Patterns of adnexal inflammatory damage: Chlamydia, the intrauterine device, and history of pelvic inflammatory disease*

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1 FERTILITY AND STERILITY Copyright 1984 The American Fertility Society Printed in U.SA. Patterns of adnexal inflammatory damage: Chlamydia, the intrauterine device, and history of pelvic inflammatory disease* Mark Gibson, M.D. t:j: Dieter Gump, M.D. Taka Ashikaga, Ph.D.11 Bruce Hall, M.D. t University of Vermont College of Medicine, Burlington, Vermont In a study of 204 consecutive infertile couples, 58 women with adnexal abnormalities. consistent with prior pelvic infection were identified. The status of those 58 subjects with respect to prior pelvic infection, prior intrauterine device use, and serologic evidence of past chlamydial infection was correlated with the types of adnexal abnormalities identified. Women with serologic evidence of past chlamydial infection were more likely to exhibit severe adhesions and hydrosalpinx formation, and hydrosalpinx formation was related to a history of clinically detected pelvic infection. Fertil Steril 41 :47, Pelvic inflammatory disease (PID) is an important cause of sterility. Although ascending infection by Neisseria gonorrhoeae is perhaps the best known cause of PID, it is identified only in a minority of cases of PID in many studies. 1, 2 Knowledge of past gonorrheal infection in women found to have evidence of prior pelvic inflammatory disease (PPID), with or without a history of an acute illness, is even less frequent. 3 Chlamydia trachomatis has been implicated as a causative agent in nongonococcal PID,I, 2 and intrauterine device (IUD) use has been shown to increase the risk of development of PID. In addition to a variety of Received May 2, 1983; revised and accepted August 30, *Supported in part by grant HD from the National Institute of Child Health and Human Development, Bethesda, Maryland. tdepartment of Obstetrics and Gynecology. :f:reprint requests: Mark Gibson, M.D., Department of Obstetrics and Gynecology, Given Medical Building, University of Vermont College of Medicine, Burlington, Vermont Department of Internal Medicine. IIDepartment of Biostatistics. known and suspected causes, PID is characterized by a spectrum of types and severities of sequelae. Direct endosalpingeal inflammation may occur and lead to hydrosalpinx formation with occlusion of the fimbriated end of the fallopian tube. Peritoneal inflammation may lead to the formation of periadnexal adhesions of a mild or severe nature. Finally, acute manifestations of PID and their sequelae may be primarily unilateral or may be symmetrically distributed within the pelvis. In this report, we examine the relation between a history of clinically evident PID, prior IUD use, and prior infection with C. trachomatis (surmised from serologic tests), on the one hand, and the formation of hydrosalpinx, the formation of severe pelvic adhesions, and the symmetry of distribution of postinflammatory abnormalities, on the other hand, in 58 infertile women with PPID. Our findings suggest that PPID associated with evidence of past C. trachomatis infection is more likely to exhibit severe adhesions and hydrosalpinx formation, and that symptomatic pelvic infections, recalled by a minority of women with PPID, are more likely to result in hydrosalpinx formation. Gibson et al. Patterns of adnexal damage 47

2 PATIENTS MATERIALS AND METHODS The 58 subjects reported oninthis paper, all of whom had findings ofppid, represent a subgroup of 204 women seen consecutively at the infertility clinic at the University of Vermont. The 204 couples who had failed to conceive after at least 1 year's effort form the basis of a report published elsewhere 3 on the relationship between evidence of past chlamydial infection, IUD use, and PPID, among other causes of infertility. Ninety-four percent of the study population had private or job-related health insurance; and in 34% of the couples, at least one member was employed in a profession. This study was approved by the Committee on Human Research at the University of Vermont, and all subjects gave informed consent. Entry into the study occurred at the time of endometrial biopsy for documentation of ovulation and assessment of luteal phase adequacy. Blood was drawn at tha time of that