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Assessing Trends in Chlamydia Positivity and Gonorrhea Incidence and Their Associations With the Incidence of Pelvic Inflammatory Disease and Ectopic Pregnancy in Washington State, 1988–2010

Moore, Miranda S. MPH*; Golden, Matthew R. MD, MPH*†‡; Scholes, Delia PhD; Kerani, Roxanne P. PhD, MPH*†‡

Sexually Transmitted Diseases: January 2016 - Volume 43 - Issue 1 - p 2–8
doi: 10.1097/OLQ.0000000000000352
Original Study
Free
SDC

Background Chlamydia and gonorrhea screening for women is beneficial if it prevents serious reproductive sequelae, such as pelvic inflammatory disease (PID) and ectopic pregnancy (EP). We assessed trends in PID and EP among women in Washington and their association with gonorrhea incidence and chlamydia positivity in a screened population of women over a 23 year period.

Methods Using data on chlamydia positivity from the Infertility Prevention Project, gonorrhea incidence from state surveillance, and PID and EP hospitalizations from hospital discharge records, we assessed trends in each condition over time. In addition, we estimated total incidence of PID and EP by incorporating information on outpatient-treated cases in alternative populations using a Bayesian approach that accounted for uncertainty in the estimates. We assessed associations between each infection and PID/EP using a linear regression model that accounts for year-to-year correlation in data points.

Results We observed substantial declines in both infections and in each outcome over time. For every 2% decrease in chlamydia positivity, there was a 35.7/100,000 decrease in estimated total PID incidence (P = 0.058) and 184.4/100,000 decrease in estimated total EP (P = 0.149). For every 32/100,000 decline in gonorrhea incidence, there was a 16.5/100,000 decrease in total PID (P = 0.292) and 159.8/100,000 decrease in total EP (P = 0.020). The associations with inpatient PID and EP were highly significant for both chlamydia and gonorrhea.

Conclusions These ecological data note concurrent and substantial declines in chlamydia positivity and gonorrhea incidence, and in PID and EP incidence in Washington from 1988 to 2010 during a time when widespread chlamydia screening was ongoing.

Chlamydia, gonorrhea, pelvic inflammatory disease, and ectopic pregnancy declined in women in Washington State from1988 to 2010. However, associations between trends in infections and their sequelae are not consistently significant.

From the *Department of Epidemiology, University of Washington School of Public Health, Seattle, WA; †Public Health–Seattle & King County, Seattle, WA; ‡Department of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, WA; and §Group Health Research Institute, Group Health Cooperative, Seattle, WA

Conflict of interest and sources of funding: The authors declare no conflicts of interest. Miranda Moore was partially funded by the de Beaumont Foundation as part of the Epi Scholars Program.

Correspondence: Roxanne Kerani, PhD, MPH, Harborview Medical Center, Box 359931, 325 9th Ave Seattle, WA 98104. E-mail: rkerani@uw.edu.

Received for publication December 12, 2014, and accepted July 28, 2015.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (http://www.stdjournal.com).

Infection with Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG), the 2 most common nationally notifiable conditions in the United States, cause serious reproductive complications, including pelvic inflammatory disease (PID), ectopic pregnancy (EP),1–3 female infertility, and chronic pelvic pain. An estimated 25% to 50% of PID cases and 40% of ectopic pregnancies are attributable to CT infection,4–6 whereas the proportion of PID and EP cases attributable to gonorrhea is less well defined and likely varies widely.4,7

Large-scale screening for CT in Washington State (WA) was offered beginning in 1988 to test young, sexually active women attending family planning clinics.8 Screening efforts expanded within WA, as well as in other regions of the country, with increased funding from the Centers for Disease Control and Prevention (CDC) by additionally offering screening to attendees of sexually transmitted disease (STD), community health, and other clinics; these screening programs became known as the Infertility Prevention Project (IPP). N. gonorrhoeae screening was also gradually incorporated into the program. The primary goals of the program were to reduce CT infections and prevent associated infertility. The IPP is no longer being supported by CDC as a standalone program; the last year IPP positivity data were sent to CDC was 2011.

