respectively). In this analysis, six neonates who either were not actively resuscitated at birth or died in the delivery room despite intensive resuscitative efforts because of either extreme prematurity (n =
.
i-1 Histologic Figure
1. Maternal
white blood cell according to the NS
= not
serum
C-reactive
count (WBC), and presence or absence
(+I chorioamnionitis protein
(CRP)
amniotic fluid of histologic
concentration, WBC (AF WBC) chorioamnionitis.
-A-A -.-O-.
significant.
-1
0.0 + 0.0
gression analysis indicated that if the results of AF WBC, WBC, and C-reactive protein were simultaneously entered into a model to describe the relationship between these variables and the log odds ratio of histologic chorioamnionitis and those of AF results
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88, NO.
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1996
AF WBC CRP WBC
0.2
0.4
0.6
0.8
1 .o
l-Specificity Figure 2. Receiver C-reactive protein
operating characteristic (CRP), white blood cell
fluid WBC chorioamnionitis.
WBC)
(AF
Yoon
et al
in
the
curves for maternal serum count (WBC), and amniotic
identification
Diagnostic
Methods
of
acute
in PROM
histologic
1037
Table
2. Diagnostic
Indices
in the Identification
of Histologic Sensitivity
Identification AF WBC
of histologic
(2 20 cells per C-reactive protein
(2
cells per of positive
mm’) amniotic
fluid
Positive
predictive value
Fluid
Culture Negative
predictive value
27135
(77%)
27128
(96%)
27128
(96%)
27135
(77%)
19135
(54%)V
24128
(86%)
19123
(83%)
24140
(60%)
14/35
(4O%)T
23 / 28 (82%)
14119
(74%)
23 / 44 (52%)
21125
(84%)
54 / 65 (83%)
21132
(66%)
54158
(93%)
14125
(56%)
50/65
(77%)
14 / 29 (48%)
50161
(82%)
8125
(32%)
53165
(82%)
53170
(76%)
culture
0.7 mg/dL) 13,000
cells
per
3. Relationship by Overall
blood
of Variables with Logistic Regression Odds
Relationship
with
cell
WBC Relationship amniotic
ratio
Different Analysis 95%
Outcomes
CI
P
74.0 protein
1.6 1.01
7.4-736.3 0.2-10.5 0.15-6.46
< ,001 NS NS
with positive fluid culture
AF WBC C-reactive WBC
protein
Relationship with chorioamnionitis
Relationship neonatal
24.2 1.1 1.1
6.0-97.5 0.3-4.2 0.3-4.1
< ,001 NS
8.9
0.9-85.6
2.9
NS
2.6
0.5-17.9 0.5-12.7
0.9 4.3 2.3
0.8-1.02 1.1-16.6 0.7-7.8
.09 < .05 NS
1.5 1.9
0.4-5.1 0.5-7.5
NS NS
NS
clinical
AF WBC
C-reactive WBC
protein
age protein
WBC AF culture
NS
Cl = confidence interval; AF = amniotic fluid; WBC = white blood count; NS = not significant. Variables were dichotomized: AF WBC (< 20 cells per mm3 versus 2 20 cells per mm”), C-reactive protein (< 0.7 mg/dL versus P 0.7 mg/dL), WBC (< 13,000 cells per mm3 versus 2 13,000 cells per mm”). cell
Yoon
et al
Dingrmtic
M~tlzods irl PROM
these women. Twenty-nine (97%) of 30 placentas available for examination had histologic evidence of acute inflammation. Fifty-two women had C-reactive protein concentration under 0.7 mg/dL and WBC under 13,000 cells per mm3; AF culture was positive in eight (15%) of these women. Sixteen (38%) of 42 placentas available for examination demonstrated histologic evidence of acute inflammation. Of these 52 women, eight had an AF WBC of 20 cells per mm3 or greater; AF culture was positive in five of these eight women. All seven placentas available for examination in these women revealed acute histologic chorioamnionitis. Congenital sepsis was diagnosed in three newborns born to women with negative amniotic fluid cultures. The placenta from each case, however, had severe histologic chorioamnionitis. One woman had an elevated AF WBC (203 cells per mm3), and labor was induced 1 week later because of mature lecithinsphingomyelin ratio. The second woman had an elevated C-reactive protein (5 mg/dL) and WBC (16,000 cells per mm3), and developed clinical chorioamnionitis and fetal distress.