visit for determination of antibody titers to C. traclwmatis. In addition to luteal phase evaluation, the patients underwent semen analysis, postcoital examination of the cervical mucus, hysterosalpingography (HSG), and laparoscopy. Evidence of PPID was documented by HSG and/or laparoscopy in all 58 subjects in this study. Hysterosalpingographic evidence of PPID was accepted only when an unequivocal terminal hydrosalpinx was demonstrated. Patients with adhesions (but not distal tubal occlusion) who.had associated endometriosis or a history of pelvic surgery were not included in the group of 58 patients with evidence ofppid described in this report. Seventy-six of the original 204 patients did not undergo laparoscopy, and only 1 did not undergo HSG. CLASSIFICATION Patient data were reviewed after at least 1 year from entry, and relevant information was recorded for statistical processing. Inclusion of the PPID group required unequivocal hydrosalpinx on HSG, laparoscopically visualized phimosis of the flbria, or peri adnexal adhesions; the latter were graded according to severity.4 The expected occasional occurrence offalsely normal hysterosalpingograms in patients whose laparoscopydemonstrated evidence of PPID was seen; but there were no instances where an abnormal hysterosalpingogram suggesting inclusion in the PPID group was followed by laparoscopy which would disqualify such a diagnosis. Hydrosalpinx formation was designated in those patients where obvious dilatation of the fallopian tube was accompanied by failure of the hysterosalpingographic medium (or transcervical methylene blue at laparoscopy) to escape into the peritoneal space. Disease was diagnosed as lateralized when hydrosalpinx was present only on one side or when in the absence of hydrosalpinx formation the degree of adhesions in one adnexa was two grades or more greater than the degree of adhesions in the opposite adnexa. Adhesions of grades 0, 1, and 2 were considered mild, and adhesions of grades 3 or 4 were considered severe. CHLAMYDIAL SEROLOGIC STUDIES Antibodies to C. trachomatis were determined in serum samples using an indirect immunofluorescence technique that utilizes lymphogranuloma venereum serotype L2 (USA 434/BUBO) inclusions as an antigen. 5 Patients with a titer of 1:16 or greater were considered to have antibodies to C. trachomatis. The laboratory personnel performing the serologic tests had no knowledge of the status of any of the patients. STATISTICAL ANALYSIS The data are presented in tabular form, reflecting the multiple categorizations by which the data were examined. The resulting multidimensional contingency tables describe the joint relationships between chlamydial infection, severity of adhesions, and symmetry of damage. These tables were analyzed using log-linear models. 6 This multivariate statistical approach allowed for the examination of relationships between any pair of the variables, adjusting for possible influences of the remaining variables by examining measures of partial association. The reported P values reflect the levels of these partial associations and will in general be larger when compared with those P values obtained from the usual chi-square statistic based on simple 2 x 2 contingency tables. RESULTS Among the 58 women with evidence ofppid, a history of PID was obtained from only 17 (29%). Twenty-two (38%) reported previous IUD use, and 33 (57%) had elevated titers (1:16) of anti- 48 Gibson et al. Patterns of adnexal damage F erlility and Sterility

3 Table 1. Characteristics of Pelvic Inflammatory Residua in Infertile Womena Adhesions Lateralization Hydrosalpinx Yes Mild Symmetric 3 18 Unilateral 6 5 Severe Symmetric 4 7 Unilateral 9 2 aallwomen were documented to have PPID (see text). One or more observations are missing in 4 of the 58 women. chlamydial antibody. Hydrosalpinx formation was observed in 23 (40%) of the subjects. Findings were lateralized, or significantly worse on one side, in 22 (38%) women, and a severe degree of adhesion formation was found in 20 (35%). Prior to evaluating the relationship of the predictor variables (evidence of previous chlamydial infection, history ofppid, and history ofiud use) to outcome variables (hydrosalpinx formation, severity of adhesions, symmetry of damage),an examination of relationships among the predictor variables alone