Screening for CT and NG is intended to reduce associated morbidity, such as PID, by identifying and treating infected individuals. However, the role of screening in reducing rates of adverse outcomes continues to be debated. Three randomized controlled trials observed a lower incidence of PID in women screened for CT than in the control groups.9–11 Although the trial findings have been consistent, the randomized controlled trials have been criticized on various grounds, and observational study findings have not been consistent.6,12–14 Population-level ecological studies have noted an association between measures of declining CT infection and declines in PID and EP.15–19 However, many of these studies relied on hospital discharge data to evaluate PID and EP trends, potentially resulting in misleading associations as treatment of both conditions has increasingly shifted to the outpatient setting.20,21

With systematic and large-scale screening for CT in place in WA between 1988 and 2010, we examined how the incidence of PID and EP changed throughout the state and whether these trends corresponded to changes in CT infections in a screened population over the same time. In addition, we examined the association of PID/EP incidence with NG incidence in women over time, as NG is also an important risk factor for PID and EP. Unlike previous ecological studies of surveillance data, we also estimated the contribution of outpatient cases to the overall incidence of PID and EP and evaluated statewide trends in each from the time widespread screening began. These results describe the changing burden of each condition in WA and may inform the ongoing discussion of the value of large-scale CT and NG screening programs.

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MATERIALS AND METHODS

CT Positivity, NG Incidence, and Associated Outcomes

The number of CT cases detected depends partially on the population being screened and the number and type of tests performed.22,23 Therefore, determining the true incidence or prevalence of CT from screened populations alone is difficult. In particular, different age and racial distributions of the screened population and the switch to nucleic acid amplification tests in the late 1990s increase the likelihood of a positive test result.16,24,25 Therefore, positivity, the proportion of positive test results out of all positive and negative test results performed, is frequently used as an alternative measure of CT burden.26

We calculated CT positivity among WA women 15 to 24 years old screened through IPP from 1988 to 2010 and through Planned Parenthood of Western Washington clinics from 2008 to 2010 (Planned Parenthood of Western Washington participated in IPP, but after 2007 tested only their uninsured women through IPP and their insured women through their own laboratories). The types of participating clinics changed during the course of IPP; until 1993, only family planning clinics participated, with other clinic types joining over time, including STD, community health, juvenile detention, and school health clinics. Given that each of these clinic types may serve different patient populations, and because of the change in test technology during the study period, we also calculated adjusted positivity. We adjusted positivity using a generalized linear-mixed model (SAS GLMMIX procedure; SAS Institute Inc, Cary, NC) with a random intercept and binary outcome, which calculates the conditional probability of a positive test result given a combination of fixed and random effects. We adjusted for age (15–17, 18–20, and 21–24 years), race/ethnicity (white, black, Hispanic, American Indian/Alaska Native, Asian/Pacific Islander, other), test type (nucleic acid test or other), and year as fixed effects and a clinic identifier as a random effect. These methods were similar to those performed by Fine et al.24 to adjust positivity.

We calculated annual NG incidence using the number of cases in all women reported to the WA Department of Health from 1988 to 2010 and WA Office of Financial Management intercensal female population estimates for denominators. We calculated NG incidence instead of positivity because early IPP testing did not include NG. In addition, we calculated NG incidence in all women instead of only those 15 to 24 years old because individual-level electronic NG reports are not available before 1992, and thus, only aggregate counts, instead of age-level data, are available for 1988 to 1991.

We identified inpatient PID and EP among WA women 15 to 44 years old from 1988 to 2010 using WA's Comprehensive Hospital Abstract Reporting System database. Table 1 displays International Classification of Diseases, Ninth Revision codes used for PID and EP case identification. We used Washington State Office of Financial Management estimates of women 15 to 44 years old and all pregnancies (live births, fetal deaths, abortions, and EP) among women 15 to 44 years old from WA vital statistics records as denominators for annual PID and EP incidence, respectively.

