By Heidi D. Nelson, M.D., M.P.H.a and Mark Helfand, M.D., M.S.a
Address correspondence to: Heidi D. Nelson, M.D., M.P.H., Oregon Health Sciences University, Division of Medical Informatics & Outcomes Research, 3181 SW Sam Jackson Park Road, Mailcode BICC, Portland, OR 97201-3098.
This article originally appeared in the American Journal of Preventive Medicine. Select for copyright and source information.
The summaries of the evidence briefly present evidence of effectiveness for preventive health services used in primary care clinical settings, including screening tests, counseling, and chemoprevention. They summarize the more detailed Systematic Evidence Reviews, which are used by the third U.S. Preventive Services Task Force (USPSTF) to make recommendations.
Abstract
Introduction
Methods
Analytic Framework and Key Questions
Literature Search and Synthesis
Results
Does Screening Reduce Adverse Health Outcomes?
Does Screening Reduce the Prevalence of Infection?
Are Risk Factors Useful for Selective Screening?
What Screening Tests Should Be Performed?
What Are the Implications of Recurrent Infection?
Harms and Costs of Screening
Discussion
Acknowledgements
References and Notes
Objectives: To examine data on the effectiveness of screening for chlamydial infection by a physician or other health care professional. Specifically, we examine the evidence that early treatment of chlamydial infection improves health outcomes, as well as evidence of the effectiveness of screening strategies in nonpregnant women, pregnant women, and men, and the accuracy of tests used for screening. This review updates the literature since the last recommendation of the U.S. Preventive Services Task Force published in 1996.
Search Strategy: We searched the topic of chlamydia in the MEDLINE, HealthSTAR, and Cochrane Library databases from January 1994 to July 2000, supplemented by reference lists of relevant articles and from experts in the field. Articles published prior to 1994 and research abstracts were cited if particularly important to the key questions or to the interpretation of included articles.
Selection Criteria: A single reader reviewed all English abstracts. Articles were selected for full review if they were about Chlamydia trachomatis genitourinary infections in nonpregnant women, pregnant women, or men and were relevant to key questions in the analytic framework. Investigators read the full-text version of the retrieved articles and applied additional eligibility criteria. For all topics, we excluded articles if they did not provide sufficient information to determine the methods for selecting subjects and for analyzing data.
Data Collection and Analysis: We systematically reviewed three types of studies about screening in nonpregnant women that relate to three key questions: (1) studies about the effectiveness of screening programs in reducing prevalence rates of infection, (2) studies about risk factors for chlamydial infection in women, and (3) studies about chlamydial screening tests in women. Our search found too few studies on pregnant women to systematically review, although pertinent studies are described. We systematically reviewed two types of studies about screening in men: (1) studies about prevalence rates and risk factors for chlamydial infection in men and (2) studies about chlamydial screening tests in men.
Main Results: Nonpregnant women. The results of a randomized controlled trial conducted in a large health maintenance organization indicate that screening women selected by a set of risk factors reduces the incidence of pelvic inflammatory disease (PID) over a 1-year period. Changes in population prevalence rates have not been well documented because few studies have employed a representative population sample. Age continues to be the best predictor of chlamydial infection in women, with most studies evaluating cut-offs at age younger than 25 years. Other risk factors may be useful predictors, but these are likely to be population specific. To determine the accuracy of screening tests for women, we retrieved and critically reviewed 34 articles on test performance. Results indicate that endocervical swab specimens and first-void urine specimens have similar performance when using DNA amplification tests and have better sensitivity than endocervical culture. Recurrent chlamydial infections in women have been associated with increased risks for PID and ectopic pregnancies.
Pregnant women. The Second Task Force recommendations for screening pregnant women were based on two major studies demonstrating improved pregnancy outcomes following treatment of chlamydial infection. We identified no recent studies on this topic in our literature search. Very few studies describe risk factors for chlamydial infection in pregnant women. Nonculture testing techniques appear to perform well in pregnant women, although studies are limited.
Men. No studies described the effectiveness of screening or early treatment for men in reducing transmission to women or in preventing acute infections or complications in men. Studies of prevalence rates and risk factors for chlamydial infection in men are limited. Age lower than 25 years is the strongest known risk factor cited so far. Results of urethral swab specimens compared to first-void urine specimens were similar for DNA amplification tests. DNA amplification techniques are more sensitive than culture.