and among the outcome variables alone was made. These analyses were based on the data shown in Tables 1 and 2. Relationships among the three outcome characteristics, lateralization, hydrosalpinx formation, and severity of adhesions are depicted in Table 1. Among the 32 patients with mild adhesions, 11 (34%) had.asymmetric or lateralized damage, and slightly over half of these had hydrosalpinx formation. By contrast, only 3 (14%) of 21 of those with mild adhesions and symmetric disease exhibited hydrosalpinx formation. Among the 22 patients with severe adhesions, lateralized findings were found in 11 (50%). This is not a significantly higher fraction than the 34% found in patients with mild adhesions. Again, as in the mild adhesion group, symmetric findings were more often accompanied by hydrosalpinx (9 of 11, or 82%) than were symmetric findings (4 of 11, or 36%). Thus, among outcome characteristics, hydrosalpinx formation and asymmetry of damage were positively associated (P > 0.002), as were hydrosalpinx formation and severe adhesions (P > 0.05), but there was no association between the asymmetry of residua and the severity of the adhesions. The distribution of cases according to the three predictor variables is shown in Table 2. Symptomatic PPID had occurred in 13 (41%) of 32 patients with positive chlamydial serologic tests but No in only 1 (7%) of 15 patients with negative chlamydial serologic tests, a difference that was statistically significant (P < 0.02). The IUD had been worn previously by 16 (50%) of 32 seropositive patients and 5 (33%) of 15 seronegative patients. This difference was not statistically significant. Finally, prior IUD users (80f21, or 38%) more frequently had a history of PID than non IUD users (6 of 26, or 23%); but, again, this was not a statistically significant difference. Each of the outcome variables was then analyzed for its relationship to predictor variables. Analysis of hydrosalpinx formation is based on the data shown in Table 3. Hydrosalpinx formation was four times more common in patients with evidence of past chlamydial infection (16 of 31, or 52%) than in those without such evidence (2 of 15, or 13%); but the statistical significance (P = 0.06) is borderline, in large part due to low numbers of observations. Of all possible combinations, the only significant association (P = 0.02) was between historical PID with a positive antichlamydial antibody titer and hydrosalpinx formation: 8 (62%) of 13 subjects with a history of PID and positive antichlamydial antibody titers showed hydrosalpinx formation, whereas only 1 (7%) of 14 with neither a history of PID nor a positive antichlamydial antibody titer had hydrosalpinx formation. Table 3 also examines the influences on the severity of adhesion formation. Women with evidence of past chlamydial infection were approximately four times as likely to have severe adhesions as women without such a history (17 of 31, or 55%, versus 2 of 14, or 14%) (P = 0.05). Severe adhesions were found more often in women with a history of PPID (9 of 13, or 69%) than in women without a history of PID (10 of 32, or 31%), but this relationship was not statistically significant (P = 0.11) according to our log-linear model. No other single or paired predictor variables were Table 2. Distribution of Risk Factors for PID in the Study Groupa History of PID Antichlamydial Prior IUD use antibody titer Yes No High (;;. 1:16) Yes 8 8 No 5 11 Low «1:16) Yes 0 5 No 1 9 aone or more observations are missing in 11 of the 58 women. Gibson et a1. Patterns of adnexal damage 49

4 Table 3. Distribution of Characteristics of Pelvic Inflammatory Residua and Risk Factors for Pelvic Infection in the Study Group Hydrosalpinx Adhesions Lateralization History of pel- Antichlamydial Prior vic infection antibody titer IUD use Yes No Severe Mild Unilateral Symmetric Yes High Yes 6 No 2 Low Yes 0 No No High Yes 4 No 4 Low Yes 1 No 0 associated with severe peri adnexal adhesion formation. The occurrence of symmetric as opposed to unilateral findings is shown in the last two columns of Table 3. The fractions of women with lateralized disease were similar whether there was a history of PPID (6 of 14, or 43%) or not (12 of 32, or 38%). It is also evident that the fraction of women with lateralized damage was similar to women with evidence of past chlamydial