Chlamydia and gonorrhea infection among female family planning clients diagnosed with pelvic inflammatory disease in California, 2003-2005 Joan M. Chow,1 Jane Guo,1 Ken Sisco,2 Ken Mueller,2 Laurie Weaver,3 Gail Bolan1 California Department of Public Health Sexually Transmitted Disease Control Branch,1 Maternal Child & Adolescent Health-Office of Family Planning;3 Quest Diagnostics/Unilab2 2008 CDC STD Prevention Meeting, Chicago, IL March 10-13 Good morning. I would like to acknowledge my co-authors listed here from the California Department of Public Health STD Control Branch and Office of Family Planning, and our laboratory colleagues from Quest Diagnostics/Unilab.

Background Over one million reported chlamydia (CT) cases and over 358,000 gonorrhea (GC) cases in US for 2006 CT and GC are important causes of Pelvic Inflammatory Disease (PID) CT/GC screening reduces the risk of PID* National recommendations for widespread CT screening of young women CT screening is still only ~50% There were over one million reported chlamydia cases and over 358,000 gonorrhea cases in the US in 2006; ¾ of the chlamydia cases were reported in women. We know that chlamydia and gonorrhea are important causes of pelvic inflammatory disease or PID, the leading risk factor for tubal factor infertility and ectopic pregnancy. We also know from the Scholes randomized clinical trial in 1996 that CT screening reduces the risk of PID by 60%. These and data from retrospective studies of PID form the basis for national recommendations for widespread CT screening of young women to identify and treat infection to prevent adverse reproductive consequences. However, while CT screening coverage has increased since the release of these recommendations, screening is only reaching about 50% of sexually active young women. *Scholes D et al. Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. NEJM 1996; 334:1362-1366.

Background II Older PID studies Current PID profile Hospitalized severe cases Laparoscopically-confirmed cases supported by pathologic and histologic findings Culture results from endometrium and fallopian tubes 50-75% PID associated with CT/GC Current PID profile Declining incidence of reported PID Out-patient cases >>hospitalized cases Inconsistent clinical criteria Testing limited to cervical and/or urine specimens Role of CT and GC in the current epidemiology of PID needs re-assessment There are some important comparisons between findings from older studies of PID and our current understanding of PID cases that should be noted. Older PID studies from before the 1990’s were characterized by— the inclusion of hospitalized and likely more severe cases the inclusion of participants who were laparoscopically confirmed cases whose diagnosis was further supported by pathologic and histologic findings And the use of culture specimens taken from the endometrium and fallopian tubes These studies found that 50-75% of PID cases were associated with CT and/or GC When we examine the current profile of PID, we first note from national data that there has been a declining incidence of reported PID cases but the reliability of reporting PID raises questions about these trends. For instance-- Current PID cases are much more likely to be treated as out-patients as opposed to being hospitalized PID cases have also been identified using relatively inconsistent clinical criteria and current testing has been limited to cervical and/or urine specimens Consequently in light of these changes in the identification and management of PID, the role of CT and GC in the current epidemiology of PID needs reassessment.

Study Objective To estimate the prevalence of current CT and GC infection among family planning clients (FP) diagnosed with pelvic inflammatory disease in out-patient settings Our study objective was to estimate the prevalence of current CT and GC infection among family planning clients diagnosed with PID in out-patient settings.

Methods I Design: Cross-sectional Data sets: Paid claims data from Family PACT with date of service in 2003-2005 CT and GC line-listed test result data from Quest Diagnostics/Unilab in 2003-2005 95% of tests were nucleic acid amplification Case definition for PID: Claims with ICD-9 code: 614, 615, 0910,09816, 09830, 09886 NDC treatment codes: 3-drug regimen ceftriaxone, doxycycline, metronidazole; or 2-drug regimen ofloxacin, metronidazole Our Methods were based on the following— The design was cross-sectional and involved two key data sets. One data set was the paid claims data from the Family PACT Family Planning program in California for dates of service from 2003 to 2005. This program provided comprehensive reproductive health services to approximately 1.5 million low income Californian women annually during this period. The other data set included CT and GC line-listed test result data from Quest Diagnostics/Unilab for 2003-2005 in just the subset of FPACT clients tested by this laboratory. Quest Diagnostics accounts for about 18% of all chlamydia testing in FPACT. Nearly 95% of these tests were nucleic acid amplification tests. We used the following case definition for PID: Claims with the following ICD-9 codes for PID: 614, 615, 0910,09816, 09830, 09886 AND associated NDC treatment codes for either a 3-drug regimen or 2-drug regimen consistent with the 2002 STD Treatment Guidelines for PID.

