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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, University of Washington; Department of Obstetrics and Gynecology, Swedish Hospital Medical Center, Seattle, Washington; and the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh/Magee-Womens Research Institute, Pittsburgh, Pennsylvania.
Address reprint requests to: Jane Hitti, MD Department of Obstetrics and Gynecology University of Washington Medical Center Box 356460 Seattle, WA 98195 E-mail: jhitti{at}u.washington.edu
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Abstract |
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Methods: One hundred ninety-seven afebrile women in preterm labor with intact membranes had vaginal and AF samples collected for Gram stain, culture, and interleukin-8 and interleukin-6 determinations. Vaginal interleukin-6, interleukin-8, neutrophils, and vaginal flora were compared in women with positive and negative AF cultures. The negative AF culture group was subdivided according to AF interleukin-6 concentration. Logistic regression was used to examine the associations between vaginal cytokines and flora and AF infection or elevated AF interleukin-6.
Results: The vaginal interleukin-8 concentration and neutrophil count were significantly higher with both AF infection and elevated concentrations of AF interleukin-6 and interleukin-8. The vaginal interleukin-6 concentration was not associated with AF infection or high concentration of AF cytokines. Amniotic fluid infection was associated with bacterial vaginosis or intermediate vaginal flora by Gram stain, absence of hydrogen peroxide–producing Lactobacillus, and presence of vaginal Bacteroides ureolyticus and Fusobacterium. Vaginal interleukin-8 levels greater than 30 ng/mL had 80% sensitivity and a positive predictive value of 35%, and an abnormal vaginal Gram stain (more than five neutrophils per 400x field, bacterial vaginosis species, or intermediate flora) had 90% sensitivity and a positive predictive value of 27% to detect AF infection or elevated AF interleukin-6.
Conclusion: A high vaginal interleukin-8 concentration, abnormal vaginal Gram stain, absent hydrogen peroxide–producing Lactobacillus, and anaerobic vaginal flora were strongly associated with AF infection among women in preterm labor.
Amniotic fluid (AF) infection, defined as the isolation of microbes from AF, occurs in 10–15% of pregnancies complicated by preterm labor.1–3 Amniotic fluid infection incites a vigorous proinflammatory response, with production of numerous cytokines that include interleukin-62,3 and interleukin-8.4,5 The presence of microorganisms or proinflammatory cytokines in AF is strongly associated with preterm delivery. When AF is infected, preterm birth usually occurs within 48 hours3 despite tocolysis and antibiotic therapy. Recent evidence suggests that AF infection and the accompanying proinflammatory response can increase the risk of adverse neonatal outcome beyond that expected solely from prematurity.6,7 Attempts to prevent preterm delivery by tocolysis alone could increase fetal injury. Thus, early identification of AF infection can provide an opportunity to influence the course of preterm labor and possibly improve neonatal outcome.
Amniotic fluid infection probably results from bacterial ascent from the lower genital tract. A noninvasive method to screen for AF infection using vaginal fluid would be useful. Transabdominal amniocentesis could then be reserved for patients who are at high risk for AF infection by vaginal fluid criteria.
Proinflammatory cytokines in vaginal fluid could indicate AF infection. Both interleukin-68,9 and interleukin-810,11 are detected in lower genital tract samples of pregnant women. One study found that an elevated concentration of cervical interleukin-8 was associated with preterm birth, AF infection, and histologic chorioamnionitis.11 Because interleukin-8 is a potent neutrophil chemoattractant,12 vaginal neutrophil counts could reflect local interleukin-8 concentrations. The purpose of this study was to determine whether a high concentration of interleukin-6, interleukin-8, or neutrophils in vaginal fluid among women in preterm labor might predict AF infection. Bacterial vaginosis is associated with AF infection and preterm delivery.13 We also examined the associations between bacterial vaginosis, abnormal vaginal flora, and AF infection.
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Materials and Methods |
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Of 309 participating women, 11 (4%) were lost to follow-up and 83 (27%) were excluded from the present analyses because of major fetal malformations, multiple gestation, or other pregnancy complications such as placenta previa, abruption, diabetes, hypertension or preeclampsia, or cervical cerclage. In 18 women vaginal cultures were not obtained because of suspected imminent delivery (n = 13) or patient refusal of the speculum examination (n = 5). Vaginal samples for cytokine analysis were available for 181 (92%) of 197 remaining participants with vaginal cultures.