infection (12 of 31, or 39%) and seronegative women (6 of 15, or 40%). The apparent increase in the frequency of asymmetric damage in past IUD users (10 of 20, or 50%) relative to non-iud users (8 of 26, or 31 %) did not achieve statistical significance (X 2 = 1.21; P = 0.19). Further, none of the combinations of predictor variables was associated with asymmetry of pelvic inflammatory damage. DISCUSSION Fallopian tube damage has been found to be the sole or contributing cause of infertility in 20% to 40% of infertile couples.7-9 Of women in the age group from 25 to 34, 19.2% were rendered infertile after one episode of clinically detected PID. 10 This value increased to 31% and 60% for second and third episodes, respectively. The data presented in this paper represent a profile of this important cause of sterility as seen by the infertility specialist in relation to risk factors for PID. The variety of causes and clinical presentations and the end-stage features of pelvic infection defy the appropriateness of the single term "PID" to describe all ascending pelvic infections. The data in this report show that hydrosalpinx formation, lateralization of damage, and severe as opposed to mild adhesion formation each occur in one third to one half of subjects with infertility related to PPID. The association of severe adhesions with hydrosalpinx formation is not unexpected and 50 Gibson et al. Patterns of adnexal damage suggests that the severity ofendosalpingeal and peritoneal insult is a common property of at least some types of PID. This is not necessarily always the case, because nearly one third of patients with mild adhesions had hydrosalpinx formation, whereas more than one third of subjects with severe adhesions did not. The association between lateralization of findings and hydrosalpinx formation may partly arise from the way we defined these categories. Our findings that only 29% of patients with PPID gave a history ofpid concurs with previous reports,3 and emphasizes that injury to the adnexa due to infection and severe enough to result in infertility may occur with minimal or absent symptoms and findings and/or that misdiagnosis of PID in young women is a common event. According to our serologic studies, 75% of the patients in our PPID group had prior infection by C. trachomatis. Previous reports from this institution and others3, clearly document an association between such evidence of past infection and subsequent evidence of PID. Prior IUD use was seen in 38% of our patients with PPID. IUD users appear to have a two- to fivefold increased risk for the development ofpid.15 We have previously reported3 that in the same group of infertile women as are the subjects of this publication, prior IUD use independently raised the probability ofppid by a factor of three. Furthermore, 76% of the women with PPID associated with prior IUD use also had serologic evidence of past chlamydial infection; thus IUD-related PID in the absence of a specific pelvic pathogen may be a relatively uncommon event. When compared with gonococcal PID, nongonococcal PID has been found endoscopically to cause more severe disease in relation to symptoms and a higher subsequent infertility rate.12, 13, 16, 17 If we assume that nongonococcal PID is often due to C. trachomatis, our finding that seropositive patients showed the se- Fertility and Sterility

5 vere form of tubal injury (hydrosalpinx), concurs with these observations. Similarly, adhesions of greater severity were associated with positive chlamydial serologic tests, more so than hydrosalpinx formation. In fact, the tendency for patients with a history of PID to exhibit more severe adhesions than patients without such a history was not statistically significant. The occurrence of infectious tuboperitoneal injury that is partially or wholly lateralized despite the unobstructed proximity of Mullerian epithelia and peritoneal surfaces on each side of the pelvis is mysterious. While unilateral infections were at one time associated with IUD use,18 subsequent studies have disproved this association.19, 20 Our data also indicate that the IUD does not appear to be related to predominantly unilateral infectious damage. Our other predictors were also unrelated to the symmetry or asymmetry of PPID. Of importance was the fact that we were unable to demonstrate