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The Preterm Prediction Study: Association of second-trimester genitourinary chlamydia infection with subsequent spontaneous preterm birth
The Preterm Prediction Study: Association of second-trimester genitourinary chlamydia infection with subsequent spontaneous preterm birth William W. Andrews, PhD, MD, Robert L. Goldenberg, MD, Brian Mercer, MD, Jay Iams, MD, Paul Meis, MD, Atef Moawad, MD, Anita Das, MS, J. Peter VanDorsten, MD, Steve N. Caritis, MD, Gary Thurnau, MD, Menachem Miodovnik, MD, James Roberts, MD, and Donald McNellis, MD, for the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network
OBJECTIVE: This study was undertaken to determine the association between genitourinary tract infection with Chlamydia trachomatis and spontaneous preterm birth. STUDY DESIGN: Genitourinary tract infection with C trachomatis was determined with a ligase chain reaction assay of voided urine samples collected at 24 weeks’ gestation (22 weeks’ to 24 weeks 6 days’ gestation) and 28 weeks’ gestation (27 weeks’ to 28 weeks 6 days’ gestation). Case patients (spontaneous preterm birth at <37 weeks’ gestation; n = 190) and control subjects (delivery at ≥37 weeks’ gestation, matched for race, parity, and center; n = 190) were selected from 2929 women enrolled in the Preterm Prediction Study of the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. RESULTS: Genitourinary C trachomatis infection (11% overall) was significantly more common among the case patients than among the control subjects at 24 weeks’ gestation (15.8% vs 6.3%; P = .003) but not at 28 weeks’ gestation (12.6% vs 10.9%; P = .61). Women with chlamydia infection were more likely to have bacterial vaginosis (57.1% vs 32.9%; P = .002) and a short cervical length (≤25 mm; 33.0% vs 17.9%; P = .02) but not a body mass index <19.8 kg/m2 (35.0% vs 23.9%; P = .17) or a positive fetal fibronectin test result (7.1% vs 9.5%; P = .62). After adjustment for risk factors for spontaneous preterm birth, women with C trachomatis infection at 24 weeks’ gestation were 2 times as likely as uninfected women to have a spontaneous preterm birth at <37 weeks’ gestation (odds ratio, 2.2; 95% confidence interval, 1.03-4.78) and 3 times as likely to have a spontaneous preterm birth at <35 weeks’ gestation (odds ratio, 3.2; 95% confidence interval, 1.08-9.57). CONCLUSION: Genitourinary C trachomatis infection at 24 weeks’ gestation was associated with a 2-fold to 3-fold increased risk of subsequent spontaneous preterm birth. (Am J Obstet Gynecol 2000;183:662-8.)
Key words: Bacterial vaginosis, Chlamydia trachomatis, fetal fibronectin, low birth weight, preterm birth
From the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network, the University of Alabama at Birmingham, the Bowman Gray School of Medicine, the University of Chicago, the University of Cincinnati, the George Washington University, the National Institute of Child Health and Human Development, The Ohio State University, the University of Oklahoma, the University of Pittsburgh, the Medical University of South Carolina, the University of Tennessee, and Wayne State University. In addition to support from the National Institute of Child Health and Human Development (grants HD 27869, HD21410, HD21414, HD21434, HD27860, HD27861, HD27883, HD27905, HD27915, HD27917, HD19897), this investigation was also partially supported by a contract from the Agency for Health Care Policy and Research (contract 290-92-0055) and a grant from the National Institute of Allergy and Infectious Diseases (U 19AI38514). Received for publication October 12, 1999; revised November 25, 1999; accepted February 17, 2000. Reprint requests: William W. Andrews, PhD, MD, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 619 19th St S, OHB 452, Birmingham, AL 35249-7333. 6/1/106556 doi:10.1067/mob.2000.106556
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Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen in the United States and is estimated to result in 4 million infections annually.1 The prevalence of cervical infection with C trachomatis among pregnant women has been estimated to range from 2% to 37%, and the effects of these infections on pregnancy outcomes and maternal and neonatal morbidity rates are an important concern for perinatal medicine.1, 2 Although abundant evidence is now available to link certain genital tract infections with spontaneous preterm birth, investigations of the association between C trachomatis infection of the female genital tract during pregnancy and subsequent spontaneous preterm birth have produced mixed results.2 Some reports have linked the presence of maternal chlamydia infection with low birth weight, premature birth, premature rupture of membranes, and even an increased risk of perinatal
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death.3-8 However, such an association with adverse pregnancy outcomes is not a universal finding.9-12 Most available studies have used insensitive screening tests to diagnose C trachomatis infection of the genital tract and also have methodologic shortcomings, including a limited ability to control for potential confounding variables.2 The Centers for Disease Control and Prevention has recommended that screening and treatment of genital tract C trachomatis infection be considered for pregnant women with certain risk factors to prevent neonatal sequelae resulting from vertical transmission of this organism.13 Because of the conflicting data regarding the association of C trachomatis infection with preterm birth and in the absence of data that treatment of this infection will prevent preterm birth, however, no recommendation has been made for a screening and treatment program expressly to prevent preterm birth. Recently, deoxyribonucleic acid amplification techniques have proved to be extremely sensitive and specific for the detection of C trachomatis infections. Indeed, ligase chain reaction assay of voided urine has been demonstrated to be a sensitive and reliable test to detect genitourinary tract infection among pregnant women.14-16 The objective of this study was to determine the association between genitourinary tract C trachomatis infection and spontaneous preterm birth in a well-characterized study population with the ligase chain reaction assay used as a sensitive means of detection of genitourinary C trachomatis infection. Material and methods This was a retrospective case-control study in which case patients and control subjects were derived from the National Institutes of Child Health and Human Development Maternal-Fetal Medicine Units Network Preterm Prediction Study. The Preterm Prediction Study was a multicenter observational investigation of 2929 symptomfree women evaluated longitudinally to determine risk factors for spontaneous preterm birth. Women enrolled in this study were not selected with regard to specific risk factors for preterm birth, and extensive information was collected on all study subjects, which resulted in an extremely well-characterized study population. During the study specimens and data were collected at each of four perinatal visits (24, 26, 28, and 30 weeks’ gestation). Voided urine specimens were collected at the 24 weeks’ gestation (22 weeks’–24 weeks 6 days’ gestation) and 28 weeks’ gestation (27 weeks’–28 weeks 6 days’ gestation) visits and were stored at –70°C until later analysis. Among the 2929 women enrolled in the Preterm Prediction Study, urine specimens from the 24 weeks’ gestation visit was available for analysis from 190 of 206 case patients who had a spontaneous preterm birth at <37 weeks’ gestation and 190 control subjects (matched for race, parity, and center) who were delivered at ≥37 weeks’ ges-