Conclusions: Screening women for Chlamydia trachomatis reduces the incidence of PID, and it is associated with reductions in prevalence of infection in uncontrolled studies. No studies were found to determine whether screening asymptomatic men would reduce transmission or prevent acute infections or complications. Age is the strongest risk factor for men and women. A variety of tests can detect chlamydial infection with acceptable sensitivity and specificity, including new DNA amplification tests that use either endocervical swabs in women, urethral swabs in men, or first-void urine specimens from men and women.
Keywords: Chlamydia trachomatis; risk factors; mass screening; preventive health services; evidence-based medicine; MEDLINE; methods; pregnancy; men; women.
In the United States, Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen. There are estimated to be three million new infections each year (1,2). Chlamydial genital tract infections are a major cause of urethritis, cervicitis, and pelvic inflammatory disease (PID) in women and are an important cause of ectopic pregnancy, infertility, and chronic pelvic pain. Chlamydial infections are responsible for 25% to 50% of the 2.5 million cases of PID that are reported annually in the United States (3). Infections are also related to adverse pregnancy outcomes such as miscarriage, premature rupture of membranes (4-6), preterm labor (4), low birth weight infants (4-7), infant mortality (5,7), and postpartum infections. Perinatal transmission to infants can cause neonatal conjunctivitis and pneumonia (8). Chlamydial infection in men is the cause of 30% to 40% of the four to six million visits each year for nongonococcal urethritis and 50% of more than 150,000 cases of acute epididymitis (9). Rarely, men may experience chronic complications of chronic prostatitis, reactive arthritis (10,11), urethral strictures (12), and possibly infertility (13). Chlamydia is a cofactor in transmission of human immunodeficiency virus infection (14,15). In the United States in 1994, the estimated cost of untreated chlamydial infections and their complications was $2 billion (16).
Seventy percent to ninety percent of women and a large percentage of men are asymptomatic (17-20). Because most men tested for chlamydia are those who present for care because they are symptomatic, or because they are a sexual contact of an infected woman, it is likely that a high proportion of infected men are asymptomatic. Untreated asymptomatic infections among women often persist for months (21) and have been associated with infertility and ectopic pregnancy. Complications of chlamydial infections may be due to immunopathologically mediated events related to predisposition of specific individuals as well as to the type of chlamydial strain (22). Young women may be particularly susceptible because of increased cervical columnar epithelium in this age group (19). Chlamydia is readily transmitted between sexual partners (23), and infected men and women without symptoms serve as important reservoirs for new infections. Rates of hospitalization for ectopic pregnancy and PID increase with the number of recurrent chlamydial infections in women (24).
The prevalence of chlamydial infection varies from less than 1% to nearly 40%, depending on the population. Chlamydia has the highest prevalence among groups who are least likely to regularly see a physician. Age is the strongest predictor of infection, with adolescent girls and young adult men recording the highest rates. Most screening programs target young women in sexually transmitted disease (STD) or family planning clinics to take advantage of the opportunity to obtain diagnostic tests in the context of other services. Young men have been much more difficult to study and screen, but their roles in transmitting initial and recurrent infections to women are important. Others considered at higher risk include those having multiple sexual partners (25-32), a new sexual partner (31,32), or an infected sexual partner (28, 32-34); those who inconsistently use barrier contraceptives (31,32,34); those with previous (31-33) or coexistent STDs (35,36); and women with abnormalities on examination, such as vaginal discharge, cervicitis, cervical friability, and cervical ectopy (25,27,28,30,32,35,37,38). Race is independently associated with chlamydial infection (25, 26, 28, 31-33, 36). Even in populations without these risk factors, however, prevalence rates of more than 5% can occur (9,32,39).
Culture analysis of endocervical or urethral swab specimens was traditionally considered the diagnostic gold standard for chlamydial infection. Culture technology posed methodologic problems and is not widely available, however, and nonculture tests that use swab specimens were developed next to improve on some of the limitations of culture. These tests initially included antigen detection tests (direct fluorescent antibody [DFA] assay, enzyme immunoassay [EIA]) and nonamplified nucleic acid hybridization. Newer technologies are based on amplified DNA assays (polymerase chain reaction [PCR], ligase chain reaction [LCR], strand displacement assay [SDA], hybrid capture system [HCS]) and transcription-mediated amplification (TMA) of RNA. New tests using urine specimens provide a noninvasive method for both men and women.