TABLE 1

TABLE 1

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Outpatient PID and EP Incidence

Because we did not have access to data on the total number of outpatient cases of PID and EP in WA, we used other data sources to estimate outpatient incidence of each condition. The National Disease and Therapeutic Index (NDTI) provides estimated counts of outpatient PID in the United States.27 Details of NDTI sampling methods are published elsewhere.28 We calculated the annual incidence of outpatient-treated PID nationally as a proxy for WA incidence, using case counts from NDTI between 1988 and 2010 as the numerator and US Census midyear population estimates of women 15 to 44 years old as the denominator. In addition, we calculated the national annual incidence of inpatient PID between 1988 and 2010 using information from the National Hospital Discharge Survey27,29 and the same denominator as for outpatient incidence.

We used data from a specific WA population—WA women enrolled in Group Health Cooperative (GH)—to estimate trends in outpatient treatment of EP. Group Health Cooperative is a mixed-model health maintenance organization that is generally representative of the broader WA population; in 2004, approximately 95,000 women aged 15 to 44 years were enrolled in GH.20 We obtained yearly counts of inpatient and outpatient EP cases and all pregnancies (live births, induced abortions, and EP) seen in GH health care facilities between 1993 and 2007. With this, we calculated the annual outpatient and inpatient EP incidence in GH.

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Estimating Total PID and EP Incidence

We estimated the incidence of total cases of PID and EP in WA by combining inpatient incidence calculated from the Comprehensive Hospital Abstract Reporting System and outpatient incidence calculated from the GH or national populations using a Bayesian approach to incorporate uncertainty in those estimates. Details of this approach have been published elsewhere.30,31

For this analysis, we assumed that at least the trend in outpatient incidence of PID and EP would be similar in WA and the national/GH populations. The outpatient incidence of EP was first adjusted to reflect the age distribution in WA. We lacked the information to age-adjust the PID outpatient incidence. Both the PID and EP models were run for each year of the analysis.

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Model Specification

Pelvic Inflammatory Disease. We assumed that the number of hospitalized cases in WA (NWAhospPID) was binomially distributed:

where IRhospPID represents the probability of a hospitalized PID case (vthe yearly incidence of inpatient PID in WA) and NfemaleWA represents the number of women 15 to 44 years old in WA. We assigned IRhospPID an informative prior β distribution based on national estimates of hospitalized PID derived from the National Hospital Discharge Survey.

We used a normally distributed likelihood for outpatient cases nationally (NUSoutPID), using the reported mean number of cases and variance from NDTI (MPID,NDTI and VPID,NDTI, respectively):

Because of the additional uncertainty of using national estimates as a stand-in for WA outpatient incidence, we doubled the reported variance for our model. MPID,NDTI had an uninformative normal prior, Normal(0,10−6).

The parameter for outpatient yearly incidence (IRoutPID) was then calculated as:

where NfemaleUS represents the number of US women 15 to 44 years old for each year. Total PID incidence for WA was calculated as:

Ectopic Pregnancy. We assumed that the numbers of outpatient and hospitalized EP cases in GH and WA (NGHoutEP and NWAhospEP) were binomially distributed:

and IRhospEP represent the probability of an outpatient and inpatient EP case each year (i.e., yearly outpatient and inpatient EP incidence), respectively, and NpregGH and NpregWA represent the number of pregnancies in GH and WA, respectively.

We used an uninformative prior distribution, β(1,1), for IRoutEP. We used an informative prior β distribution for IRhospEP, based on the inpatient incidence in GH.

We estimated the total EP incidence for WA from these parameters:

Statistical Inference. We estimated the posterior distributions of all parameters using the Markov Chain Monte Carlo simulation procedure using the open-source program WinBUGS version 1.4. In both models, we ran 2 independent chains for 100,000 iterations, discarding the first 50,000 iterations as burn-in. We assessed chain convergence by examining Brooks-Gelman-Rubin diagnostic plots.