tation. This study population included 117 case patients with a spontaneous preterm birth at <35 weeks’ gestation, with corresponding matched control subjects. Because some women were delivered before or failed to return for the 28 weeks’ gestation visit, urine specimens at 28 weeks’ gestation were available for 132 case patients with a spontaneous preterm birth at <37 weeks’ gestation and 69 case patients who were delivered at <35 weeks’ gestation (with corresponding matched control subjects). These women were therefore the case patients and control subjects analyzed for this report. Informed consent was obtained from each participant before enrollment, and the study was approved by the human use committee at each of the participating centers. The voided urine specimens were transported on dry ice to the Obstetrics and Gynecology Infectious Disease Research Laboratory at the University of Alabama at Birmingham, where they remained stored at –70°C until analysis. Genitourinary infection with C trachomatis was determined from these voided urine samples with a ligase chain reaction assay. The assay is specific for C trachomatis plasmid deoxyribonucleic acid, and detailed descriptions of the assay technique and performance have been previously published.15-17 Analysis of the data was performed with SAS statistical software (SAS Institute, Inc, Cary, NC). Univariate analyses included the χ2 test and the Fisher exact test as appropriate. Logistic regression models were developed for C trachomatis at 24 and 28 weeks’ gestation. The final logistic models were checked by forward regression. Odds ratios with 95% confidence intervals were calculated. Results Demographic and other characteristics of the study population are depicted in Table I. Overall the case patients and control subjects were predominantly African American and of lower socioeconomic status. Factors that were significantly more common (P ≤ .04 for each case patient) among case patients than among control subjects included the following: maternal body mass index <19.8 kg/m2, previous spontaneous preterm birth, vaginal bleeding in the first or second trimester, urinary tract infections during the pregnancy, acute pulmonary disorder (bronchitis or pneumonia) at <24 weeks’ gestation, and use of antimicrobial therapy during the index pregnancy. The overall frequencies of genitourinary tract C trachomatis infection among the combined case patients and control subjects were 11.1% at 24 weeks’ gestation and 11.9% at 28 weeks’ gestation. In a comparison with C trachomatis infection in control women who had a term birth, genitourinary tract C trachomatis infection was significantly more common at 24 weeks’ gestation among case patients who had a spontaneous preterm birth at <37 weeks’ gestation (15.8% vs 6.3%; P = .003; odds ratio, 2.8;
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Table I. Characteristics of study population Case patients (%, n = 190)
Control subjects (%, n = 190)
Statistical significance
0.5 3.7 73.2 25.8 41.6 66.7 67.4 9.0 9.0 32.6 34.2 29.5 9.5 5.8 36.8 18.4 26.8 49.0 6.3
2.6 3.2 73.2 21.6 35.8 60.4 57.9 11.1 5.8 12.1 34.2 27.4 15.3 7.4 23.7 9.5 25.8 37.9 2.1
P = .215 P = .778 P > .999 P = .334 P = .247 P = .231 P = .056 P = .494 P = .239 P = .001 P > .999 P = .649 P = .087 P = .535 P = .005 P = .012 P = .816 P = .030 P = .041
Maternal age <16 y Maternal age ≥35 y African American Lives alone Education <12 y Family income <$800/mo Poor social environment* Medical illnesses Previous pelvic inflammatory disease Previous spontaneous preterm birth Nulliparous Smoking during pregnancy Alcohol use during pregnancy Illicit drug use during pregnancy Vaginal bleeding† Urinary tract infections‡ Other infections‡ Antimicrobial therapy‡ Acute pulmonary disorder§ *Patient described residence as poor. †In the first or second trimester. ‡During index pregnancy. §Bronchitis or pneumonia before 24 weeks’ gestation.
95% confidence interval, 1.4-5.6) and at <35 weeks’ gestation (12.8% vs 5.13%; P = .040; odds ratio, 2.7; 95% confidence interval, 1.04-7.07). At the 28 weeks’ gestation visit the observed difference in genitourinary tract C trachomatis infection was not statistically significant for spontaneous preterm birth at <37 weeks’ gestation (12.9% vs 10.9%; P = .614; odds ratio, 1.2; 95% confidence interval, 0.6-2.6) or at <35 weeks’ gestation (11.9% vs 10.1%; P = .738; odds ratio, 1.2; 95% confidence interval, 0.4-3.5). Compared with term control subjects the case patients with spontaneous preterm birth at <37 weeks’ gestation (25.6% vs 15.9%; P = .055; odds ratio, 1.8; 95% confidence interval, 1.0-3.4) and at <35 weeks’ gestation (26.0% vs 14.9%; P = .105; odds ratio, 2.0; 95% confidence interval, 0.8-4.7) were almost twice as likely to have genitourinary tract C trachomatis infection present at either the 24 weeks’ gestation visit or the 28 weeks’ gestation visit. Also, although C trachomatis genitourinary infection was twice as common among case patients as among control subjects at both 24 and 28 weeks’ gestation, it was not significantly different between the 2 groups for spontaneous preterm birth at <37 weeks’ gestation (9.9% vs 5.0%; P = .142; odds ratio, 2.1; 95% confidence interval, 0.8-5.8) or at <35 weeks’ gestation (6.2% vs 4.6%; P > .999; odds ratio, 1.4; 95% confidence interval, 0.3-6.3). Numerous major risk factors for spontaneous preterm birth have been previously identified in the study population of 2929 women who participated in the Preterm Prediction Study. Reports describing these associated risk factors have been published elsewhere.18-21 In addition to bacterial vaginosis19 at 28 weeks’ gestation and the pres-
ence of cervical or vaginal fetal fibronectin (≥50 mg/mL),20 these risk factors included a low body mass index (<19.8 kg/m2)21 and a short cervical length (≤25 mm)18 as determined by transvaginal ultrasonography. In this case-control study all these major risk factors were significantly more common among the case patients than among the control subjects (Table II). A comparison of the frequencies of genitourinary tract C trachomatis infection among the case patients and among the control subjects evaluated in this investigation with these other established risk factors for spontaneous preterm birth is depicted in Table III. Women with chlamydia infection were significantly more likely than women without chlamydia infection at both the 24 and 28 weeks’ gestation visits to have bacterial vaginosis (P = .002 and P = .05, respectively). Women with C trachomatis infection at 24 weeks’ gestation (but not at 28 weeks’ gestation) were also more likely than uninfected women to have a short cervix (P = .02 and P = .12, respectively). No differences were observed at either gestational age between women with and without chlamydia infection in the frequencies of a positive cervical or vaginal fetal fibronectin test result (P = .78 and P = .14, respectively) and a body mass index <19.8 kg/m2 (P = .13 and P = .65, respectively; Table III). Logistic regression analyses were performed to adjust for risk factors found to be predictive of spontaneous preterm birth in the overall Preterm Prediction Study population. These included poor social environment, a previous spontaneous preterm birth, vaginal bleeding in the first or second trimester, urinary tract infections, a body mass index <19.8 kg/m2, a short cervix, African American race, bacterial vaginosis, and a positive fetal fibronectin
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Table II. Frequencies of selected risk factors for spontaneous preterm birth among case patients and control subjects at 24 weeks’ gestation and 28 weeks’ gestation visits Risk factor Bacterial vaginosis 24 wk 28 wk Short cervix (≤25 mm) 24 wk 28 wk Fetal fibronectin detected 24 wk 28 wk Low maternal body mass index (<19.8 kg/m2)
Table III. Frequencies of genitourinary tract C trachomatis infection among women with other established risk factors for spontaneous preterm birth at 24 weeks’ gestation and 28 weeks’ gestation visits Chlamydia infection
Case patients Control subjects Statistical (%, n = 190) (%, n = 190) significance Risk factor 39.5 32.8
31.8 20.5
P = .116 P = .028
30.2 39.3
09.0 17.1
P < .001 P < .001
16.8 13.0
01.6 04.5
P < .001 P = .031
30.6
19.6
P = .015
test result. Separate analyses were performed excluding previous spontaneous preterm birth from the regression model. The results of these analyses are depicted in Table IV. C trachomatis infection at 24 weeks’ gestation was associated with a 2-fold to 3-fold increased odds ratio for subsequent spontaneous preterm birth (<35 and <37 weeks’ gestation; Table IV). Although the odds ratio was even higher for spontaneous preterm birth at <32 weeks’ gestation when chlamydia infection was detected at 24 weeks’ gestation, this increase in the odds ratio was not statistically significant (Table IV). C trachomatis infection at 28 weeks’ gestation was not statistically associated with an increased odds ratio of spontaneous preterm birth (Table IV). Comment The potential association between chlamydia infection and spontaneous preterm birth remains a controversial subject and a topic of debate in perinatal medicine. This investigation offers the advantage of an extremely wellcharacterized study population with respect to pregnancy outcomes and risk factors for spontaneous preterm birth. In addition a sensitive, specific, and reliable means of testing for genitourinary tract infection with C trachomatis (ligase chain reaction) was used. In an unadjusted analysis women who subsequently had a spontaneous preterm birth were twice as likely to have a genitourinary tract infection with C trachomatis at 24 weeks’ gestation as were control women who were delivered at term. C trachomatis infection was also significantly associated with two established risk factors for spontaneous preterm birth in this population, bacterial vaginosis and short cervical length. However, it is interesting that C trachomatis infection was not significantly associated with two other established risk factors, low maternal body mass index and the cervical or vaginal presence of fetal fibronectin.