,057
with significant morbidity
Gestational AF WBC C-reactive
(40%)
count.
histologic
chorioamnionitis AF WBC C-reactive
8120
mm”)
2) or congenital anomalies (IZ = 4) were excluded. Multiple logistic regression analysis demonstrated that of all tests under study, only the results of AF WBC had a significant relationship with the occurrence of morbid neonatal events (Table 3). Thirty-two women had AF WBC of at least 20 cells per mm3, and AF culture was positive in 21 (66%) of
1038
Amniotic
mm’)
AF = amniotic fluid; WBC = white * P < .05 compared with AF WBC.
Table
Positive
mm3)
(2 20 cells per C-reactive protein (2 WBC
Specificity
and
chorioamnionitis
(2 0.7 mg/dL) WBC (2 13,000 Identification AF WBC
Chorioamnionitis
Discussion We found elevated maternal serum C-reactive protein to be associated with positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity in women with preterm PROM. These results are in keeping with observations by other investigators.16,17 Our findings indicate clearly, however, that AF WBC performs better than WBC and C-reactive protein in the identification of positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity. The
current observations are consistent with those reported previously by our group in women with preterm labor and intact membranes.18 An AF WBC of at least 20 cells per mm3 had a sensitivity of 77% and a specificity of 96% in the identification of acute histologic chorioamnionitis, and a sensitivity of 84% and a specificity of 83% in the detection of positive AF culture. These sensitivities were significantly higher than those of either C-reactive protein (54% and 56%, respectively) or WBC (40% and 32%, respectively). These data indicate that although an elevated C-reactive protein or blood WBC is associated with intrauterine infection, the poor diagnostic performance might limit the usefulness of these blood tests in the management of patients with preterm PROM. Why did the AF WBC perform better than maternal blood tests? C-reactive protein is an acute phase reactant protein primarily synthesized by liver cells in response to various cytokines released from the site of inflammation.” In cases of intrauterine infection, cytokines produced within the uterine cavity first mount a local inflammatory response and must reach the maternal circulation and then the liver to stimulate the synthesis of C-reactive protein by hepatocytes or bonemarrow targets to induce leukocytosis. Therefore, it is not surprising that AF WBC determination performed better diagnostically than did maternal C-reactive protein or WBC in the identification of intrauterine infection or its surrogate outcome (histologic or clinical chorioamnionitis). A central question is whether it is justifiable to perform an amniocentesis to obtain the improved diagnostic performance achieved by direct examination of AF. In addition to the rapid identification of infection, AF studies afford the precise identification of involved pathogens and, consequently, provide the basis for a rational choice for antibiotic selection. The introduction of modern molecular biologic techniques, including polymerase chain reaction and microsequencing, would allow rapid and precise diagnosis of microbial invasion of amniotic cavity. These objectives cannot be accomplished by relying on maternal blood tests that provide no direct information about the status of the intrauterine cavity and fetus. Further studies using clinical decision analysis are required to determine if the benefits of early diagnosis and treatment outweigh the risks of amniocentesis. Evidence that intrapartum treatment of women with clinical chorioamnionitis reduces the rate of proven neonatal sepsis in term patients23 is adequate justification in our units for the performance of amniocentesis and treatment with antibiotic in women with evidence of microbial invasion of the amniotic cavity.
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8
by
Copyqht Gynecologists.
1996
Published
\uiy
.The
29, 1996.