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Analysis for Association Between Infections and Outcomes of Interest

To assess the association of annual CT positivity and NG incidence with the annual incidence of each outcome, we developed a linear regression model that included a first-order autoregressive covariance structure (SAS MIXED) to account for the year-to-year correlation in outcome measures. We developed separate models for each outcome of interest: inpatient PID/EP incidence, outpatient PID/EP incidence, and total PID/EP incidence. The means of the posterior distributions of total PID/EP incidence estimated from the above-described Bayesian analyses were used to model the relationships between total PID/EP and CT/NG. These models also captured the uncertainty in the posterior distributions by incorporating weights inversely proportional to the variance of the posterior distributions for each outcome. Each outcome was modeled with CT positivity or NG incidence alone, as well as with both predictors together. In addition, we decided a priori to include a 2-year lag in the EP analyses.15 Given the acute nature of PID, we did not incorporate a lag for the PID analysis.4,7,32 Statistical analyses were performed in SAS version 9.3.

Study procedures were granted an exemption from review by the University of Washington Institutional Review Board.

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RESULTS

From 1988 to 2010, there were 908,996 and 44,593 CT tests performed at IPP and PP sites, respectively (265 total clinics), of which a total of 60,401 were positive. In addition, there were 36,500 NG cases reported over the same period. Figure 1 displays trends in CT positivity, NG incidence, and the incidence of inpatient PID and EP from 1988 to 2010. Both adjusted and unadjusted CT positivity are presented. Between 1988 and 1997, adjusted positivity declined 62.2% (test for negative linear trend: P = 0.0003), and then increased 17.2% between 1997 and 2010 (P = 0.045). N. gonorrhoeae incidence declined nearly 80% from 1988 to 1998 (P < 0.0001), and thereafter rose and then fell, although these more recent changes were not statistically significant. Inpatient PID declined consistently by 75% (P < 0.0001). Inpatient EP incidence declined nearly 70% (P < 0.0001).

FIGURE 1

FIGURE 1

We calculated the proportion of PID and EP cases treated in the outpatient setting in the national and GH populations, respectively. Nationally, an average of 71% of PID cases each year (range, 59.4%–77.6%) were treated as outpatients. The proportion of PID cases managed as outpatients declined 6.2% over the study period (slope for linear trend: −0.41%, P = 0.008; see Figure 1, Supplementary Digital Content 1 http://links.lww.com/OLQ/A118, which displays the trend in the proportion treated in an outpatient setting). Likewise, the national outpatient incidence of PID declined over time (see Fig. 2, Supplementary Digital Content 2 http://links.lww.com/OLQ/A119, which displays trends in national and GH incidence). In GH, 64.3% (range, 46.4%–76.8%) of EP cases on average were treated as outpatients each year. This percentage increased significantly over the study period from 55.1% in 1993 to 59.8% in 2007 (slope for linear trend: +1.04%, P = 0.02; Supplementary Digital Content 1 http://links.lww.com/OLQ/A118). The outpatient EP incidence in GH remained stable over the study period (Supplementary Digital Content 2 http://links.lww.com/OLQ/A119).

We assessed the assumption that WA trends in outpatient PID and EP would be similar to the trends in the US or GH populations by comparing trends in the inpatient incidence of each condition in the different populations (Supplementary Digital Content 2 http://links.lww.com/OLQ/A119). The magnitude and trend in inpatient EP incidence were similar between the GH and WA populations. Although inpatient PID incidence was higher nationally than in WA, trends over time were comparable.

We observed a declining trend in estimated total PID incidence in WA from 1988 to 2010 (P < 0.0001), with total incidence decreasing 80.8% (Fig. 2A). The Bayesian credible intervals include the uncertainty due to NDTI sampling and due to the difference between the national and WA populations. Estimated total EP incidence decreased 27.5% from 1993 to 2007 (P = 0.017; Fig. 2B).

FIGURE 2

FIGURE 2

Table 2 shows the results of the regression models relating CT positivity and NG incidence to either PID or EP incidence. Because of multicollinearity when both CT and NG were modeled together, results are presented as unadjusted for the other infection.