No. of women 24 wk 28 wk Bacterial vaginosis 24 wk 28 wk Short cervix (≤25 mm) 24 wk 28 wk Fetal fibronectin detection 24 wk 28 wk Low maternal body mass index (<19.8 kg/m2) 24 wk 28 wk
Yes (%)
42 27
No (%)
Statistical significance
338 193
57.1 41.4
32.9 24.6
P = .002 P = .054
33.0 40.0
17.9 26.2
P = .018 P = .115
7.1 0.0
9.5 9.8
P = .783 P = .139
35.0 20.7
23.9 24.5
P = .125 P = .649
When a multivariate analysis was performed to control for factors associated with spontaneous preterm birth in this population, including a history of previous spontaneous preterm birth, an association between genitourinary tract C trachomatis infection at 24 weeks’ gestation and subsequent spontaneous preterm birth was confirmed, with a 2-fold to 3-fold increased risk. The causal relationship between a history of previous preterm birth and the increased likelihood of another preterm birth is poorly understood and is probably multifactorial. Indeed, at least for some women a previous preterm birth may represent a surrogate variable for chlamydia infection. Thus it is debatable whether a history of previous preterm birth should be included in the logistic regression model. When such a history was excluded from the model, the point estimates of increased risk for spontaneous preterm birth with chlamydia infection at 24 weeks’ gestation remained almost unchanged. The results from both the univariate and multivariate analyses were consistent and support the conclusion that women with C trachomatis infection at 24 weeks’ gestation are at least twice as likely as those without this infection to have a subsequent spontaneous preterm birth. Our failure to confirm a statistically significant adjusted association between C trachomatis infection at 28 weeks’ gestation and subsequent spontaneous preterm birth may have resulted from an inadequate sample size or the case-control design. Although it was economically less feasible, a population-based study design with samples collected from all 2929 women enrolled in the Preterm Prediction Study might have resulted in a statistically significant adjusted odds ratio. In addition we could not control in this population for the potential effect of
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Table IV. Adjusted odds ratios for spontaneous preterm birth among women with C trachomatis infection at 24 or 28 weeks’ gestation Spontaneous preterm birth <32 wk
Regression model Previous spontaneous preterm birth included 24 wk 28 wk Previous spontaneous preterm birth excluded 24 wk 28 wk
Spontaneous preterm birth <35 wk
Spontaneous preterm birth <37 wk
Odds ratio
95% Confidence interval
Odds ratio
95% Confidence interval
Odds ratio
95% Confidence interval
5.0 —*
0.8-32.2 —*
2.8 1.1
0.90-8.81 0.25-4.61
2.3 0.95
1.01-5.03 0.36-2.47
5.2 —*
0.8-33.8 —*
3.2 0.8
1.08-9.57 0.19-3.27
2.4 0.8
1.08-5.29 0.31-2.04
Regression model includes or excludes previous spontaneous preterm birth as specified. *Sample size insufficient for analysis.
antibiotic treatment of C trachomatis infection that may have occurred before or after study enrollment. Many participants were screened and treated for C trachomatis infection according to individual protocols in place at the time of enrollment in each of the 10 participating centers. Data regarding the timing, screening results, and treatment of participants identified as having chlamydia infection were not recorded in the database. However, we are unaware of any current clinical recommendation to screen and treat chlamydia infection between 24 and 28 weeks’ gestational age. The results of the ligase chain reaction assays performed in this investigation were not available to clinicians providing prenatal care to participants in the observational Preterm Prediction Study. Indeed, this study was not conceived until after the Preterm Prediction Study had been completed. Thus these ligase chain reaction assays were performed in batches well after the completion of the Preterm Prediction Study. Although we cannot determine whether there was a difference in diagnosis and treatment of chlamydia infection during prenatal care between the case and control groups, neither do we have any reason to speculate that such a difference is likely to have occurred. However, it is possible that the observed results might be explained by a higher rate of chlamydia infection recurrence or treatment in the case group than in the control group. In addition, any deterioration of C trachomatis plasmid deoxyribonucleic acid during specimen storage that might have resulted in false-negative ligase chain reaction results would be anticipated to have occurred with equal frequencies among both the case patient and control subject specimens. The overall chlamydia infection rate in this study of 11% is reassuring that such specimen deterioration was not a major factor. This rate is consistent with findings previously reported in population studies with the ligase chain reaction technique.14-16 Sweet et al12 and Harrison et al10 have reported that women with chlamydia infection who are also immunoglobulin M seropositive may have a higher inci-
dence of low-birth-weight infants, premature deliveries, and premature rupture of membranes than either immunoglobulin M–seronegative women with chlamydia infection or women with cultures negative for C trachomatis. In other words, acute acquisition of C trachomatis infection may play a more important role than chronic infection as an associated risk factor for spontaneous preterm birth. Because the C trachomatis serologic status was unknown in our study, we could not control for this status in our analysis. Such knowledge might have allowed identification of a subgroup within our study population (those who were anti–chlamydial immunoglobulin M seropositive) in which an adjusted association between C trachomatis infection and spontaneous preterm birth might have been more definitively observed. The association between chlamydia infection and a short cervical length but not between chlamydia infection and a positive fetal fibronectin test result may provide an interesting clue to the mechanisms through which chlamydia infection might result in a spontaneous preterm birth. A prevailing hypothesis is that the presence of fetal fibronectin in cervical and vaginal secretions during the late second trimester is a marker for amniochorial matrix disruption, allowing this protein to “leak” down to the lower genital tract where it can then be detected. The absence of an association between genitourinary chlamydia infection and a positive fetal fibronectin test result is consistent with the observation that C trachomatis is rarely isolated from the amniotic fluid or amnion-chorion in pregnant women with spontaneous preterm labor or preterm premature rupture of membranes. Conversely, the association of chlamydia infection with a short cervical length may indicate that lower genital tract infection with this organism acts directly on the cervix to result in effacement, which may ultimately lead to preterm birth. If so, the mechanisms leading to preterm birth among women with chlamydia infection may be distinctly different from those associated with bacterial vaginosis which is more likely to be a lower genital
