Can diagnostic laparoscopy be avoided in routine investigation for infertility?

BJOG 000,10(), pp. 118 Can diagnostic laparoscopy be avoided in routine investigation for infertility? N. P. Johnson Senior Registrar, K. Taylor Medical Student, A. A. Nadgir Specialist Registrar, D. J. Chinn Senior Research Fellow (Epidemiology), P. J. Taylor Consultant Department of Obstetrics and Gynaecology, South Cleveland Hospital, Middlesbrough Objective To determine whether routine testing for serum Chlamydia trachomatis antibodies, considered in combination with a woman's clinical features, may avoid the need for diagnostic laparoscopy in routine investigation for infertility. Design Retrospective case notes analysis. Setting Secondary level care infertility clinic. Population Eighty women who had undergone both laparoscopy and serum Chlamydia trachomatis antibody testing. Methods Ascertainment of any history of suspected pelvic inflammatory disease, pelvic pain, cervical intraepithelial neoplasia, pelvic surgery or appendicectomy ; any abnormality on clinical pelvic examination; the findings at laparoscopy ; the result of serum Chlamydia trachomatis antibody testing by enzymelinked immunosorbent assay (ELISA) screening with microimmunofluorescence (MIF) confirmatory diagnostic testing. The usefulness of clinical features, the serum Chlamydia trachomatis antibody test and these two variables combined in the detection of tubal disease and pelvic pathology of relevance to infertility were measured statistically. Main outcome measures Specificity, sensitivity, positive predictive value, negative predictive value and likelihood ratio for each of the tests. Results The combination of any positive clinical feature with a positive test for serum Chlamydia trachomatis antibodies detects tubal disease with sensitivity 9%, specificity 0%, positive predictive value %, negative predictive value 91% and likelihood ratio 3.1; it detects bilateral tubal obstruction with sensitivity 8%, specificity 51 %, positive predictive value 35%, negative predictive value 91% and likelihood ratio 1.; it detects pelvic pathology relevant to infertility with sensitivity 6%, specificity 1%, positive predictive value 80%, negative predictive value 65% and likelihood ratio.6. The negative predictive value for pelvic pathology from the use of clinical features in addition to the chlamydia antibody test is not significantly higher than that from the chlamydia antibody test alone (53%). Conclusions A policy of selective laparoscopy in routine investigation for infertility, based on the result of the test for serum Chlamydia truchomatis antibodies and a woman's clinical features, is not supported. INTRODUCTION While Chlamydia trachomatis is not the sole cause of damage to the fallopian tubes, Chlamydia truchomatis antibodies have been a consistent finding over the last two decades in the serum of women with tubal subfertility',*. The seventy of adnexal adhesions is associated with the chlamydia antibody titre3. The test for chlamydia antibodies also appears to have some value in predicting tubal subfertility : optimum cutoff antibody titres Correspondence: Dr N. P. Johnson, 1 Monteigne Drive, The Woodlands, Bowburn, Durham DH6 5QB, UK. have been defined by receiveroperator characteristic analysis. Metaanalysis has shown that the discriminative capacity of chlamydia antibody titres by enzymelinked immunosorbent assay, microimmunofluorescence or immunofluorescence is comparable to that of hysterosalpingogram in the diagnosis of tubal pathology, when laparoscopy is used as the reference standard5. Some clinicians have adopted the test, while others remain unconvinced of the value of testing for serum Chlamydia trachomatis antibodies in the routine investigation of infertility. There is to date no evidence that performing this test has any influence on the investigation and treatment of couples with infertility, nor that 1 0 RCOG 000 BJOG

LA PA RO S COPY AND IN FERTILITY INVESTIGATION 15 more invasive tests, such as laparoscopy, can be avoided. Whether the value of the test can be improved by considering clinical features in addition to the test has not previously been assessed rigorously. The aim of this study was to determine whether routine testing for serum Chlamydia trachomatis antibodies, considered in combination with a woman s clinical features, could be used to avoid diagnostic laparoscopy in routine investigation of infertility. METHODS The study sample comprised women consecutively referred for secondary level investigation of infertility to the Reproductive Medicine Department at South Cleveland Hospital, which also offers tertiary level infertility investigation and treatment. Routine investigations included a semen analysis, midluteal progesterone estimation, early follicular phase follicle stimulating hormone and luteinising hormone estimations and the test for serum Chlamydia