Methods II Inclusion criteria: PID clients linked to CT and GC test results by client HAP identifier Test result 14 days prior to 30 days after PID date for prevalence estimates Exclusion criteria: Clients not tested by Quest Diagnostics/Unilab Missing CT and GC test results For the final study sample, we included PID clients who were able to be linked to CT and GC test results by unique client HAP identifier. Further, the test results with a date 14 days prior to 30 days after PID date were used for prevalence estimates. This wide window was used because billing dates for laboratory test claims can lag behind dates for PID clinical services and vice versa. We excluded clients not tested by Quest Diagnostics/Unilab and cases with missing CT and GC test results.

Results: Study Sample Based on Claims Data Linkage to Laboratory Data 2003-2005 335,600 CT/GC test results from FPACT providers using Quest 4138 PID cases in FPACT 542 providers 1,209 providers 647 PID cases with Quest test results 175 providers 117 providers This flow chart shows how we arrived at the final study sample based on the claims data linkage to the laboratory data. USE LASER POINTER FOR EACH BOX: There were 1209 FPACT providers that used the Quest laboratory and they were associated with the over 335,000 CT/GC test results. There were 4138 PID cases identified in FPACT overall. 647 PID cases with Quest test results were identified by 175 providers during this period. Of these 647 PID cases, 381 PID cases or 59% were linked to test results between -14 and 30 days of the PID date. The remaining 266 PID cases had test results outside of this time frame. 111 providers 266 PID cases with CT/GC test results NOT -14 to 30 days of PID date 381 PID cases with CT/GC test results -14 to +30 days of PID date

Results: Demographic Characteristics of PID Cases by Test Data Status, FPACT 2003-2005 Age (years) PID cases without Quest test data (n=3,491) PID cases with test result -14 to 30 days (n=381) ≤ 20 22% 25% 21-25 29% 32% > 25 48% 43% Race/ethnicity Hispanic 65% 56%* White 23% 28%* African-American 7% 5% Other** 10% 11% This table shows the age and race/ethnic distribution for PID cases identified in FPACT during 2003-2005 without Quest test data compared with the age and race/ethnic distribution for the PID cases with concurrent Quest CT/GC test results shown here in the orange columns. The age distribution of the PID cases was essentially evenly divided between younger and older women in both groups. We did not found statistically differences in the age distributions across these two groups. The racial/ethnic distribution of the PID cases shows that the highest proportion of cases were among Hispanic women. However, the PID cases with test results had a significantly lower proportion of Hispanic women and a significantly higher proportion of white females compared with PID cases without Quest test data. * P-value <0.05; **Other Race/Ethnicity includes Asian/PI, AI/AN, multiple race/ethnicity

RESULTS: Current Chlamydia Prevalence RESULTS: Current Chlamydia Prevalence* Among PID Cases and non-PID Female Clients by Age and Race/Ethnicity, FPACT, 2003-2005 PID Non-PID Age N % CT Positive ≤20 97 20.6 73,196 6.5 21-25 121 15.7 105,197 4.7 >25 163 5.5 154,940 1.9 Race** Hispanic 209 10.5 192,867 3.3 White 108 13.0 79,567 3.5 African-American 21 14.3 19,994 8.8 Other** 42 21.4 37,573 4.5 TOTAL 381 12.6 333,333 3.8 This table shows the age and race-specific chlamydia and gonorrhea prevalence among the 381 PID cases compared with female clients without a PID diagnosis in the Quest data. The overall CT prevalence was 12.6% with the highest prevalence among adolescents and young adult female PID cases at 20 and 15%, respectively, compared with PID cases aged over 25 years at 5.5%. In contrast, all age-specific prevalences for females without PID were significantly lower as seen here in the last column. When we look at the race-specific CT prevalence estimates for PID cases, the prevalence ranges from 10% among Hispanic PID cases to 21% among women of Other race/ethnicity. Interestingly, when we examine race/ethnic differences for non-PID cases in the last column, CT prevalence among African-American females at over 8% is significantly higher than for all other groups. *-14 to 30 days of PID diagnosis date; **1 case with missing race/ethnicity; ***Other includes A/PI, AI/AN, multiple race

RESULTS: Current Gonorrhea Prevalence RESULTS: Current Gonorrhea Prevalence* Among PID Cases and non-PID Female Clients by Age and Race/Ethnicity, FPACT, 2003-2005 PID Non-PID Age N % GC Positive ≤20 92 4.3 62,611 0.9 21-25 113 1.8 89,380 0.6 >25 155 1.2 143,373 0.3 Race** Hispanic 203 1.0 179,675 White 108 2.1 62,435 0.4 African-American 21 5.0 18,187 2.6 Other** 42 7.7 32,040 0.5 TOTAL 360 2.2 295,364 Here we show the age and race/ethnic-specific gonorrhea prevalence among the PID cases compared with female clients without a PID diagnosis in the Quest data. The overall GC prevalence for PID cases was 2.2% which is significantly lower than what was seen for CT prevalence. The highest GC prevalence was in the ≤20 year age group at 4.3% followed by <2% among older females. In contrast, all age-specific GC prevalences for females without PID were significantly lower as seen here in the last column. Looking at the race-specific CT prevalence estimates for PID cases, the prevalence ranges from 1% among Hispanic PID cases to over 7% among PID cases of Other race/ethnicity. When we examine race/ethnic differences for non-PID cases in the last column, GC prevalence among African-American females at 2.6% is significantly higher than for all other groups. *-14 to 30 days of PID diagnosis date