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tract marker of upper genital tract infection with bacterial vaginosis–associated microorganisms. Alternatively, a shortened cervical length resulting from C trachomatis infection could allow microorganisms normally confined to the lower genital tract to gain access to the upper genital tract, thereby resulting in an upper genital tract bacterial infection that would lead to a spontaneous preterm birth. If this mechanism prevailed, however, a significant relationship between chlamydia infection and a positive fetal fibronectin test result would have been anticipated. In conclusion, genitourinary C trachomatis infection was significantly more common among women with certain risk factors for spontaneous preterm birth, including bacterial vaginosis and a short cervical length. C trachomatis infection was not associated with other important risk factors, however, such as a low maternal body mass index or the presence of fetal fibronectin in cervical and vaginal secretions. After adjustment for established risk factors for spontaneous preterm birth women with genitourinary C trachomatis infection at 24 weeks’ gestation were 2 to 3 times as likely as women without this infection to have a spontaneous preterm birth. Whether the relationship between C trachomatis infection and spontaneous preterm birth is mediated through its association with bacterial vaginosis or short cervical length will require additional study. Whether universal screening and treatment for C trachomatis infection with a sensitive deoxyribonucleic acid amplification method for detection would significantly reduce spontaneous preterm delivery remains an unanswered question. It should be noted that the frequency of preterm birth in the United States has increased during recent years despite the recommendation of the Centers for Disease Control and Prevention for chlamydia infection screening among pregnant women. Ligase chain reaction assay kits were provided by Abbott Laboratories, Abbott Park, Ill. We acknowledge the participation of the following institutions and others who participated in the study: Rachel L. Copper, MSN, CRNP, John C. Hauth, MD, and Allison Northen, RN, The University of Alabama at Birmingham; Eberhard Meuller-Heubach, MD, Melissa Swain, RN, and Allison Frye, RN, Bowman Gray School of Medicine, Winston-Salem, NC; Marshall Lindheimer, MD, and Phyllis Jones, MPH, RN, University of Chicago; Tariq A. Siddiqi, MD, and Nancy Elder, MSN, RN, University of Cincinnati; Elizabeth Thom, PhD, Lucy Leuchtenburg, and Molly Fischer, MPH, CRNP, The Biostatistics Center, George Washington University, Bethesda, Md; James H. Harger, MD, Margaret Cotroneo, RN, and Cynthia Stallings, MSN, Magee Women’s Hospital, Pittsburgh, Pa; Sumner J. Yaffe, MD, Charlotte Catz, MD, and Mark Klebanoff, MD, the National Institute of Child Health and Human Development, Bethesda, Md; Francee Johnson, RN, BSN, and Mark B. Landon, MD, The Ohio State University, Columbus; J. Christopher
Carey, MD, and Arlene Meier, RN, University of Oklahoma, Oklahoma City; Roger B. Newman, MD, Beth A. Collins, PhD, RNC, and Faye LeBoeuf, MSN, CNM, Medical University of South Carolina, Charleston; Baha Sibai, MD, Risa Ramsey, BSN, RN, and Joyce Fricke, RNC, University of Tennessee, Memphis; Sydney F. Bottoms, MD (deceased), and Gwendolyn S. Norman, MPH, RN, Wayne State University, Detroit, Mich. REFERENCES
1. Centers for Disease Control and Prevention. Recommendations for the prevention and management of Chlamydia trachomatis infections, 1993. MMWR Morb Mortal Wkly Rep 1993;42(RR12):1-39. 2. Andrews WW, Goldenberg RL, Hauth JC. Preterm labor: emerging role of genital tract infections. Infect Agents Dis 1995;4:196211. 3. Alger LS, Lovchik JC, Hebel JR, Blackmon LR, Crenshaw MC. The association of Chlamydia trachomatis, Neisseria gonorrhoeae, and group B streptococci with preterm rupture of the membranes and pregnancy outcome. Am J Obstet Gynecol 1988;159: 397-404. 4. Gravett MG, Nelson HP, DeRouen T, Crichlow C, Eschenbach DA, Holmes KK. Independent associations of bacterial vaginosis and chlamydia trachomatis infection with adverse pregnancy outcome. JAMA 1986;256:1899-903. 5. Martin DH, Koutsky L, Eschenbach DA, Daling JR, Alexander ER, Benedetti JK, et al. Prematurity and perinatal mortality in pregnancies complicated by maternal Chlamydia trachomatis infections. JAMA 1982;247:1585-8. 6. Martius J, Krohn MA, Hillier SL, Stamm WE, Holmes KK, Eschenbach DA. Relationships of vaginal Lactobacillus species, cervical Chlamydia trachomatis, and bacterial vaginosis to preterm birth. Obstet Gynecol 1988;71:89-95. 7. The Johns Hopkins Study of Cervicitis and Adverse Pregnancy Outcome. Association of Chlamydia trachomatis and Mycoplasma hominis with intrauterine growth retardation and preterm delivery. Am J Epidemiol 1989;129:1247-57. 8. Claman P, Toye B, Peeling RW, Jessamine P, Belcher J. Serologic evidence of Chlamydia trachomatis infection and risk of preterm birth. CMAJ 1995;153:259-62. 9. Hardy PH, Hardy JB, Nell EE, Graham DA, Spence MR, Rosenbaum RC. Prevalence of six sexually transmitted disease agents among pregnant inner-city adolescents and pregnancy outcome. Lancet 1984;2:333-7. 10. Harrison HR, Alexander ER, Weinstein L, Lewis M, Nash M, Sim DA. Cervical Chlamydia trachomatis and mycoplasmal infections in pregnancy: epidemiology and outcomes. JAMA 1983;250: 1721-7. 11. Thompson S, Lopez B, Wong KH, Ramsey C, Thomas T, Reising C, et al. A prospective study of chlamydia and mycoplasmal infections during pregnancy. In: Mardh PA, Holmes KK, Oriel JD, Piat P, Schachter J, editors. Chlamydial infections. Amsterdam: Elsevier; 1982. p. 155-8. 12. Sweet RL, Landers DV, Walker C, Schachter J. Chlamydia trachomatis infection and pregnancy outcome. Am J Obstet Gynecol 1987;156:824-33. 13. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 1998;47(RR-1):1-111. 14. Schachter J, Moncada J, Whidden R, Shaw H, Bolan G, Burczak JD, et al. Noninvasive tests for the diagnosis of Chlamydia trachomatis infection: application of a ligase chain reaction to firstcatch urine specimens of women. J Infect Dis 1995;172:1411-4. 15. Lee HH, Chernesky MA, Schachter J, Burczak JD, Andrews WW, Muldoon S, et al. Diagnosis of Chlamydia trachomatis genitourinary tract infection in women by ligase chain reaction in urine. Lancet 1995;345:213-6. 16. Andrews WW, Lee HH, Roden WJ, Mott CW. Detection of genitourinary tract Chlamydia trachomatis infection in pregnant
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women by ligase chain reaction assay. Obstet Gynecol 1997;89: 556-60. 17. Schachter J, Stamm WE, Quinn TC, Andrews WW, Burczak JD, Lee HH. Ligase chain reaction to detect Chlamydia trachomatis infection of the cervix. J Clin Microbiol 1994;32:2540-3. 18. Iams JD, Goldenberg RL, Meis PJ, Mercer BM, Moawad A, Das A, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. N Engl J Med 1996;334:567-72. 19. Meis PJ, Goldenberg RL, Mercer B, Moawad A, Das A, McNellis D, et al. The Preterm Prediction Study: significance of vaginal in-
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fections. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 1995;173:1231-5. 20. Goldenberg RL, Mercer BM, Meis PJ, Copper RL, Das A, McNellis D, et al. The Preterm Prediction Study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal-Fetal Medicine Units Network. Obstet Gynecol 1996;87:643-8. 21. Goldenberg RL, Iams JD, Mercer BM, Meis PJ, Moawad AH, Copper RL, et al. The Preterm Prediction Study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network. Am J Public Health 1998;88:233-8.