American
by Elsevier
College Science
of Obstetricians Inc
and
1034
0029~7844/96/$15.00 PII s002Y-~~44(Y6)00~~9~~~
Conclusion: Amniotic fluid WBC performs better than C-reactive protein and maternal blood WBC in the diagnosis of positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity in women with preterm Copyright 0 2996 PROM. (Obstet GynecoZ1996;88:1034-40. by 7’he American
College
of Obstetricians
and Gynecologists.)
invasion of the amniotic cavity occurs in approximately 30% of women with preterm premature rupture of membranes (PROM) and is frequently subclinical.‘-7 Women with microbial invasion of the amniotic cavity have a shorter latency period and a higher frequency of clinical chorioamnionitis, endometritis, and perinatal morbidity than those with sterile amniotic fluid.rP7 Of major importance is that acute histologic chorioamnionitis, the histologic correlate of intrauterine infection, is a risk factor for the subsequent development of brain white matter lesions, which may lead to cerebral palsy.* The early and accurate detection of intrauterine infection is an important challenge in clinical obstetrics. Although the use of microbiological cultures of amniotic fluid (AF) obtained by amniocentesis has been the standard for the diagnosis of intrauterine infection, culture results may take several days and thus are not available for immediate patient management decisions. Consequently, other rapid AF tests such as the Gram stain,4m7 catalase activity,’ limulus amebocyte lysate,“’ leukocyte esterase,s”r leukoattractants activity,” glucose,5-7 white blood cell count ( WBC),h,7 and interleukin-6 determinations7,‘3m15 have been proposed to be of value in the rapid identification of women at risk for intrauterine infection or adverse perinatal outcome. All of these tests require amniocentesis, however, which is an invasive procedure. Several studies16”7 have indicated that an elevated Microbial
Obstetrics & Gynecology
maternal serum C-reactive protein is associated with intrauterine infection (histologic, clinical) in women with preterm PROM. Little information is available as to whether maternal serum C-reactive protein determination can replace AF analysis in the diagnosis of positive AF culture in women with preterm PROM. We have examined this question previously in women with preterm labor and intact membranes and found that AF WBC was a better predictor of AF culture results and neonatal sepsis than maternal C-reactive protein and WBC.i8 The purpose of this study is to compare the diagnostic performance of maternal serum C-reactive protein and WBC with that of AF WBC in the identification of positive AF culture, acute histologic chorioamnionitis, clinical chorioamnionitis, and neonatal complications in women with preterm PROM. We selected AF WBC as an AF test because previous studiesh,7,‘8 demonstrated the simplicity and usefulness of this test for the identification of women with positive AF culture.
Material and Methods The study population consisted of women admitted to Seoul National University Hospital from April 1993 to April 1995 with the diagnosis of preterm PROM who met the following criteria: 1) singleton gestation, 2) transabdominal amniocentesis performed for microbiologic assessment of the amniotic cavity, and 3) maternal blood drawn for the determination of WBC and C-reactive protein concentration at the time of amniocentesis. Data from some of these women have been reported in our previous two papers (14 women15 and 31 women’“). The C-reactive protein concentrations, WBC, and AF WBC of these women, however, have not been reported previously. Amniocentesis is offered for microbiologic assessment of the amniotic cavity to all women admitted to our institution with a diagnosis of preterm PROM. Written informed consent was obtained from all subjects. Eighty-three percent of women with preterm PROM and singleton pregnancy admitted during the study period underwent transabdominal amniocentesis. Repeat amniocentesis was offered for routine surveillance of intraamniotic infection or fetal lung maturity every 7-10 days after the initial amniocentesis. Rupture of membranes was diagnosed by examination with sterile speculum confirming pooling of AF in the vagina, a positive nitrazine paper test result, and a positive ferning test result. Amniotic fluid obtained by transabdominal amniocentesis under ultrasonographic guidance was cultured for aerobic and anaerobic bacteria, as well as for mycoplasmas (Ureaplasma wealyticum and Mycoplasma hominis), according to methods described previously.r5 An
VOL.
88, NO.