Vaginal specimens were obtained by saturating six polyester swabs with fluid from the posterior vaginal fornix. One swab was used for a Gram stain of the vaginal flora, which were characterized as normal, intermediate flora, or bacterial vaginosis, using published criteria.15 The number of neutrophils on the vaginal Gram stain was counted in five nonadjacent fields at 400x magnification, and the mean number of vaginal neutrophils per 400x field was determined.
Two vaginal swabs were placed immediately into an anaerobic transport device (Port-a-Cul; Becton Dickinson Microbiology Systems, Cockeysville, MD). Vaginal fluid was cultured for aerobic and anaerobic microorganisms and genital mycoplasmas, as previously described.16 All Lactobacillus isolates were tested for hydrogen peroxide production using a tetramethylbenzidine agar plate.17 Women with both hydrogen peroxide-positive and hydrogen peroxide-negative isolates were considered hydrogen peroxide-positive. The concentration of vaginal bacteria was estimated using methods designed to detect log concentration differences in the isolates.18 For analysis, isolates that occurred frequently and over a wide range of concentrations were categorized as either no growth, light growth (less than or equal to median concentration), or heavy growth (greater than median concentration).19 Infrequent isolates (Bacteroides ureolyticus, Fusobacterium sp, and Mycoplasma hominis) were characterized as present or absent.
Three vaginal swabs were stored at -70C in pyrogenfree containers until assayed for cytokines. Approximately 100 µL of vaginal fluid was eluted from each swab with 0.9 mL of phosphate-buffered saline, resulting in a 1:10 dilution. Vaginal interleukin-6 and interleukin-8 concentrations were determined by commercial enzyme immunoassays specific for each cytokine (Genzyme Diagnostics, Cambridge, MA; Biosource, Camarillo, CA). The mean concentration of two duplicate samples of 25 µL each was calculated. The coefficient of variation between duplicate samples was 20% or less. Standard positive controls of recombinant interleukin-6 or interleukin-8 in buffered solution were run simultaneously with the study specimens for each cytokine assay. Because the samples were run at a 1:10 dilution, the lower limit of detection was 0.70 ng/mL for interleukin-6 and 0.15 ng/mL for interleukin-8.
All participants had AF collected by transabdominal amniocentesis at study enrollment. Amniotic fluid was placed immediately in an anaerobic transport vial and within 12 hours was inoculated into culture media for aerobic and anaerobic bacteria and genital mycoplasmas. The methods used to culture and identify these organisms were designed to detect low quantities of bacteria through the use of broth enrichment, as previously described.1
The remaining AF was stored at -70C until assayed for interleukin-6 and interleukin-8. Amniotic fluid interleukin-6 assays were done as described for the vaginal interleukin-6 assays, except that the AF was not diluted. The lower limit of detection for interleukin-6 was 0.07 ng/mL. An AF interleukin-6 level of over 2 ng/mL was considered elevated, as previously reported.7,14 This value was at the 80th percentile for the study population. Amniotic fluid interleukin-6 assays were done for 187 (95%) of 197 participants.
Amniotic fluid interleukin-8 assays were done for 145 (74%) of 197 participants. Interleukin-8 concentrations were determined for a single 100-µL sample, using a commercial enzyme immunoassay (R&D Systems, Minneapolis, MN). There were no significant differences in demographic or reproductive characteristics for patients who did and did not have AF interleukin-8 assays done. The lower limit of detection for the AF interleukin-8 assay was 0.03 ng/mL.
Categoric data were analyzed using the 
2 test or Fisher two-tailed test for significance. The Spearman rank correlation was used to examine the relationships between vaginal neutrophils and vaginal and AF concentrations of interleukin-6 and interleukin-8. The Mann-Whitney U test was used to compare continuous demographic variables, vaginal neutrophil counts, and vaginal and AF interleukin-6 and interleukin-8 concentrations for women with positive and negative AF cultures. In addition, the group with negative AF cultures was subdivided into those with AF interleukin-6 greater than 2 ng/mL and those with AF interleukin-6 of 2 ng/mL or less. Two-way comparisons were conducted between the following three groups according to amniocentesis results: women with a positive AF culture, a negative culture with AF interleukin-6 greater than 2 ng/mL, and a negative AF culture with AF interleukin-6 2 ng/mL or less. Comparisons between these three groups were accomplished using the Mann-Whitney U test with Bonferroni correction for multiple comparisons. Multivariable logistic regression was used to examine the associations between log interleukin-6 and log interleukin-8 concentrations, high vaginal neutrophil count, bacterial vaginosis or intermediate vaginal flora by Gram stain and various vaginal isolates, and the presence of AF infection or AF interleukin-6 greater than 2 ng/mL. Odds ratios were adjusted for gestational age at enrollment for all variables considered. The odds ratios for log interleukin-6, log interleukin-8, and vaginal neutrophils also were adjusted for cervical dilation at enrollment. The sensitivity, specificity, and positive and negative predictive values of various vaginal indicators were calculated for the detection of AF infection or elevated AF interleukin-6. Receiver-operating characteristic (ROC) curves were constructed for vaginal interleukin-8 and vaginal neutrophil counts as predictors of AF infection or elevated AF interleukin-6.