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OBJECTIVE: This study was undertaken to determine the association between genitourinary tract infection with Chlamydia trachomatis and spontaneous preterm birth. STUDY DESIGN: Genitourinary tract infection with C trachomatis was determined with a ligase chain reaction assay of voided urine samples collected at 24 weeks’ gestation (22 weeks’ to 24 weeks 6 days’ gestation) and 28 weeks’ gestation (27 weeks’ to 28 weeks 6 days’ gestation). Case patients (spontaneous preterm birth at <37 weeks’ gestation; n = 190) and control subjects (delivery at ≥37 weeks’ gestation, matched for race, parity, and center; n = 190) were selected from 2929 women enrolled in the Preterm Prediction Study of the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. RESULTS: Genitourinary C trachomatis infection (11% overall) was significantly more common among the case patients than among the control subjects at 24 weeks’ gestation (15.8% vs 6.3%; P = .003) but not at 28 weeks’ gestation (12.6% vs 10.9%; P = .61). Women with chlamydia infection were more likely to have bacterial vaginosis (57.1% vs 32.9%; P = .002) and a short cervical length (≤25 mm; 33.0% vs 17.9%; P = .02) but not a body mass index <19.8 kg/m2 (35.0% vs 23.9%; P = .17) or a positive fetal fibronectin test result (7.1% vs 9.5%; P = .62). After adjustment for risk factors for spontaneous preterm birth, women with C trachomatis infection at 24 weeks’ gestation were 2 times as likely as uninfected women to have a spontaneous preterm birth at <37 weeks’ gestation (odds ratio, 2.2; 95% confidence interval, 1.03-4.78) and 3 times as likely to have a spontaneous preterm birth at <35 weeks’ gestation (odds ratio, 3.2; 95% confidence interval, 1.08-9.57). CONCLUSION: Genitourinary C trachomatis infection at 24 weeks’ gestation was associated with a 2-fold to 3-fold increased risk of subsequent spontaneous preterm birth. (Am J Obstet Gynecol 2000;183:662-8.)
Key words: Bacterial vaginosis, Chlamydia trachomatis, fetal fibronectin, low birth weight, preterm birth
From the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network, the University of Alabama at Birmingham, the Bowman Gray School of Medicine, the University of Chicago, the University of Cincinnati, the George Washington University, the National Institute of Child Health and Human Development, The Ohio State University, the University of Oklahoma, the University of Pittsburgh, the Medical University of South Carolina, the University of Tennessee, and Wayne State University. In addition to support from the National Institute of Child Health and Human Development (grants HD 27869, HD21410, HD21414, HD21434, HD27860, HD27861, HD27883, HD27905, HD27915, HD27917, HD19897), this investigation was also partially supported by a contract from the Agency for Health Care Policy and Research (contract 290-92-0055) and a grant from the National Institute of Allergy and Infectious Diseases (U 19AI38514). Received for publication October 12, 1999; revised November 25, 1999; accepted February 17, 2000. Reprint requests: William W. Andrews, PhD, MD, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 619 19th St S, OHB 452, Birmingham, AL 35249-7333. 6/1/106556 doi:10.1067/mob.2000.106556
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Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen in the United States and is estimated to result in 4 million infections annually.1 The prevalence of cervical infection with C trachomatis among pregnant women has been estimated to range from 2% to 37%, and the effects of these infections on pregnancy outcomes and maternal and neonatal morbidity rates are an important concern for perinatal medicine.1, 2 Although abundant evidence is now available to link certain genital tract infections with spontaneous preterm birth, investigations of the association between C trachomatis infection of the female genital tract during pregnancy and subsequent spontaneous preterm birth have produced mixed results.2 Some reports have linked the presence of maternal chlamydia infection with low birth weight, premature birth, premature rupture of membranes, and even an increased risk of perinatal
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death.3-8 However, such an association with adverse pregnancy outcomes is not a universal finding.9-12 Most available studies have used insensitive screening tests to diagnose C trachomatis infection of the genital tract and also have methodologic shortcomings, including a limited ability to control for potential confounding variables.2 The Centers for Disease Control and Prevention has recommended that screening and treatment of genital tract C trachomatis infection be considered for pregnant women with certain risk factors to prevent neonatal sequelae resulting from vertical transmission of this organism.13 Because of the conflicting data regarding the association of C trachomatis infection with preterm birth and in the absence of data that treatment of this infection will prevent preterm birth, however, no recommendation has been made for a screening and treatment program expressly to prevent preterm birth. Recently, deoxyribonucleic acid amplification techniques have proved to be extremely sensitive and specific for the detection of C trachomatis infections. Indeed, ligase chain reaction assay of voided urine has been demonstrated to be a sensitive and reliable test to detect genitourinary tract infection among pregnant women.14-16 The objective of this study was to determine the association between genitourinary tract C trachomatis infection and spontaneous preterm birth in a well-characterized study population with the ligase chain reaction assay used as a sensitive means of detection of genitourinary C trachomatis infection. Material and methods This was a retrospective case-control study in which case patients and control subjects were derived from the National Institutes of Child Health and Human Development Maternal-Fetal Medicine Units Network Preterm Prediction Study. The Preterm Prediction Study was a multicenter observational investigation of 2929 symptomfree women evaluated longitudinally to determine risk factors for spontaneous preterm birth. Women enrolled in this study were not selected with regard to specific risk factors for preterm birth, and extensive information was collected on all study subjects, which resulted in an extremely well-characterized study population. During the study specimens and data were collected at each of four perinatal visits (24, 26, 28, and 30 weeks’ gestation). Voided urine specimens were collected at the 24 weeks’ gestation (22 weeks’–24 weeks 6 days’ gestation) and 28 weeks’ gestation (27 weeks’–28 weeks 6 days’ gestation) visits and were stored at –70°C until later analysis. Among the 2929 women enrolled in the Preterm Prediction Study, urine specimens from the 24 weeks’ gestation visit was available for analysis from 190 of 206 case patients who had a spontaneous preterm birth at <37 weeks’ gestation and 190 control subjects (matched for race, parity, and center) who were delivered at ≥37 weeks’ ges-
tation. This study population included 117 case patients with a spontaneous preterm birth at <35 weeks’ gestation, with corresponding matched control subjects. Because some women were delivered before or failed to return for the 28 weeks’ gestation visit, urine specimens at 28 weeks’ gestation were available for 132 case patients with a spontaneous preterm birth at <37 weeks’ gestation and 69 case patients who were delivered at <35 weeks’ gestation (with corresponding matched control subjects). These women were therefore the case patients and control subjects analyzed for this report. Informed consent was obtained from each participant before enrollment, and the study was approved by the human use committee at each of the participating centers. The voided urine specimens were transported on dry ice to the Obstetrics and Gynecology Infectious Disease Research Laboratory at the University of Alabama at Birmingham, where they remained stored at –70°C until analysis. Genitourinary infection with C trachomatis was determined from these voided urine samples with a ligase chain reaction assay. The assay is specific for C trachomatis plasmid deoxyribonucleic acid, and detailed descriptions of the assay technique and performance have been previously published.15-17 Analysis of the data was performed with SAS statistical software (SAS Institute, Inc, Cary, NC). Univariate analyses included the χ2 test and the Fisher exact test as appropriate. Logistic regression models were developed for C trachomatis