6, DECEMBER
1996
aliquot was examined in a hemocytometer chamber and AF WBC was determined. White blood cell count was determined with a Coulter counter (Coulter STKS, Hialeah, FL). Blood not used for WBC was centrifuged at 700 X 8 for 10 minutes at 4C, and the supernatant was stored in polypropylene tubes at -70C until C-reactive protein was determined. C-reactive protein was quantitated according to a method described previously.‘8 Samples were not subjected to freeze-thaw cycles before being assayed. Acute histologic chorioamnionitis was defined as the presence of acute inflammatory changes in any of the tissue samples (amnion, chorion-decidua, umbilical cord, or chorionic plate) using criteria published previ0us1y.‘~ Clinical chorioamnionitis was diagnosed according to the criteria of Gibbs et a1.2” Clinically significant neonatal morbidity (respiratory distress syndrome, pneumonia, congenital proven or suspected sepsis, intraventricular hemorrhage [grade II or higher], bronchopulmonary dysplasia, or necrotizing enterocolitis) was defined according to criteria described previously in detail.15,‘” Mann-Whitney U test, Student’s t test, or Wilcoxon test for censored data was used for comparison of continuous variables. Comparisons of proportions were performed with a 2 test or Fisher exact test. Receiver operating characteristic (ROC) curves were constructed to describe the relationship between the sensitivity (true-positive rate) and the false-positive rate for different values of maternal serum C-reactive protein concentration, WBC, and AF WBC in the identification of positive AF culture, acute histologic chorioamnionitis, clinical chorioamnionitis and significant neonatal morbidity. A modified t test for correlated samples, as described by Gallen and Gambino,2’ was used to compare sensitivity and specificity. Logistic regression analysis was used to explore the relationship between explanatory variables (C-reactive protein, WBC, and AF WBC) and the log odds of a number of different outcomes. Statistical significance was defined as P <
.05.
Results One of the 91 women who met the entry criteria had a bloody tap with AF WBC of 101 cells per mm3 and was excluded in the final analysis because the WBC of this sample might have been from maternal blood. The prevalence of positive AF culture was 28% (25 of 90). Microorganisms isolated from the amniotic cavity included U urealyticum (n = 22), Escherickia coli (II = 2), Candida sp (n = 2), and one isolate each of Acinetobacter baumanii, Streptococcus mitis, and coagulase negative Staphylococcus. The coagulase negative Staphylococcus
Yoon
et al
Diapostic
M&hods
it7
PROM
1035
Table
1. Characteristics
of Women
According
to Amniotic
Fluid
Negative Maternal age (years, mean ? SD) Nulliparous Gestation at admission (wk, median and range) Gestation at delivery (wk, median and range) Clinical chorioamnionitis Significant neonatal morbidity*+ RDS+ Pneumonia+ Proven neonatal sepsis’ Neonatal sepsis (proven/suspected)’ Intraventricular hemorrhage (grade II or higher)’ Bronchopulmonary dysplasia? Necrotizing enterocolitis’ Perinatal death C-reactive protein (mg/ dL, median and range) WBC (cells per mm3, median and range) AF WBC (cells per mm3, median and range)
Culture
amniotic fluid (n = 65)
28.4 I 3.9 40 (62%) 34.3 (20-36.7) 35.3 (24.3-41.4) 2 (3%) IS/ 61 (30%) 2/61 (3%) l/61 (2%) 3/61 (5%) S/61 (13%) 14161 (23%) 1/ 61(2%) 3/61(5%) 5/65 (8%) 0.2 (O-8.9) 9400 (3300-19,000) 2 (O-1000 or greater)
Results culture
Positive
amniotic fluid (n = 25) 29.4 + 5.1 11 (44%) 32.7 (23.1-36.4) 33.0 (23.3-36.3) 6 (24%) 16/23 (70%) 5123 (22%) 2/23 (9%) 0 4123 (17%) 12123 (52%) 2123 (9%) 2123 (9%) 3125 (12%) 0.8 (0.1-13.0) 11300 (4500-23,800) 268 (O-2800)
culture P NS NS NS i ,001 < .Ol < ,005 < .05 NS NS NS < .05 NS NS NS i ,005 < .02 i ,001
SD = standard deviation; NS = not significant; RDS = respiratory distress syndrome; WBC = white blood cell count; AF = amniotic fluid. * Significant neonatal morbidity was defined as the presence of RDS, pneumonia, congenital proven or suspected sepsis, intraventricular hemorrhage (grade II or higher), bronchopulmonary dysplasia, or necrotizing enterocolitis. ‘Six neonates who either were not activelv resuscitated at birth or died in the delivery room despite intensive resuscitative efforts, because of either extreme prematurity (n = 2) or congenital anomaly (11 = 4) and, thus, could not be evaluated about the presence or absence of complications, were excluded from the analysis.