trachomatis antibodies. The study sample included women who had a positive chlamydia antibody test (whether or not there was another cause for infertility) and those in whom routine investigations had not revealed a cause for infertility. Laparoscopy with hydrotubation was performed in all women. Eighty women were included in the study, all of whom had undergone laparoscopy over a twoyear period between July 19% and July 1998. The range of their ages was 1939 years (mean years). All women had experienced at least one year of infertility at the time of laparoscopy; 56 had primary infertility and had secondary infertility. Of the 35 women with a positive test for Chlamydia trachomatis antibodies, two also had anovulatory polycystic ovarian syndrome and two male partners had mild oligoasthenospermia. The causes of infertility were: tubal disease in 36 women (four of whom also had significant endometriosis); anovulatory polycystic ovarian syndrome in two women; oligoasthenospennia in two men; endometriosis in 13 women and unexplained infertility in couples. Five women whose case notes were examined were excluded from the study: one had achieved a pregnancy before laparoscopy and four had no result of the chlamydia antibody test available. The women were identified from computer records of diagnostic laparoscopy. A retrospective case notes analysis was performed on all women eligible for entry into the study to ascertain: 1 The baseline characteristics of the study group. Whether there was a history of pelvic inflammatory disease, chronic pelvic pain, pelvic surgery, appendicectomy or cervical intraepithelial neoplasia. 3 Whether pelvic tenderness was elicited on vaginal examination. The result of the test for serum Chlamydia trachomatis antibodies. 5 The findings at laparoscopy. The cause of infertility, based on the above investigations, was defined. A woman was considered to have a positive clinical history if she had any of the features detailed in points and 3 above. This retrospective ascertainment of clinical features, based on recording by different clinicians, is acknowledged as a limitation of the study. The initial test for serum chlamydia antibodies (nonspeciesspecific) was by enzymelinked immunosorbent assay (ELISA) using as substrate tetramethylbenzadine to detect immunoglobulin G antibodies directed against chlamydia (IgG TMB ELISA, Clark Laboratories, Jamestown, New York, USA). Those sera which gave a positive or equivocal result were retested using a microimmunofluorescence assay for serological diagnosis of speciesspecific chlamydia1 infections, allowing positive identification of Chlamydia trachomatis immunoglobulin G antibodies and differentiation from antibodies to Chlamydia pneumoniae or Chlamydia psittaci (Multiscreen Chlamydia, I. 0. International Ltd, London, UK). The operative notes of each laparoscopy were examined to identify the following: 1 Tubal disease (defined as the presence of peritubal adhesions, tuboovarian adhesions, hydrosalpinx or the absence of bilateral spill of dye at hydrotubation). Bilateral tubal obstruction. 3 Endometriosis. Women were considered to have pelvic pathology of relevance to infertility if tubal disease, bilateral tubal obstruction or endometriosis was diagnosed at laparoscopy. Estimates of specificity, sensitivity, positive predictive value, negative predictive value and likelihood ratio for each of the tests were obtained using standard statistical techniques6. There was no external funding for the study, which was conducted by NHS employees. No power calculation was performed before the study. No blinding was employed in the study design, for example the clinician performing the laparoscopy may have been aware of the results of the routine investigations. RESULTS In this group of women the prevalence of tubal disease was 5% and both fallopian tubes were blocked in %. The prevalence of endometriosis was 1%, including two women who had an endometrioma. The prevalence of pelvic pathology of relevance to infertility was 61%. The performance of the tests for tubal disease, bilateral 0 RCOG 000 BJOG 10,118

16 N.P. JOHNSON ET AL. Table 1. Performance of tests for tubal disease. Sens. = sensitivity; Spec. = specificity; PPV = positive predictive value; NPV = negative predictive value; PID = pelvic inflammatory disease; CIN = cervical intraepithelial neoplasia. Tuba1 No tubal Sens. spec. PPV NPV Likelihood disease (n) disease (n) (%) (%) (% (95% CI)) ratio Pelvic tenderness or history of PID or chronic pelvic pain History of pelvic surgery History of appendicectomy History of CIN Any positive clinical features Chlamydia antibodies positive clinical features 9 5 3 3 13 3 9 33 3 5 5 5 55 11 33 1 95 1 58 6 86 5 53 6 38 6 95 50 55 36 8 6 61 (50).0 8 35 81 86 83 8 (69) 5.8 6 38 9 0 91 (859) 3.1 13 1.o.8 0. 