at 24 and 28 weeks’ gestation. The final logistic models were checked by forward regression. Odds ratios with 95% confidence intervals were calculated. Results Demographic and other characteristics of the study population are depicted in Table I. Overall the case patients and control subjects were predominantly African American and of lower socioeconomic status. Factors that were significantly more common (P ≤ .04 for each case patient) among case patients than among control subjects included the following: maternal body mass index <19.8 kg/m2, previous spontaneous preterm birth, vaginal bleeding in the first or second trimester, urinary tract infections during the pregnancy, acute pulmonary disorder (bronchitis or pneumonia) at <24 weeks’ gestation, and use of antimicrobial therapy during the index pregnancy. The overall frequencies of genitourinary tract C trachomatis infection among the combined case patients and control subjects were 11.1% at 24 weeks’ gestation and 11.9% at 28 weeks’ gestation. In a comparison with C trachomatis infection in control women who had a term birth, genitourinary tract C trachomatis infection was significantly more common at 24 weeks’ gestation among case patients who had a spontaneous preterm birth at <37 weeks’ gestation (15.8% vs 6.3%; P = .003; odds ratio, 2.8;
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Table I. Characteristics of study population Case patients (%, n = 190)
Control subjects (%, n = 190)
Statistical significance
0.5 3.7 73.2 25.8 41.6 66.7 67.4 9.0 9.0 32.6 34.2 29.5 9.5 5.8 36.8 18.4 26.8 49.0 6.3
2.6 3.2 73.2 21.6 35.8 60.4 57.9 11.1 5.8 12.1 34.2 27.4 15.3 7.4 23.7 9.5 25.8 37.9 2.1
P = .215 P = .778 P > .999 P = .334 P = .247 P = .231 P = .056 P = .494 P = .239 P = .001 P > .999 P = .649 P = .087 P = .535 P = .005 P = .012 P = .816 P = .030 P = .041
Maternal age <16 y Maternal age ≥35 y African American Lives alone Education <12 y Family income <$800/mo Poor social environment* Medical illnesses Previous pelvic inflammatory disease Previous spontaneous preterm birth Nulliparous Smoking during pregnancy Alcohol use during pregnancy Illicit drug use during pregnancy Vaginal bleeding† Urinary tract infections‡ Other infections‡ Antimicrobial therapy‡ Acute pulmonary disorder§ *Patient described residence as poor. †In the first or second trimester. ‡During index pregnancy. §Bronchitis or pneumonia before 24 weeks’ gestation.
95% confidence interval, 1.4-5.6) and at <35 weeks’ gestation (12.8% vs 5.13%; P = .040; odds ratio, 2.7; 95% confidence interval, 1.04-7.07). At the 28 weeks’ gestation visit the observed difference in genitourinary tract C trachomatis infection was not statistically significant for spontaneous preterm birth at <37 weeks’ gestation (12.9% vs 10.9%; P = .614; odds ratio, 1.2; 95% confidence interval, 0.6-2.6) or at <35 weeks’ gestation (11.9% vs 10.1%; P = .738; odds ratio, 1.2; 95% confidence interval, 0.4-3.5). Compared with term control subjects the case patients with spontaneous preterm birth at <37 weeks’ gestation (25.6% vs 15.9%; P = .055; odds ratio, 1.8; 95% confidence interval, 1.0-3.4) and at <35 weeks’ gestation (26.0% vs 14.9%; P = .105; odds ratio, 2.0; 95% confidence interval, 0.8-4.7) were almost twice as likely to have genitourinary tract C trachomatis infection present at either the 24 weeks’ gestation visit or the 28 weeks’ gestation visit. Also, although C trachomatis genitourinary infection was twice as common among case patients as among control subjects at both 24 and 28 weeks’ gestation, it was not significantly different between the 2 groups for spontaneous preterm birth at <37 weeks’ gestation (9.9% vs 5.0%; P = .142; odds ratio, 2.1; 95% confidence interval, 0.8-5.8) or at <35 weeks’ gestation (6.2% vs 4.6%; P > .999; odds ratio, 1.4; 95% confidence interval, 0.3-6.3). Numerous major risk factors for spontaneous preterm birth have been previously identified in the study population of 2929 women who participated in the Preterm Prediction Study. Reports describing these associated risk factors have been published elsewhere.18-21 In addition to bacterial vaginosis19 at 28 weeks’ gestation and the pres-
ence of cervical or vaginal fetal fibronectin (≥50 mg/mL),20 these risk factors included a low body mass index (<19.8 kg/m2)21 and a short cervical length (≤25 mm)18 as determined by transvaginal ultrasonography. In this case-control study all these major risk factors were significantly more common among the case patients than among the control subjects (Table II). A comparison of the frequencies of genitourinary tract C trachomatis infection among the case patients and among the control subjects evaluated in this investigation with these other established risk factors for spontaneous preterm birth is depicted in Table III. Women with chlamydia infection were significantly more likely than women without chlamydia infection at both the 24 and 28 weeks’ gestation visits to have bacterial vaginosis (P = .002 and P = .05, respectively). Women with C trachomatis infection at 24 weeks’ gestation (but not at 28 weeks’ gestation) were also more likely than uninfected women to have a short cervix (P = .02 and P = .12, respectively). No differences were observed at either gestational age between women with and without chlamydia infection in the frequencies of a positive cervical or vaginal fetal fibronectin test result (P = .78 and P = .14, respectively) and a body mass index <19.8 kg/m2 (P = .13 and P = .65, respectively; Table III). Logistic regression analyses were performed to adjust for risk factors found to be predictive of spontaneous preterm birth in the overall Preterm Prediction Study population. These included poor social environment, a previous spontaneous preterm birth, vaginal bleeding in the first or second trimester, urinary tract infections, a body mass index <19.8 kg/m2, a short cervix, African American race, bacterial vaginosis, and a positive fetal fibronectin
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Table II. Frequencies of selected risk factors for spontaneous preterm birth among case patients and control subjects at 24 weeks’ gestation and 28 weeks’ gestation visits Risk factor Bacterial vaginosis 24 wk 28 wk Short cervix (≤25 mm) 24 wk 28 wk Fetal fibronectin detected 24 wk 28 wk Low maternal body mass index (<19.8 kg/m2)
Table III. Frequencies of genitourinary tract C trachomatis infection among women with other established risk factors for spontaneous preterm birth at 24 weeks’ gestation and 28 weeks’ gestation visits Chlamydia infection
Case patients Control subjects Statistical (%, n = 190) (%, n = 190) significance Risk factor 39.5 32.8
31.8 20.5
P = .116 P = .028
30.2 39.3
09.0 17.1
P < .001 P < .001
16.8 13.0
01.6 04.5
P < .001 P = .031
30.6
19.6
P = .015
test result. Separate analyses were performed excluding previous spontaneous preterm birth from the regression model. The results of these analyses are depicted in Table IV. C trachomatis infection at 24 weeks’ gestation was associated with a 2-fold to 3-fold increased odds ratio for subsequent spontaneous preterm birth (<35 and <37 weeks’ gestation; Table IV). Although the odds ratio was even higher for spontaneous preterm birth at <32 weeks’ gestation when chlamydia infection was detected at 24 weeks’ gestation, this increase in the odds ratio was not statistically significant (Table IV). C trachomatis infection at 28 weeks’ gestation was not statistically associated with an increased odds ratio of spontaneous preterm birth (Table IV). Comment The potential association between chlamydia infection and spontaneous preterm birth remains a controversial subject and a topic of debate in perinatal medicine. This investigation offers the advantage of an extremely wellcharacterized study population with respect to pregnancy outcomes and risk factors for spontaneous preterm birth. In addition a sensitive, specific, and reliable means of testing for genitourinary tract infection with C trachomatis (ligase chain reaction) was used. In an unadjusted analysis women who subsequently had a spontaneous preterm birth were twice as likely to have a genitourinary tract infection with C trachomatis at 24 weeks’ gestation as were control women who were delivered at term. C trachomatis infection was also significantly associated with two established risk factors for spontaneous preterm birth in this population, bacterial vaginosis and short cervical length. However, it is interesting that C trachomatis infection was not significantly associated with two other established risk factors, low maternal body mass index and the cervical or vaginal presence of fetal fibronectin.