Although culture is 100% specific for chlamydial infection (i.e., no false positives), there is growing recognition that culture is not 100% sensitive and is, therefore, not an acceptable gold standard for assessing newer diagnostic technologies. Investigators have advocated the use of an "expanded gold standard" for the calculation of sensitivity and specificity of assays. In this case, a positive result is defined by a positive culture, or a negative culture with either a positive PCR or LCR test that has been confirmed positive by a DFA assay, or a PCR or LCR test directed against the major outer membrane protein. In these studies, however, the additional confirmation tests are usually performed only on specimens that had discrepant results from two or more other tests. These tests themselves often constitute part of the expanded gold standard, particularly when culture is not used in the study. Although use of "discrepant analysis" is very common in test performance studies, it is biased and can overestimate sensitivity and specificity results, depending on the reference test (40).
Effective and low-cost treatment is available for chlamydial infections of the genital tract. Results of clinical trials indicate that a 7-day course of doxycycline or a single-dose of azithromycin are equally efficacious and lead to high cure rates (97%) in nonpregnant women and men (9, 41-44). A Cochrane review of 11 trials for treatment in pregnancy concluded that amoxicillin was as effective as erythromycin in achieving microbiologic cure (few trials are available for other drugs) (45). These drugs are orally administered and are generally well tolerated.
The purpose of this review is to update the evidence on the effectiveness of screening for chlamydial infection by a physician or other health care professional in a clinical setting since the second U.S. Preventive Services Task Force considered it in 1996. Specifically, we examine the evidence that early treatment of chlamydial infection improves health outcomes, as well as evidence of the effectiveness of screening strategies in nonpregnant women, pregnant women, and men, and the accuracy of tests used for screening.
We defined screening to include testing of asymptomatic persons, and "casefinding" testing of those found to have another sexually transmitted infection or symptom. Universal screening means testing everyone regardless of symptoms or risk factors; selective screening indicates that only those who meet specific criteria are tested.
The analytic framework in Figure 1 (9 KB) indicates the strategy that we used to guide our literature search about screening nonpregnant women, pregnant women, and men. Key questions were identified as areas with unresolved issues pertinent to clinical practice that had new literature published since the last Task Force recommendations were published in 1996. These key questions correspond to selected arrows in the analytic framework and include:
We searched the topic of chlamydia in the MEDLINE, HealthSTAR, and Cochrane Library databases from January 1994 through July 2000. A single reader reviewed all English abstracts. Articles were selected for full review if they were about Chlamydia trachomatis genitourinary infections in nonpregnant women, pregnant women, or men and were relevant to key questions in the analytic framework. Reviewing reference lists of other relevant articles and consulting experts in the field identified additional studies. Articles published prior to 1994 and research abstracts were cited if particularly important to the key questions or to the interpretation of included articles.
For our review of diagnostic tests, we focused on the new DNA amplification tests that use both swab and urine specimens. Studies comparing antigen detection tests that use swab specimens with culture were not reviewed here because the performance of antigen detection tests has been previously acknowledged, and they are currently widely used in clinical practice. Antigen detection tests that use urine samples were also not reviewed because they have low sensitivity and are not recommended.
We assigned evidence codes and quality ratings to all studies based on criteria developed by the U.S. Preventive Services Task Force. To demonstrate screening strategy outcomes, we developed a balance sheet that compared three populations, including a low- risk health maintenance organization (HMO) population using a risk factor questionnaire and assumptions from a randomized, controlled trial of screening (46), a theoretical high-risk population, and a theoretical low-risk population not using a risk factor questionnaire.
Nonpregnant women: We systematically reviewed three types of studies about screening nonpregnant women: (1) studies about the effectiveness of screening programs in reducing prevalence rates of infection, (2) studies about risk factors for chlamydial infection in women, and (3) studies about chlamydia screening tests in women.
Studies about screening programs were included if they provided descriptions of the study population, features of the screening program, and prevalence rates at the beginning of the study period compared to those at a point in time several years later. Studies of risk factors for chlamydial infection were included if they reported descriptions of the study population, screening criteria (universal vs selective), type of chlamydial test, other forms of data collection (e.g., questionnaire), and prevalence rate of the tested population. We also reviewed studies of new DNA amplification tests that used both swab and urine specimens. Studies of test performance were included only if they met quality criteria, including (1) the test was appropriately performed in a standardized manner; (2) the index test, gold standard/expanded gold standard, and discrepant test were appropriately used; (3) the study population was adequately described; and (4) data were sufficient to determine the sensitivity and specificity of tests. We abstracted data about the test, study population, and outcome measures such as sensitivity, specificity, and positive and negative predictive values.