TABLE 2

TABLE 2

Trends in CT and NG were each significantly associated with inpatient PID and EP incidence. Interpretation of regression coefficients is based on one standard deviation change in CT positivity or NG incidence during the study period; the SD was 2.1% for CT positivity and 32.3/100,000 for NG incidence. Therefore, the hospitalized PID model indicates that for every 2% decrease in CT positivity, mean inpatient PID incidence decreases by 24.7/100,000 (95% confidence interval [CI], 16.5–32.9; P < 0.0001), whereas for every decrease of 32/100,000 NG cases, mean inpatient PID incidence decreases by 28.1/100,000 (95% CI, 16.7–39.4; P < 0.0001). The coefficients of the other models should be interpreted similarly.

The magnitudes of association between CT positivity and both total PID and total EP incidence were larger than those between NG incidence and each outcome. There was a significant association between NG incidence and total EP incidence, whereas the association between CT positivity and total PID incidence neared significance. There was a significant association between NG incidence and outpatient PID rates.

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DISCUSSION

Although we have not directly evaluated the impact of CT and NG screening programs in WA, we have observed that PID and EP incidence in reproductive-aged women throughout WA declined and those trends were roughly mirrored in CT positivity trends in a population of women experiencing screening. Trends in NG incidence in all women also declined in a similar fashion, although systematic screening for NG did not occur through the entire study period. The incidence of PID and EP decreased when both inpatient and outpatient diagnoses were taken into account, indicating that these declines were not simply caused by changing treatment practices. We observed strong associations between STD trends and trends in inpatient incidence for each condition. The observed associations with estimated total PID and EP, which included cases treated as outpatients, were generally larger in magnitude, and a statistically significant relationship was observed between NG incidence and total EP incidence.

The statistically significant associations between CT/NG trends and inpatient incidence of PID and EP suggest that screening of and treatment for these women may have impacted subsequent rates of severe reproductive sequelae. For PID, the associations are larger for outpatient than inpatient, as expected, though nonsignificant. For EP, because of the smaller number of data points that are only around the time where CT/NG was slightly increasing and EP outpatient rates were steady, the associations are negative. The lack of statistically significant associations with total incidence of each condition may be a reflection of the limitations in our data sources. However, it may also suggest that factors other than these screening programs have driven declines in PID and EP rates. For example, declines in risky sexual behaviors and STDs, including others that may cause PID/EP, in the early 1990s may have been driven by fears of HIV and subsequent prevention campaigns.33 Other factors may similarly be influencing the decline, especially because, in general, only a portion of PID and EP cases are attributable to CT and NG. There were some discrepancies in the patterns we observed. For example, the steepest declines in CT and NG, as well as PID and EP, occurred early in the study period, when screening coverage was likely somewhat lower than in later years. It may be that at the time that screening began, there were high levels of prevalent infection in the population which were decreased dramatically by the advent of screening, which in turn impacted PID and EP. In addition, although the declines observed for CT and NG stabilized between 1994 and 1996, incidence for PID and EP continued to decrease until around 2000. Some delay in the effect of treatment of CT and NG is expected for EP and was built into our models, but a similar lag would not be expected for PID. It is possible that the longer period of decline in EP and PID inpatient incidence is due, in part, to the shift in PID and EP treatment to outpatient settings.

The increase in adjusted CT positivity we observed after 1997 is consistent with findings of a previous study of positivity in WA and surrounding Western states from 1997 to 2004.24 However, the significant decreases in both inpatient and total EP incidence that we observed differ from prior findings in WA and in British Columbia, Canada. Both these studies reported stables rates of EP over time.16,19 We believe that this disparity may reflect differences in the periods of observation included in each study. The prior WA and British Columbia studies began in 1997 and 1992, respectively. We observed that the decline in inpatient EP incidence occurred mainly before 1994 and was thereafter largely stable. That prior studies did not observe a decline in EP may reflect failure to include the earlier period during which EP rates were dropping. In addition, the years during our study period when inpatient EP was declining correspond to the initial years of IPP screening, where potentially many women with prevalent infections were being treated and therefore avoiding adverse outcomes such as EP in the years following. In these other studies, the beginning of the study period may not have corresponded with the initiation of screening programs, which might explain not observing any declines. Of note, a Swedish study evaluating trends in EP between 1985 and 1995 observed declines in EP for most age groups; CT screening in this population was also was initiated in the 1980s.15