No. of women 24 wk 28 wk Bacterial vaginosis 24 wk 28 wk Short cervix (≤25 mm) 24 wk 28 wk Fetal fibronectin detection 24 wk 28 wk Low maternal body mass index (<19.8 kg/m2) 24 wk 28 wk
Yes (%)
42 27
No (%)
Statistical significance
338 193
57.1 41.4
32.9 24.6
P = .002 P = .054
33.0 40.0
17.9 26.2
P = .018 P = .115
7.1 0.0
9.5 9.8
P = .783 P = .139
35.0 20.7
23.9 24.5
P = .125 P = .649
When a multivariate analysis was performed to control for factors associated with spontaneous preterm birth in this population, including a history of previous spontaneous preterm birth, an association between genitourinary tract C trachomatis infection at 24 weeks’ gestation and subsequent spontaneous preterm birth was confirmed, with a 2-fold to 3-fold increased risk. The causal relationship between a history of previous preterm birth and the increased likelihood of another preterm birth is poorly understood and is probably multifactorial. Indeed, at least for some women a previous preterm birth may represent a surrogate variable for chlamydia infection. Thus it is debatable whether a history of previous preterm birth should be included in the logistic regression model. When such a history was excluded from the model, the point estimates of increased risk for spontaneous preterm birth with chlamydia infection at 24 weeks’ gestation remained almost unchanged. The results from both the univariate and multivariate analyses were consistent and support the conclusion that women with C trachomatis infection at 24 weeks’ gestation are at least twice as likely as those without this infection to have a subsequent spontaneous preterm birth. Our failure to confirm a statistically significant adjusted association between C trachomatis infection at 28 weeks’ gestation and subsequent spontaneous preterm birth may have resulted from an inadequate sample size or the case-control design. Although it was economically less feasible, a population-based study design with samples collected from all 2929 women enrolled in the Preterm Prediction Study might have resulted in a statistically significant adjusted odds ratio. In addition we could not control in this population for the potential effect of
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Table IV. Adjusted odds ratios for spontaneous preterm birth among women with C trachomatis infection at 24 or 28 weeks’ gestation Spontaneous preterm birth <32 wk
Regression model Previous spontaneous preterm birth included 24 wk 28 wk Previous spontaneous preterm birth excluded 24 wk 28 wk
Spontaneous preterm birth <35 wk
Spontaneous preterm birth <37 wk
Odds ratio
95% Confidence interval
Odds ratio
95% Confidence interval
Odds ratio
95% Confidence interval
5.0 —*
0.8-32.2 —*
2.8 1.1
0.90-8.81 0.25-4.61
2.3 0.95
1.01-5.03 0.36-2.47
5.2 —*
0.8-33.8 —*
3.2 0.8
1.08-9.57 0.19-3.27
2.4 0.8
1.08-5.29 0.31-2.04
Regression model includes or excludes previous spontaneous preterm birth as specified. *Sample size insufficient for analysis.
antibiotic treatment of C trachomatis infection that may have occurred before or after study enrollment. Many participants were screened and treated for C trachomatis infection according to individual protocols in place at the time of enrollment in each of the 10 participating centers. Data regarding the timing, screening results, and treatment of participants identified as having chlamydia infection were not recorded in the database. However, we are unaware of any current clinical recommendation to screen and treat chlamydia infection between 24 and 28 weeks’ gestational age. The results of the ligase chain reaction assays performed in this investigation were not available to clinicians providing prenatal care to participants in the observational Preterm Prediction Study. Indeed, this study was not conceived until after the Preterm Prediction Study had been completed. Thus these ligase chain reaction assays were performed in batches well after the completion of the Preterm Prediction Study. Although we cannot determine whether there was a difference in diagnosis and treatment of chlamydia infection during prenatal care between the case and control groups, neither do we have any reason to speculate that such a difference is likely to have occurred. However, it is possible that the observed results might be explained by a higher rate of chlamydia infection recurrence or treatment in the case group than in the control group. In addition, any deterioration of C trachomatis plasmid deoxyribonucleic acid during specimen storage that might have resulted in false-negative ligase chain reaction results would be anticipated to have occurred with equal frequencies among both the case patient and control subject specimens. The overall chlamydia infection rate in this study of 11% is reassuring that such specimen deterioration was not a major factor. This rate is consistent with findings previously reported in population studies with the ligase chain reaction technique.14-16 Sweet et al12 and Harrison et al10 have reported that women with chlamydia infection who are also immunoglobulin M seropositive may have a higher inci-
dence of low-birth-weight infants, premature deliveries, and premature rupture of membranes than either immunoglobulin M–seronegative women with chlamydia infection or women with cultures negative for C trachomatis. In other words, acute acquisition of C trachomatis infection may play a more important role than chronic infection as an associated risk factor for spontaneous preterm birth. Because the C trachomatis serologic status was unknown in our study, we could not control for this status in our analysis. Such knowledge might have allowed identification of a subgroup within our study population (those who were anti–chlamydial immunoglobulin M seropositive) in which an adjusted association between C trachomatis infection and spontaneous preterm birth might have been more definitively observed. The association between chlamydia infection and a short cervical length but not between chlamydia infection and a positive fetal fibronectin test result may provide an interesting clue to the mechanisms through which chlamydia infection might result in a spontaneous preterm birth. A prevailing hypothesis is that the presence of fetal fibronectin in cervical and vaginal secretions during the late second trimester is a marker for amniochorial matrix disruption, allowing this protein to “leak” down to the lower genital tract where it can then be detected. The absence of an association between genitourinary chlamydia infection and a positive fetal fibronectin test result is consistent with the observation that C trachomatis is rarely isolated from the amniotic fluid or amnion-chorion in pregnant women with spontaneous preterm labor or preterm premature rupture of membranes. Conversely, the association of chlamydia infection with a short cervical length may indicate that lower genital tract infection with this organism acts directly on the cervix to result in effacement, which may ultimately lead to preterm birth. If so, the mechanisms leading to preterm birth among women with chlamydia infection may be distinctly different from those associated with bacterial vaginosis which is more likely to be a lower genital