Pregnant women: Our search found too few studies on pregnant women to apply review criteria. Individual studies related to key questions are described in this report.
Men: We reviewed two types of studies about screening men: (1) studies about risk factors for chlamydial infection in men and (2) studies about chlamydial screening tests in men. Studies about chlamydial risk factors in men were included if they described the study population, type of test used, prevalence, and significant associations of risk factors with infection. Studies of chlamydial screening tests for men were abstracted in a similar way as that described for women. We focused particularly on the performance of tests that used urine specimens because this type of testing would have the biggest effect on screening strategies for men.
Nonpregnant women: The best evidence to date about the effectiveness of screening for chlamydial infection in preventing PID is a good quality, randomized controlled trial conducted in a large HMO population in Seattle (46). Screening and treatment of chlamydial infections in unmarried, asymptomatic women aged 18 to 34 years in this study were associated with a significantly reduced incidence of PID after 1 year of follow-up. Inclusion criteria for subjects were based on an earlier study of chlamydia prevalence and risk factors conducted in the primary care clinics of the same HMO (47). On the basis of responses to a mailed questionnaire, women were assigned a risk score determined by age (24 years or LESS=1 point), race (black=2 points), nulligravidity (1 point), douching (1 point), and having two or more sexual partners in the preceding 12 months (1 point). Those with a score of 3 or more were eligible for the screening trial and were randomly assigned to screening or usual-care groups.
A total of 645 women in the screening group (64% of eligible subjects) were tested for chlamydia, and 7% had positive tests and were treated. The 1598 women in the usual-care group were not tested. After 12 months, there were 9 confirmed cases of PID among women in the screening group (1.4%), and 33 among women in usual care (2.1%) (relative RISK=0.44; 95% confidence interval [CI]=0.20 to 0.90). Adjustment for various combinations of baseline characteristics did not alter the reduction in risk of PID associated with screening.
Long-term outcomes such as rates of recurrences, ectopic pregnancies, infertility, or chronic pelvic pain were not addressed in this study. Also, women younger than age 18 years, a group with generally higher prevalence rates than older women, were not included.
Two Swedish ecologic analyses of chlamydia screening and reduction of PID and ectopic pregnancies support the findings of the screening trial (48,49).
Pregnant women: The previous Task Force recommendations for screening pregnant women were based on two studies that demonstrated improved pregnancy outcomes following treatment of chlamydial infection. In a time-series design study, untreated patients had a significantly higher incidence of premature rupture of membranes and low birth weight as well as a lower infant survival rate compared to treated patients and patients with negative cultures (5). In a case-control study, the frequencies of premature rupture of membranes, premature contractions, and small-for-gestational-age infants were significantly lower among successfully treated patients compared to chlamydia-positive patients who were unresponsive to treatment, but they were not significantly different when compared to chlamydia-negative control patients (4). We identified no recent studies on this topic.
Men: No studies were found that described the effectiveness of screening or early treatment for men in reducing transmission to women or of preventing acute infections or complications in men. Many investigators advocate screening men as the next essential step to reduce infections, complications, and recurrences in women, as well as to improve the health of men themselves. However, these health outcomes have not yet been studied.
No adequately controlled study has prospectively addressed this question, although several studies have been published that report declining prevalence rates in women after instituting chlamydia testing and treatment programs (39, 50-54). Changes in population prevalence rates have not been well documented because few studies have employed a representative population sample. Other unmeasured factors, such as condom use, changes in sexual behavior, and changes in testing methods (55), could also be responsible for changes in prevalence rates.
Nonpregnant women: Several studies describe risk factors for chlamydial infection among women tested in military, community, primary care, family planning, and STD clinics. Nearly all studies, representing a wide range of settings and prevalence rates (2.3% to 21.5%), report age as an important predictor (usually expressed as less than 25 years old). Current Task Force guidelines (56), and those of the Centers for Disease Control and Prevention (CDC) (9), already use age as the primary determinant for screening. Sociodemographic factors such as black and other nonwhite race, marital status, urban location, and low income were also associated with infection in some studies (25, 26, 28, 31-33, 36, 37). Behavioral risk factors cited in these studies include multiple sexual partners, new partners, partner with symptoms of an STD, and inconsistent or no barrier contraception use (25-34, 57). Personal history of PID, STD, pregnancy, douching, and oral contraceptive use were also noted as risk factors in some studies (26-32). Most studies found that physical findings, symptoms, and coexistent gonorrheal infection were also predictive of chlamydial infection (25, 27, 28, 30, 32, 35-38). These factors, however, would necessitate chlamydial testing for reasons other than screening and would not be helpful in forming a selective screening strategy. Inconsistencies between studies are likely due to the different populations and risk factors examined.