The original study sample size was determined with the objective of detecting various risk factors for preterm delivery among women in preterm labor. The sample size for the present study, 39 women with AF infection or elevated AF interleukin-6 and 158 women with negative AF cultures or low AF interleukin-6 levels, had over 90% power to detect an odds ratio of 2.0 for variables with a prevalence of 20% or more in the negative culture or low AF interleukin-6 group.
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Results |
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Of 179 women with negative AF cultures, 21 (12%) had a negative AF culture but an AF concentration of interleukin-6 greater than 2.0 ng/mL, and 158 (88%) had both a negative AF culture and an AF interleukin-6 concentration of 2.0 ng/mL or less. Women with AF infection were more likely to be of white ethnicity (P < .05) but otherwise had demographic and reproductive characteristics similar to those of women without AF infection. At enrollment, women with both a positive AF culture and a negative AF culture with elevated AF interleukin-6 (over 2.0 mg/mL) presented at earlier gestational ages and had more advanced cervical dilation than women with a negative AF culture plus low AF interleukin-6 (less than 2.0 mg/mL, P < .05, Table 1
). Women with a positive AF culture or a negative AF culture with elevated AF interleukin-6 also had a shorter admission-to-delivery interval, lower gestational age at delivery, and lower infant birth weight compared with women who had negative AF culture with low AF interleukin-6 (median birth weights 1203, 1296, and 2708 g, respectively; P < .01, Table 1). These same variables were also significantly different in women with a positive compared with a negative AF culture (Table 1).
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Vaginal interleukin-8 concentrations were significantly correlated with AF interleukin-6 (Spearman R = .31, P < .001) and AF interleukin-8 concentrations (Spearman R = .31, P < .001). Vaginal neutrophils were also significantly correlated with AF interleukin-6 (Spearman R = .30, P < .001) and AF interleukin-8 (Spearman R = .27, P = .001). In contrast, vaginal interleukin-6 concentrations did not correlate with AF interleukin-6 concentrations (Spearman R = .09) or AF interleukin-8 concentrations (Spearman R = .12).
Vaginal interleukin-8 concentrations were significantly higher among women with a positive AF culture or a negative AF culture with elevated AF interleukin-6, compared with women with a negative AF culture plus low interleukin-6 (medians 140.2, 94.2, and 15.3 ng/mL, respectively; P < .01; Table 2). The vaginal neutrophil count was also significantly higher for women with a negative AF culture plus elevated AF interleukin-6 compared with women with a negative AF culture plus low AF interleukin-6.
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). A negative AF culture plus elevated AF interleukin-6 was also negatively associated with isolation of hydrogen peroxide–producing Lactobacillus (P < .05) and positively associated with the isolation of Fusobacterium (P < .05) from the vagina.
We next examined the distributions of vaginal interleukin-8, neutrophil counts, and interleukin-6 in relation to vaginal flora determined by Gram stain and vaginal culture (Table 3). Vaginal cytokine concentrations and neutrophil counts were not different for women with bacterial vaginosis or intermediate vaginal flora, compared with women with normal Gram stains. M hominis was associated with a higher vaginal interleukin-8 concentration (P < .01) and neutrophil count (P < .05). Higher vaginal interleukin-8 concentrations were also found with heavy growth of Gardnerella vaginalis (greater than 106; P < .05) and isolation of Fusobacterium (P < .05). Vaginal interleukin-6 concentrations were significantly higher with heavy growth of Peptostreptococcus (greater than 104; P < .05) but not with other isolates.
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). A log increase in interleukin-8 was highly associated with AF infection or high AF interleukin-6. A vaginal neutrophil count greater than five was also significantly associated with AF infection or elevated AF interleukin-6. Vaginal Gram stain characteristics and isolates were also examined as predictors of AF infection or elevated AF interleukin-6, with adjustment for gestational age at enrollment. The finding of bacterial vaginosis or intermediate vaginal flora on Gram stain was significantly associated with AF infection or elevated AF interleukin-6. The presence of hydrogen peroxide–producing Lactobacillus was negatively associated (odds ratio 0.5, 95% confidence interval 0.3, 0.8), whereas isolation of B ureolyticus or Fusobacterium was positively associated with AF infection or elevated AF interleukin-6.