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tract marker of upper genital tract infection with bacterial vaginosis–associated microorganisms. Alternatively, a shortened cervical length resulting from C trachomatis infection could allow microorganisms normally confined to the lower genital tract to gain access to the upper genital tract, thereby resulting in an upper genital tract bacterial infection that would lead to a spontaneous preterm birth. If this mechanism prevailed, however, a significant relationship between chlamydia infection and a positive fetal fibronectin test result would have been anticipated. In conclusion, genitourinary C trachomatis infection was significantly more common among women with certain risk factors for spontaneous preterm birth, including bacterial vaginosis and a short cervical length. C trachomatis infection was not associated with other important risk factors, however, such as a low maternal body mass index or the presence of fetal fibronectin in cervical and vaginal secretions. After adjustment for established risk factors for spontaneous preterm birth women with genitourinary C trachomatis infection at 24 weeks’ gestation were 2 to 3 times as likely as women without this infection to have a spontaneous preterm birth. Whether the relationship between C trachomatis infection and spontaneous preterm birth is mediated through its association with bacterial vaginosis or short cervical length will require additional study. Whether universal screening and treatment for C trachomatis infection with a sensitive deoxyribonucleic acid amplification method for detection would significantly reduce spontaneous preterm delivery remains an unanswered question. It should be noted that the frequency of preterm birth in the United States has increased during recent years despite the recommendation of the Centers for Disease Control and Prevention for chlamydia infection screening among pregnant women. Ligase chain reaction assay kits were provided by Abbott Laboratories, Abbott Park, Ill. We acknowledge the participation of the following institutions and others who participated in the study: Rachel L. Copper, MSN, CRNP, John C. Hauth, MD, and Allison Northen, RN, The University of Alabama at Birmingham; Eberhard Meuller-Heubach, MD, Melissa Swain, RN, and Allison Frye, RN, Bowman Gray School of Medicine, Winston-Salem, NC; Marshall Lindheimer, MD, and Phyllis Jones, MPH, RN, University of Chicago; Tariq A. Siddiqi, MD, and Nancy Elder, MSN, RN, University of Cincinnati; Elizabeth Thom, PhD, Lucy Leuchtenburg, and Molly Fischer, MPH, CRNP, The Biostatistics Center, George Washington University, Bethesda, Md; James H. Harger, MD, Margaret Cotroneo, RN, and Cynthia Stallings, MSN, Magee Women’s Hospital, Pittsburgh, Pa; Sumner J. Yaffe, MD, Charlotte Catz, MD, and Mark Klebanoff, MD, the National Institute of Child Health and Human Development, Bethesda, Md; Francee Johnson, RN, BSN, and Mark B. Landon, MD, The Ohio State University, Columbus; J. Christopher
Carey, MD, and Arlene Meier, RN, University of Oklahoma, Oklahoma City; Roger B. Newman, MD, Beth A. Collins, PhD, RNC, and Faye LeBoeuf, MSN, CNM, Medical University of South Carolina, Charleston; Baha Sibai, MD, Risa Ramsey, BSN, RN, and Joyce Fricke, RNC, University of Tennessee, Memphis; Sydney F. Bottoms, MD (deceased), and Gwendolyn S. Norman, MPH, RN, Wayne State University, Detroit, Mich. REFERENCES
1. Centers for Disease Control and Prevention. Recommendations for the prevention and management of Chlamydia trachomatis infections, 1993. MMWR Morb Mortal Wkly Rep 1993;42(RR12):1-39. 2. Andrews WW, Goldenberg RL, Hauth JC. Preterm labor: emerging role of genital tract infections. Infect Agents Dis 1995;4:196211. 3. Alger LS, Lovchik JC, Hebel JR, Blackmon LR, Crenshaw MC. The association of Chlamydia trachomatis, Neisseria gonorrhoeae, and group B streptococci with preterm rupture of the membranes and pregnancy outcome. Am J Obstet Gynecol 1988;159: 397-404. 4. Gravett MG, Nelson HP, DeRouen T, Crichlow C, Eschenbach DA, Holmes KK. Independent associations of bacterial vaginosis and chlamydia trachomatis infection with adverse pregnancy outcome. JAMA 1986;256:1899-903. 5. Martin DH, Koutsky L, Eschenbach DA, Daling JR, Alexander ER, Benedetti JK, et al. Prematurity and perinatal mortality in pregnancies complicated by maternal Chlamydia trachomatis infections. JAMA 1982;247:1585-8. 6. Martius J, Krohn MA, Hillier SL, Stamm WE, Holmes KK, Eschenbach DA. Relationships of vaginal Lactobacillus species, cervical Chlamydia trachomatis, and bacterial vaginosis to preterm birth. Obstet Gynecol 1988;71:89-95. 7. The Johns Hopkins Study of Cervicitis and Adverse Pregnancy Outcome. Association of Chlamydia trachomatis and Mycoplasma hominis with intrauterine growth retardation and preterm delivery. Am J Epidemiol 1989;129:1247-57. 8. Claman P, Toye B, Peeling RW, Jessamine P, Belcher J. Serologic evidence of Chlamydia trachomatis infection and risk of preterm birth. CMAJ 1995;153:259-62. 9. Hardy PH, Hardy JB, Nell EE, Graham DA, Spence MR, Rosenbaum RC. Prevalence of six sexually transmitted disease agents among pregnant inner-city adolescents and pregnancy outcome. Lancet 1984;2:333-7. 10. Harrison HR, Alexander ER, Weinstein L, Lewis M, Nash M, Sim DA. Cervical Chlamydia trachomatis and mycoplasmal infections in pregnancy: epidemiology and outcomes. JAMA 1983;250: 1721-7. 11. Thompson S, Lopez B, Wong KH, Ramsey C, Thomas T, Reising C, et al. A prospective study of chlamydia and mycoplasmal infections during pregnancy. In: Mardh PA, Holmes KK, Oriel JD, Piat P, Schachter J, editors. Chlamydial infections. Amsterdam: Elsevier; 1982. p. 155-8. 12. Sweet RL, Landers DV, Walker C, Schachter J. Chlamydia trachomatis infection and pregnancy outcome. Am J Obstet Gynecol 1987;156:824-33. 13. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 1998;47(RR-1):1-111. 14. Schachter J, Moncada J, Whidden R, Shaw H, Bolan G, Burczak JD, et al. Noninvasive tests for the diagnosis of Chlamydia trachomatis infection: application of a ligase chain reaction to firstcatch urine specimens of women. J Infect Dis 1995;172:1411-4. 15. Lee HH, Chernesky MA, Schachter J, Burczak JD, Andrews WW, Muldoon S, et al. Diagnosis of Chlamydia trachomatis genitourinary tract infection in women by ligase chain reaction in urine. Lancet 1995;345:213-6. 16. Andrews WW, Lee HH, Roden WJ, Mott CW. Detection of genitourinary tract Chlamydia trachomatis infection in pregnant
668 Andrews et al
women by ligase chain reaction assay. Obstet Gynecol 1997;89: 556-60. 17. Schachter J, Stamm WE, Quinn TC, Andrews WW, Burczak JD, Lee HH. Ligase chain reaction to detect Chlamydia trachomatis infection of the cervix. J Clin Microbiol 1994;32:2540-3. 18. Iams JD, Goldenberg RL, Meis PJ, Mercer BM, Moawad A, Das A, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. N Engl J Med 1996;334:567-72. 19. Meis PJ, Goldenberg RL, Mercer B, Moawad A, Das A, McNellis D, et al. The Preterm Prediction Study: significance of vaginal in-
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fections. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 1995;173:1231-5. 20. Goldenberg RL, Mercer BM, Meis PJ, Copper RL, Das A, McNellis D, et al. The Preterm Prediction Study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal-Fetal Medicine Units Network. Obstet Gynecol 1996;87:643-8. 21. Goldenberg RL, Iams JD, Mercer BM, Meis PJ, Moawad AH, Copper RL, et al. The Preterm Prediction Study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network. Am J Public Health 1998;88:233-8.
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