Discussion CT and GC prevalence among out-patient PID cases in FP is low compared with older studies More data are needed to assess the impact of screening to reduce asymptomatic CT/GC and risk of PID Low GC prevalence among out-patient PID cases in FP consistent with low overall GC prevalence in FP Etiology of PID in women over 25 may be different than in younger women So we see that CT and GC prevalence among out-patient PID cases in FP is low at 12% compared with older studies of hospitalized PID cases where the prevalence of CT/GC was 50-75%. More data are clearly needed though to assess the impact of screening over time to reduce asymptomatic CT/GC and consequently the risk of CT/GC PID. We also note that the CT and GC prevalence among out-patient PID is still significantly higher than among women without PID. The case for screening women at risk for CT remains a strong based on these data. Secondly, the low GC prevalence of 2% among out-patient PID cases in FP is consistent with low overall GC prevalence among females with lower genital tract infections in FP settings which has been consistently less than 1%. Thirdly, the significantly higher CT/GC prevalence among younger PID cases suggests that the etiology of PID in women over 25 may be different than in younger women. This is consistent with the very low levels of cervical CT and GC that we consistently observe among older women in national and local prevalence monitoring data.

Limitations Case ascertainment CT/GC prevalence estimates Inconsistent clinical diagnostic criteria Inconsistent use of billing codes No validation of ICD-9 codes against clinical data→ misclassification of cases CT/GC prevalence estimates Not all PID cases were tested Assumption that lower genital tract CT concordant with upper genital tract infection in PID No data on other PID-associated organisms and conditions, e.g. anaerobes, mycoplasmas, BV There were three main limitations to the analysis we conducted. First, with respect to case ascertainment, there were likely inconsistent clinical diagnostic criteria, and inconsistent use of billing codes, especially ICD-9 codes for PID. There was no validation of ICD-9 codes against clinical data and thus there was potential for lower sensitivity and specificity of the case definition due to misclassification of PID cases. Secondly, with respect to the CT/GC prevalence estimates, not all PID cases were tested. We are concerned about the potential for bias in our estimates due to the 40% of PID cases that were not linked to test results within days. We also made the assumption that lower genital tract CT infection is concordant with upper genital tract infection in PID. Older studies based on culture tended to isolate a higher proportion of CT and GC infections from the cervix than from tubal and abdominal specimens of acute PID cases. On the other hand, use of NAATs with significantly higher sensitivity than culture can capture DNA associated with non-viable organisms that may have a role in ascending infection. Lastly, there were no other data available related to the prevalence of other PID-associated organisms and conditions such as anaerobic bacteria, mycoplasmas, and bacterial vaginosis to evaluate their current role in PID.

Recommendations Increased testing for CT and GC for suspected PID is important for appropriate treatment Emergence of fluoroquinolone-resistant GC Use administrative data bases for ongoing monitoring of out-patient CT/GC PID Validation against confirmed PID needed Develop additional methods to evaluate the impact of CT/GC screening on PID incidence Longitudinal data collection linking incidence trends to screening Recommendations based on these findings are as follows— Increased testing for CT and GC for suspected PID is needed and important for appropriate treatment to prevent further complications and especially in light of emerging fluoroquinolone-resistant GC. Use of administrative data bases should be further developed for ongoing monitoring of out-patient CT/GC-associated PID. However, medical record validation against confirmed PID is also needed to further refine PID case definitions and verify testing. Lastly, we should be developing better methods to evaluate the impact of CT/GC screening on PID incidence. Longitudinal data collection linking incidence trends to screening would be particularly helpful. Increasing screening levels combined with apparent decreases in PID incidence would suggest such a relationship but we need stronger data to support this.

Acknowledgements Quest Diagnostics/Unilab Sue Barbosa Fred Laughton Andrew Shaw UCSF Bixby Center for Reproductive Health Research & Policy Mary Bradsberry Aileen Barandas MSN, NP Heike Thiel de Bocanega PhD MPH Philip Darney MD MSc Contact information- Joan M. Chow, MPH, DrPH Sexually Transmitted Disease Control Branch California Department of Public Health 510/620-3718 Joan.Chow@cdph.ca.gov Thank you and I am happy to take your questions and comments.