any association of prior IUD use with specific characteristics of pelvic inflammatory residua. This supports the concept that IUD use facilitates the occurrence of PID caused by a variety of pathogens, and would discourage the belief that IUD use causes a specific type of pelvic infection. Finally, a role for C. trachomatis in the causation of pelvic infection is strengthened by these data: beyond the association of antibodies to this organism and PPID, we found that antibodies to this organism were associated with specific features of pelvic inflammatory damage. In particular, antibodies to C. trachomatis were associated with relatively more severe degrees of endosalpingeal and peritoneal insult. This observation encourages further study of the epidemiology of C. trachomatis and calls for inclusion of specific antibiotic therapy for this organism in the treatment of pelvic. infections where its presence is suspected. 21 Acknowledgments. The authors gratefully acknowledge the assistance of Janet Basiliere and Betty Twitchell in the collec tion of data and the preparation of the manuscript. We would also like to thank Dr. Roger Nichols of the Harvard School of Public Health for the gift of the L2 serotype as well as high-titer antiserum from a patient with lymphogranuloma venereum (used as a serologic control). REFERENCES 1. Mardh P-A, Ripa KT, Svensson L, Westrom L: Chlamydia trachomatis in patients with acute salpingitis. N Engl J Med 296:1377, Punnonen J: Chlamydia trachomatis in acute salpingitis. Am J Obstet GynecoI138:957, Gump DW, Gibson M, Ashikaga T: Evidence of prior pelvic inflammatory disease and its relationship to C. trachomatis antibody and intrauterine contraceptive device use in infertile women. Am J Obstet GynecoI146:153, Caspi E, Halperin Y, Bukovsky I: The importance of periadnexal adhesions in tubal reconstructive surgery for infertility. Fertil Steril 31:296, Richmond SJ, Caul EO: Fluorescent antibody studies in Chlamydia infections. J Clin Microbiol 1:345, Feinberg SE: The Analysis of Cross-Classified Categorical Data. Boston, MIT Press, Jones GS, Pourmand K: An evaluation of etiologic factors and therapy in 555 private patients with primary infertility. Fertil Steril 13:398, Thomas AK, Forrest MS: Infertility: a review of291 infertile couples over eight years. Fertil Steril 34:106, Sorensen SS: Infertility factors: their relative importance and share in an unselected material of infertility patients. Acta Obstet Gynecol Scand 59:513, Westrom L: Incidence, prevalence and kinds of acute pelvic inflammatory disease and its consequences in industrialized countries. Am J Obstet Gynecol 138:880, Jones RB, Ardery BR, Hui SL, Cleary RE: Correlation between serum antichlamydial antibodies and tubal factor as a cause of infertility. Fertil Steril 38:553, Henry-Suchet J, Catalan F, Loffredo V, Sanson MJ, Debache C, Pigeau F, Coppin R: Chlamydia trachomatis associated with chronic inflammation in abdominal specimens from women selected for tuboplasty. Fertil Steril 36:599, Punnonen R, Terho P, Nikkanen V, Meurman 0: Chlamydial serology in infertile women by immunofluorescence. Fertil Steril 31:656, Moore DE, Foy HM, Dalin JR, Grayston JT, Wang SP, Spadoni LR, Kuo CC, Eschenbach DA: Increased frequen cy of serum antibodies to Chlamydia trachomatis in infertility due to tubal disease. Lancet 2:574, Burkman RT: Intrauterine device and the risk of pelvic inflammatory disease. Am J Obstet Gynecol 138:861, Gjonnaess H, Dalaker K, Anestad G, Mardh P-A, Kvile G, Bergan T: Pelvic inflammatory disease: etiologic studies with emphasis on chlamydial infection. Obstet Gynecol 59:550, Svennson L, Westrom L, Ripa KT, Mardh P-A: Differences in some clinical and laboratory parameters in acute salpingitis related to cultures and serologic findings. Am J Obstet Gynecol 138:1017, Gold SR, Israel R, Ledger WJ: Unilateral tubo-ovarian abscess: a distinct entity. Am J Obstet Gynecol 127:807, Edelman DA, Berger GS: Contraceptive practice and tubo ovarian abscess. Am J Obstet GynecoI138:541, Ginsburg DS, Stern JL, Harwood KA, Genadry R, Spence MR: Tubo-ovarian abscess: a retrospective review. Am J Obstet GynecoI138:1055, Center for Disease Control: Sexually transmitted diseases treatment guidelines Morbidity and Mortality Weekly Report 31 (2S):435, 1982 Gibson et ai. Patterns of adnexal damage 51