was isolated from one woman with an AF culture positive for multiple microorganisms. Table 1 compares the clinical characteristics of women according to AF culture results. There were no differences between the women in these two groups in mean maternal age, distribution of parous and nonparous women, and median gestational age at admission. Women with positive AF cultures, however, had a statistically significant lower median gestational age at delivery (P < .OOl), higher rate of clinical chorioamnionitis (P < .Ol), significant neonatal morbidity (P < .005), and higher median maternal plasma C-reactive protein concentration, WBC, and AF WBC (P < ,005, P < .02, and P < .OOl, respectively) than did women with a negative AF culture (Table 1). The relationship between histologic chorioamnionitis and the results of various tests was examined in women who delivered within 72 hours of amniocentesis. This time was selected to preserve a meaningful temporal relationship between the results of various amniotic fluid and maternal blood tests and those of placental histology. Fifty-six women met this criteria; seven of the remaining 34 patients delivered within 72 hours of repeat amniocentesis, the results of which were included in this analysis to examine the relationship with placental histology. The prevalence of acute histologic chorioamnionitis was 56% (35 of 63). Women with acute
1036
Yoon et al
Diagnostic
Methods
in PROM
histologic chorioamnionitis had significantly higher median C-reactive protein concentration and AF WBC (but not WBC) than did women without histologic chorioamnionitis (Figure 1) (C-reactive protein: median 0.9 [range O-13.01mg/dL versus median 0.25 [range O-3.91 mg/dL; P < .05, WBC: median 11,400 [range 420023,800] cells per mm3 versus median 11,000 [range 6300-14,700] cells per mm3; P > .l, AF WBC: median 198 [range O-2800] cells per mm3 versus median 2 [range O-561 cells per mm3; P < .OOl, respectively). Figure 2 displays ROC curves describing the performance of maternal serum C-reactive protein, WBC, and AF WBC in the identification of acute histologic chorioamnionitis (area under the curve: C-reactive protein, 0.67, z = 2.49, P < .Ol; WBC, 0.61, z = 1.58, P = .058; AF WBC, 0.84, z = 6.54, P < .OOl, respectively). The following cutoffs were chosen: 20 cells per mm3 for AF WBC, 0.7 mg / dL for maternal serum C-reactive protein, and 13,000 cells per mm3 for WBC (seeFigure 2). Table 2 describes the diagnostic indices and predictive values of different laboratory tests in the identification of histologic chorioamnionitis and positive amniotic fluid culture. An AF WBC of at least 20 cells per mm3 had the highest sensitivity (P < .05 compared with C-reactive protein or WBC) and specificity in the identification of acute histologic chorioamnionitis and positive amniotic fluid culture. Furthermore, logistic re-
Obstetrics t? Gynecology
PC05 6 T 9 2
4
9 0 2
&
0
.
.. .
t
aA
t-1
(+I
Histologic
67 E’
chorioamnionitis
.
24000 20000
g k
16000
8000
t-1 Histologic
(4 chorioamnionitis 0 2800
4
P<.OOi
. . .
(positive AF culture), only AF WBC retained a significant relationship (Table 3). Clinical chorioamnionitis occurred in eight of 90 women (8.9%). Six patients had positive AF cultures for microorganisms. All delivered preterm neonates and their placentas had histologic evidence of acute inflammation. Patients with clinical chorioamnionitis had a significantly higher median C-reactive protein concentration, WBC, and AF WBC than did those without clinical chorioamnionitis (C-reactive protein: median 3.4 [range O.l-13.01 mg/dL versus median 0.3 [range O-8.91 mg/dL; P < .05, WBC: median 12,550 [range 6600-16,700] cells per mm3 versus median 9650 [range 3300-23,800] cells per mm3; P < .Ol, AF WBC: median 103.5 [range 3-4051 cells per mm3 versus median 3 [range O-28801 cells per mm3; P < .Ol, respectively). Logistic regression analysis using AF WBC, C-reactive protein, and WBC as explanatory variables indicated, however, that AF WBC had the best relationship with the log odds of clinical chorioamnionitis (Table 3). Mothers delivering newborns with significant morbidity had significantly higher median C-reactive protein concentration and AF WBC than mothers delivering newborns without significant complications (C-reactive protein: median 0.65 [range O-12.21 mg/dL versus median 0.2 [range O-4.01 mg/dL; P < .005, WBC: median 10,950 [range 4200-19,000] cells per mm3 versus median 9450 [range 3300-23,800] cells per mm3; P = .08, AF WBC: median 79.5 [range O-1000 or greater] cells per mm3 versus median 2 [range 0 -28801 cells per mm3; P < ,001, respectively). In this analysis, six neonates who either were not actively resuscitated at birth or died in the delivery room despite intensive resuscitative efforts because of either extreme prematurity (n =
.