One of the largest studies of risk factors universally screened 13,204 asymptomatic female U.S. Army recruits from 50 states with urine LCR and found a prevalence rate of 9.2% (31). Independent predictors for infection included age younger than 25 years, black or other nonwhite race, more than one sexual partner or a new partner in the previous 90 days, not using a condom, and history of a previous STD. When the investigators tested the value of selective screening criteria in this population by using the risk factors of age younger than 25 years, more than one partner or a new partner in the previous 90 days, failure to use condoms in the previous 90 days, or history of a previous STD, they found that virtually all of the population would be eligible for screening. If they limited their screening to all women aged 25 years or younger, 87.9% of the population would need to be tested, and 95.3% of the positive subjects would be identified. Other studies found that use of age alone or in combination with one or two other variables (race, marital status, symptoms, or physical findings) as screening criteria could lead to the detection of 85% to 95% of infections (25,36,37,58). Another study of 28,000 women aged 15 to 19 years seeking care in family planning clinics in the northwestern United States also identified several factors independently associated with chlamydial infection (32,39). No single risk factor or combination of risk factors was particularly sensitive for selective screening. The lowest-risk group in this study, representing 21% of the total, accounted for 17% of all infections and had a 6% chlamydial prevalence rate (overall prevalence was 12.3%). Two other studies conducted in settings with greater than 20% prevalence rates also concluded that no risk factors could adequately select which women to screen in their populations (34,38).
The usefulness of three sets of selective screening criteria was evaluated by using data from more than 37,000 female patients with risk factor information who were originally all universally tested in family planning and STD clinics (59). Criteria based on age alone (younger than age 25 years) performed best among women from family planning clinics with lower prevalence rates (3.3%) than the STD clinics (6.6%), detecting 84% to 92% of cases by screening 59% to 71% of women.
A similar study that tested sets of screening criteria, including age alone, in 6672 women in public family planning and STD clinics in North Carolina found sensitivities of criteria, ranging from 0.50 to 0.97, and specificities from 0.05 to 0.66 (60). The best-performing criteria were age alone and those based on scores calculated from a set of risk factors determined from a study from an HMO population in Seattle (47).
Pregnant women: Previous studies reported prevalence rates for chlamydial infections in pregnant women, ranging from 2% to 31%. Very few studies describe risk factors for chlamydial infection in pregnant women, but, in general, they are similar to those for nonpregnant women with the addition of late onset of prenatal care (61,62).
Men: Risk factors for chlamydial infections in men have been much less studied than for women. The most cited risk factor is age, with men younger than 25 years considered at higher risk than older men. Peak incidence occurs among older adolescents and younger adult men. A multiple-site study of adolescents in Seattle reported a prevalence rate of 5.4% by urine LCR and increased risk of infection for nonwhite race or ethnicity, two or more sexual partners in the previous 2 months, presence of symptoms, and increasing age within the cohort (63). Using a condom was associated with a reduced risk of infection. Other studies concurred that age groups younger than 25 years were at increased risk of infection (29,38,54,64,65). One of these studies reported elevated odds ratios for chlamydial infection with early onset of sexual activity (younger than age 13 years) and with known STD in a partner (38).
An abstract of findings from the 1995 National Survey of Adolescent Males indicated prevalence rates for chlamydia tested by urine PCR in a national household survey performed in the United States (66). The prevalence among sexually active men aged 18 to 19 years was 4.2% (95% CI=1.9 to 6.5), and among single, non-cohabiting sexually active men aged 22 to 26 years it was 8.3% (95% CI=4.2 to 12.3). Rates varied by racial groups, with black men aged 18 to 19 years having rates of 15.4% (95% CI=8.6 to 22.1) and white men with rates of 1.2% (95% CI=0.0 to 2.9).
A research abstract from the CDC found that, among 4797 asymptomatic men presenting to STD clinics in Ohio, those younger than 30 years, with more than one sexual partner in the past month, or with a sexual partner with syphilis had higher risk for chlamydial infection (67). Use of these risk factors as screening criteria in this low prevalence cohort (1.3%) would have resulted in screening 73% of men and detecting 93% of infections. No studies have been published, however, that prospectively test risk factor screening criteria in men.