We observed that outpatient cases constitute a large and changing proportion of all PID and EP cases. Failing to include outpatient cases in studies of PID and EP trends may substantially underestimate the incidence of each condition, distort trends over time, and bias associations with CT and NG infection. Previous ecological analyses have not adequately captured outpatient cases15,17,18 or have done so only in a subset of the population.16 We believe that by estimating outpatient cases, our calculations of PID and EP incidence provide a more complete picture of the burden of each condition in WA. However, we were not able to calculate total EP incidence from 1988 to 1993, and as these years correspond to the years with the greatest declines in CT, NG, and inpatient EP incidence, we suspect that we have underestimated the magnitude of the true decline in total EP over the study period.

Our study had several limitations. Because we did not have data on the incidence of outpatient PID and EP diagnoses for WA, we relied on other data sources for outpatient information. Therefore, our estimates of total incidence may not reflect the true total PID and EP incidence in WA. In particular, the small number of outpatient EP cases in GH each year may have contributed to unstable estimates of annual incidence of total EP. However, trends in the inpatient incidence of both conditions between WA and national PID or GH EP were very similar, lending some support for our use of these alternative data sources to estimate overall trends. Furthermore, we observed similar declines in outpatient PID in an analysis of cases identified at a large Seattle-based STD clinic from 1992 to 2010 (data not shown). However, despite these findings, we may still have inaccurately calculated the total incidence of each condition in WA.

In addition, as noted earlier, we did not have EP data from GH for the period in the late 1980s and early 1990s. This limited our ability to assess the relationship between STD trends and total EP incidence, and may account for the lack of statistically significant associations between total EP incidence and both CT positivity and NG incidence. Also related to time frame, data on CT positivity are unavailable before the start of the IPP program in WA state, and therefore, we were unable to include time points before the start of the program. Furthermore, although data on PID for the period prior to 1988 are available from the NDTI, similar data for EP are not available before 1988. This may have limited the ability to detect an association between rates of CT and PID/EP.

We were also limited to calculating NG incidence with all female cases due to limitations in available data. Because NG incidence in women 15 to 29 years old is greater than in all women, magnitudes of association with PID and EP may be underestimated. In addition, our estimates of CT positivity came from a subset of women in WA. Women screened through IPP were younger and may have been at greater risk for infection than other sexually active women in WA.34 Ideally, we would have had positivity data from a more representative population of screened women; however, these data are not available. By adjusting for certain demographic characteristics and accounting for the changing clinic types over time, we believe that we have accounted for some of these issues, although bias may still be present. As with all ecological associations, we cannot definitively conclude that any associations between trends in each STD and their sequelae are causal. Finally, because our study did not capture the period before widespread screening for CT and NG was in place in WA, we cannot definitively demonstrate that screening caused the declines in these 2 infection; in addition, we may have underestimated the effect that the observed decrease in rates in these infections had on PID and EP.

In summary, we observed that both PID and EP declined concurrent with a drop in NG incidence and CT positivity from 1988 to 2010. Although the associations we observed between each infection and total PID and EP incidence were not consistently significant, we would argue that there is still evidence of a relationship between these trends in some cases. Additional studies will be needed to further evaluate and describe this relationship.

We believe that our findings clearly demonstrate that important reproductive health morbidity among women is declining and that declines in inpatient incidence can be attributed to more than just changes in treatment settings. We cannot conclude that large-scale screening programs in WA were the ultimate cause, but these findings are consistent with the conclusion that the decreasing occurrence of NG and CT in WA women has contributed to declining incidence of PID and EP in the state.

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