i-1 Histologic Figure
1. Maternal
white blood cell according to the NS
= not
serum
C-reactive
count (WBC), and presence or absence
(+I chorioamnionitis protein
(CRP)
amniotic fluid of histologic
concentration, WBC (AF WBC) chorioamnionitis.
-A-A -.-O-.
significant.
-1
0.0 + 0.0
gression analysis indicated that if the results of AF WBC, WBC, and C-reactive protein were simultaneously entered into a model to describe the relationship between these variables and the log odds ratio of histologic chorioamnionitis and those of AF results
VOL.
88, NO.
6, DECEMBER
1996
AF WBC CRP WBC
0.2
0.4
0.6
0.8
1 .o
l-Specificity Figure 2. Receiver C-reactive protein
operating characteristic (CRP), white blood cell
fluid WBC chorioamnionitis.
WBC)
(AF
Yoon
et al
in
the
curves for maternal serum count (WBC), and amniotic
identification
Diagnostic
Methods
of
acute
in PROM
histologic
1037
Table
2. Diagnostic
Indices
in the Identification
of Histologic Sensitivity
Identification AF WBC
of histologic
(2 20 cells per C-reactive protein
(2
cells per of positive
mm’) amniotic
fluid
Positive
predictive value
Fluid
Culture Negative
predictive value
27135
(77%)
27128
(96%)
27128
(96%)
27135
(77%)
19135
(54%)V
24128
(86%)
19123
(83%)
24140
(60%)
14/35
(4O%)T
23 / 28 (82%)
14119
(74%)
23 / 44 (52%)
21125
(84%)
54 / 65 (83%)
21132
(66%)
54158
(93%)
14125
(56%)
50/65
(77%)
14 / 29 (48%)
50161
(82%)
8125
(32%)
53165
(82%)
53170
(76%)
culture
0.7 mg/dL) 13,000
cells
per
3. Relationship by Overall
blood
of Variables with Logistic Regression Odds
Relationship
with
cell
WBC Relationship amniotic
ratio
Different Analysis 95%
Outcomes
CI
P
74.0 protein
1.6 1.01
7.4-736.3 0.2-10.5 0.15-6.46
< ,001 NS NS
with positive fluid culture
AF WBC C-reactive WBC
protein
Relationship with chorioamnionitis
Relationship neonatal
24.2 1.1 1.1
6.0-97.5 0.3-4.2 0.3-4.1
< ,001 NS
8.9
0.9-85.6
2.9
NS
2.6
0.5-17.9 0.5-12.7
0.9 4.3 2.3
0.8-1.02 1.1-16.6 0.7-7.8
.09 < .05 NS
1.5 1.9
0.4-5.1 0.5-7.5
NS NS
NS
clinical
AF WBC
C-reactive WBC
protein
age protein
WBC AF culture
NS
Cl = confidence interval; AF = amniotic fluid; WBC = white blood count; NS = not significant. Variables were dichotomized: AF WBC (< 20 cells per mm3 versus 2 20 cells per mm”), C-reactive protein (< 0.7 mg/dL versus P 0.7 mg/dL), WBC (< 13,000 cells per mm3 versus 2 13,000 cells per mm”). cell
Yoon
et al
Dingrmtic
M~tlzods irl PROM
these women. Twenty-nine (97%) of 30 placentas available for examination had histologic evidence of acute inflammation. Fifty-two women had C-reactive protein concentration under 0.7 mg/dL and WBC under 13,000 cells per mm3; AF culture was positive in eight (15%) of these women. Sixteen (38%) of 42 placentas available for examination demonstrated histologic evidence of acute inflammation. Of these 52 women, eight had an AF WBC of 20 cells per mm3 or greater; AF culture was positive in five of these eight women. All seven placentas available for examination in these women revealed acute histologic chorioamnionitis. Congenital sepsis was diagnosed in three newborns born to women with negative amniotic fluid cultures. The placenta from each case, however, had severe histologic chorioamnionitis. One woman had an elevated AF WBC (203 cells per mm3), and labor was induced 1 week later because of mature lecithinsphingomyelin ratio. The second woman had an elevated C-reactive protein (5 mg/dL) and WBC (16,000 cells per mm3), and developed clinical chorioamnionitis and fetal distress.