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for vaginal interleukin-8).
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. An elevated vaginal interleukin-8 level had 80% sensitivity, 64% specificity, a positive predictive value of 35%, and negative predictive value of 93%. Bacterial vaginosis or intermediate flora on Gram stain had the lowest sensitivity (31%) but highest specificity (87%) and a positive predictive value of 38%. The combination of either increased vaginal neutrophils or bacterial vaginosis or intermediate flora on Gram stain had a sensitivity of 90%, a specificity of 41%, a positive predictive value of 27%, and a negative predictive value of 94% to detect AF infection or elevated AF interleukin-6.
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Discussion |
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We examined vaginal indicators and pregnancy outcomes among three groups of women, ie, those with a positive AF culture, those with elevated concentrations of AF interleukin-6 alone, and those who were uninfected. Women with AF isolates and those with elevated concentrations of AF interleukin-6 alone presented at earlier gestational ages, delivered shortly after admission, and had infants with markedly lower birth weight than uninfected women, as previously reported.1–3 There were no significant differences in pregnancy outcome between women with a positive AF culture and those with a negative AF culture but elevated AF interleukin-6. At least one-third of women with high AF interleukin-6 appear to have AF infection with low colony counts or microorganisms that are only detectable by more sensitive methods such as broad-spectrum bacterial 50S ribosomal polymerase chain reaction.14 Taken together, these findings suggest that women with a negative AF culture but elevated AF interleukin-6 are clinically indistinguishable from women with a positive AF culture, and that indeed many of those with negative AF culture plus elevated AF interleukin-6 have AF infection that is not detectable by standard methods.
An elevated concentration of interleukin-8 was detected in both AF and vaginal fluid among women with a positive AF culture and women with a negative AF culture but elevated AF interleukin-6. Other investigators reported that elevated concentrations of interleukin-8 in lower genital tract specimens are associated with AF infection and preterm delivery.11 However, we directly compared AF and vaginal concentrations of interleukin-8 and interleukin-6 and found that the median concentration of interleukin-8 was much higher in vaginal fluid samples than in AF samples. This strongly suggests that much of the vaginal interleukin-8 is produced outside the amniotic cavity and that vaginal interleukin-8 did not simply result from transudation of AF. The interleukin-8 found in the vagina could be produced in the chorion, decidua, and cervix or by cells in the vagina. Because cervical interleukin-8 production increases with the onset of labor,20 the cervix is probably a major source of vaginal interleukin-8. Indeed, in this study women with a positive AF culture or negative AF culture but elevated AF interleukin-6 presented with more advanced cervical dilatation than women with no evidence of AF infection. It is therefore possible that interleukin-8 appears in the vagina in increased concentrations as a result of labor and not in relation to AF infection. However, in a multivariate analysis that controlled for the degree of cervical dilatation at admission, both vaginal interleukin-8 concentration and increased vaginal neutrophils remained strongly associated with AF infection (Table 4). The relationships between AF infection, labor, and cervical and vaginal interleukin-8 and neutrophils should be investigated further.
Interleukin-8 has neutrophil chemoattractant properties,12 and it is not surprising that vaginal interleukin-8 concentrations and neutrophil counts correlated closely. Vaginal neutrophil counts also correlated with AF interleukin-6 and interleukin-8 concentrations and were significantly higher among women with AF infection or negative AF culture but elevated AF interleukin-6. In fact, vaginal neutrophil counts approached the predictive values of vaginal interleukin-8 to identify or exclude AF infection (Table 5). The close correlation between vaginal interleukin-8 concentrations and neutrophil counts suggests that interleukin-8 attracted neutrophils to the vagina.
Amniotic fluid interleukin-6 is a highly sensitive marker for AF infection and preterm delivery.2,3 However, in this study, vaginal interleukin-6 concentrations did not predict AF infection or AF interleukin-6 or interleukin-8 concentrations. Our findings contrast with those of other investigators who found that high concentrations of interleukin-6 in the cervix were associated with AF infection9 and preterm delivery.8 Concentrations of interleukin-6 might differ in cervical and vaginal secretions, and we did not have cervical samples to test.