,057
with significant morbidity
Gestational AF WBC C-reactive
(40%)
count.
histologic
chorioamnionitis AF WBC C-reactive
8120
mm”)
2) or congenital anomalies (IZ = 4) were excluded. Multiple logistic regression analysis demonstrated that of all tests under study, only the results of AF WBC had a significant relationship with the occurrence of morbid neonatal events (Table 3). Thirty-two women had AF WBC of at least 20 cells per mm3, and AF culture was positive in 21 (66%) of
1038
Amniotic
mm’)
AF = amniotic fluid; WBC = white * P < .05 compared with AF WBC.
Table
Positive
mm3)
(2 20 cells per C-reactive protein (2 WBC
Specificity
and
chorioamnionitis
(2 0.7 mg/dL) WBC (2 13,000 Identification AF WBC
Chorioamnionitis
Discussion We found elevated maternal serum C-reactive protein to be associated with positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity in women with preterm PROM. These results are in keeping with observations by other investigators.16,17 Our findings indicate clearly, however, that AF WBC performs better than WBC and C-reactive protein in the identification of positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity. The
current observations are consistent with those reported previously by our group in women with preterm labor and intact membranes.18 An AF WBC of at least 20 cells per mm3 had a sensitivity of 77% and a specificity of 96% in the identification of acute histologic chorioamnionitis, and a sensitivity of 84% and a specificity of 83% in the detection of positive AF culture. These sensitivities were significantly higher than those of either C-reactive protein (54% and 56%, respectively) or WBC (40% and 32%, respectively). These data indicate that although an elevated C-reactive protein or blood WBC is associated with intrauterine infection, the poor diagnostic performance might limit the usefulness of these blood tests in the management of patients with preterm PROM. Why did the AF WBC perform better than maternal blood tests? C-reactive protein is an acute phase reactant protein primarily synthesized by liver cells in response to various cytokines released from the site of inflammation.” In cases of intrauterine infection, cytokines produced within the uterine cavity first mount a local inflammatory response and must reach the maternal circulation and then the liver to stimulate the synthesis of C-reactive protein by hepatocytes or bonemarrow targets to induce leukocytosis. Therefore, it is not surprising that AF WBC determination performed better diagnostically than did maternal C-reactive protein or WBC in the identification of intrauterine infection or its surrogate outcome (histologic or clinical chorioamnionitis). A central question is whether it is justifiable to perform an amniocentesis to obtain the improved diagnostic performance achieved by direct examination of AF. In addition to the rapid identification of infection, AF studies afford the precise identification of involved pathogens and, consequently, provide the basis for a rational choice for antibiotic selection. The introduction of modern molecular biologic techniques, including polymerase chain reaction and microsequencing, would allow rapid and precise diagnosis of microbial invasion of amniotic cavity. These objectives cannot be accomplished by relying on maternal blood tests that provide no direct information about the status of the intrauterine cavity and fetus. Further studies using clinical decision analysis are required to determine if the benefits of early diagnosis and treatment outweigh the risks of amniocentesis. Evidence that intrapartum treatment of women with clinical chorioamnionitis reduces the rate of proven neonatal sepsis in term patients23 is adequate justification in our units for the performance of amniocentesis and treatment with antibiotic in women with evidence of microbial invasion of the amniotic cavity.
VOL.
88, NO.
6, DECEMBER
1996
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Accq~fed
Aupsf
28, 1996.
8
by
Copyqht Gynecologists.
1996
Published
\uiy
.The
29, 1996.
American
by Elsevier
College Science
of Obstetricians Inc
and