Bacterial vaginosis and certain anaerobic vaginal isolates have been associated with AF infection and preterm delivery.1,13,16 We found that the presence of hydrogen peroxide–producing Lactobacillus was negatively associated with AF infection. Vaginal interleukin-8 concentrations and neutrophil counts were not related to bacterial vaginosis or the absence of Lactobacillus. However, the isolation of several microorganisms associated with bacterial vaginosis (M hominis, Fusobacterium, and heavy growth of Gardnerella vaginalis) correlated with high vaginal interleukin-8 concentrations. A subset of strains of these microorganisms might be more likely than others to incite an inflammatory response in the lower genital tract. Some bacterial products such as sialidase are associated with degradation of cervical immunoglobulin A,21 which could allow increased invasion of the cervix by microbes. In addition, some women might produce more cytokines than others in response to specific microorganisms, as has been documented in other infections.22 The relationships between vaginal flora, lower genital tract inflammation, and AF infection require further study.
A recent study found no decrease in preterm delivery when women with bacterial vaginosis were given oral metronidazole compared with placebo.23 One cannot draw certain conclusions from a failure to reduce preterm delivery by treating bacterial vaginosis.23 The negative results cannot be used to conclude that bacterial vaginosis does not cause preterm delivery, because so much is still unknown about the treatment of bacterial vaginosis to prevent preterm delivery. We have not yet established the target population to treat (low or high risk of preterm delivery, or some other criterion), the appropriate site to treat (vagina or endometrium), or the time in pregnancy to treat (first or second trimester). Data from the current and previous studies1,13,16 relate bacterial vaginosis to AF infection. Although the relationship between bacterial vaginosis and AF certainly does not prove that bacterial vaginosis causes preterm delivery any more than the negative treatment trial proved the opposite, the consistent finding that bacterial vaginosis is related to AF infection provides evidence that bacterial vaginosis is more than just a marker for preterm delivery and raises the possibility that it causes AF infection and preterm delivery.
A high vaginal interleukin-8 concentration among women in preterm labor might be a useful, noninvasive marker for AF infection and proinflammatory cytokine production. At present, interleukin-8 cannot be measured easily in a clinical setting. However, either increased vaginal neutrophils or abnormal vaginal flora by Gram stain is nearly as sensitive as vaginal interleukin-8 to detect AF infection among women in preterm labor. Use of either vaginal interleukin-8 or vaginal Gram stain characteristics might identify women at higher risk of AF infection who would be candidates for amniocentesis. Alternatively, a vaginal fluid Gram stain with normal flora and fewer than five neutrophils per high-power field had a relatively high negative predictive value for AF infection in our study population, suggesting that in those women amniocentesis for the detection of AF infection might have a lower yield. If validated in other populations, examination of vaginal fluid for interleukin-8 or vaginal Gram stain characteristics could be a useful adjunct for the treatment of women in preterm labor.
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Footnotes |
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Received April 10, 2000. Received in revised form August 18, 2000. Accepted August 31, 2000.
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2. Romero R, Yoon BH, Mazor M, Gomez R, Diamond MP, Kenney JS, et al. The diagnostic and prognostic significance of amniotic fluid white blood cell count, glucose, interleukin-6, and Gram stain in patients with preterm labor and intact membranes. Am J Obstet Gynecol 1993;169:805–16.[Medline]
3. Hillier SL, Witkin SS, Krohn MA, Watts DH, Kiviat NB, Eschenbach DA. The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis and chorioamnion infection. Obstet Gynecol 1993;81:941–8.
4. Romero R, Ceska M, Avila C, Mazor M, Behnke E, Lindley I. Neutrophil attractant/activating peptide-1/interleukin-8 in term and preterm parturition. Am J Obstet Gynecol 1991;165:813–20.[Medline]
5. Cherouny PH, Pankuch GA, Romero R, Botti JJ, Kuhn DC, Demers LM, et al. Neutrophil attractant/activating peptide-1/interleukin-8: Association with histologic chorioamnionitis, preterm delivery, and bioactive amniotic fluid leukoattractants. Am J Obstet Gynecol 1993;169:1299–303.[Medline]
6. Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi JH, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1B and tumor necrosis factor-a) and neonatal brain white matter lesions and cerebral palsy. Am J Obstet Gynecol 1997;177: 19–26.[Medline]
7. Hitti J, Krohn MA, Patton DL, Tarczy-Hornoch P, Hillier SL, Cassen EM, et al. Anniotic fluid tumor necrosis factor-alpha and risk of respiratory distress syndrome among preterm infants. Am J Obstet Gynecol 1997;177:50–6.[Medline]
8. Lockwood CJ, Ghidini A, Wein R, Lapinski R, Casal D, Berkowitz RL. Increased interleukin-6 concentrations in cervical secretions are associated with preterm delivery. Am J Obstet Gynecol 1994; 171:1097–102.[Medline]
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15. Nugent RP, Krohn MJ, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of Gram stain interpretation. J Clin Microbiol 1991;29:297–301.
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