1. tubal obstruction and pelvic pathology of relevance to infertility is summarised in Tables 13. For tubal disease the negative predictive value of the serum Chlamydia trachomatis antibody test is 8%, significantly higher than the negative predictive value of 61 % of clinical features alone. If a positive test or positive clinical features are used in combination, the negative predictive value is 91%. The test for Chlamydia trachomatis antibodies also has high negative predictive value for bilateral obstruction of the fallopian tubes (93%), not improved by also considering positive clinical features. However, for pelvic pathology of relevance to infertility the negative predictive value of the serum Chlamydia trachomatis antibody test is 53%, not significantly better than the negative predictive value of 9% of clinical features alone. When a positive test or positive clinical features are considered, this negative predictive value is 65%. The test for serum Chlamydia trachomatis antibodies failed to identify seven women with tubal disease (sensitivity 81%) and, even when the women with either a positive chlamydia antibody test or positive clinical features were considered, there were still three women with tubal disease who could not be identified (sensitivity 9%), all of whom had significant pelvic pathology with bilateral tubal obstruction. Indeed there were twelve Table. Performance of tests for bilateral obstruction of the fallopian tubes. Key as for Table 1. Bilateral Some Sens. Spec. PPV NF V Likelihood block (n) patency (n) (a) (%I (%) (%I ratio Any positive clinical features _. 80 3 83.3 9 1 10 9 Chlamydia antibodies 8 69 6 93. 16 19 3 positive clinical features 8 51 35 91 1. 16 30 3 0 RCOG 000 BJOG 10,118

LAPAROSCOPY AND INFERTILITY INVESTIGATION 1 Table 3. Performance of tests for pelvic pathology of relevance to infertility. Key as for Table 1; NE = not estimable. Pelvic Normal Sens. Spec. PPV NPV Likelihood abnormality (n) pelvis (n) (%) (%I (% (95%CI)) ratio Pelvic tenderness or history of PID or chronic pelvic pain History of pelvic surgery History of appendicectomy History of CIN Any positive clinical features Chlamydia antibodies positive clinical features 1 3 5 5 19 30 8 1 3 1 35 90 85 1 3.5 3 8 1 100 100 NJ! 0 8 8 50 38 0.6 8 100 100 1 NJ! 0 39 9 90 9 (3860) 6.5 9 5 80 53 (6).5 6 1 80 65 (56).6 9 women who had pelvic pathology of relevance to infertility who could not be identified by a positive test or positive clinical features (sensitivity 6%). DISCUSSION This study confirms the findings of others that the test for serum Chlamydia trachomatis antibodies has discriminative value in detecting tubal di~ease~,~ and the test is more dlscriminatory than clinical features alone. It is no surprise that the test is less discriminatory in detecting pelvic pathology of relevance to infertility than in detecting tubal disease. Endometriosis is important in subfertility and can be diagnosed only at laparoscopy. The other tests of tubal status are hysterosalpingography and laparoscopy with hydrotubation. Hysterosalpingography is uncomfortable, embarrassing and expensive. It is no more useful than chlamydia antibody testing in detecting tubal pathology5 with particularly poor sensitivity for the detection of peritubal adhesions*. Laparoscopy causes discomfort, carries the hazards of general anaesthesia, the rare but recognised hazards of gastrointestinal, urinary tract or vascular injury and is expensive, even when performed as day surgery. Chlamydia antibody testing is inexpensive but has a psychological burden5, since a positive test may stigmatise a woman as having had a sexually transmittable disease, requiring sensitive counselling. Can diagnostic laparoscopy be performed selectively or avoided in the investigation of infertility? While a normal laparoscopy with hydrotubation does not exclude the possibility of intraluminal disease and tubal dysfunction, many women who test positive for serum Chlamydia trachomatis antibodies have entirely normal pelvic organs (0% in this study) and may have normal fertility. There is no evidence to justify omitting laparoscopy in women with antibodies to Chlamydia on the grounds that tubal disease is likely. Indeed, a positive test for chlamydia antibodies is widely regarded as a positive indication for laparoscopy. In this study less than 10% of women with no positive clinical features and a negative test for chlamydia antibodies had tubal disease, but 35% of these women had pelvic pathology of relevance to infertility. The use of clinical features in addition to the chlamydia antibody test did not significantly improve the negative predictive value for tubal disease or pelvic pathology. This negative predictive value for pelvic pathology is insufficiently high to support a policy of performing laparoscopy selectively in routine investigation of infertility. The role of serum Chlamydia trachomatis antibody testing and the possibility of avoiding laparoscopy depends on the perspective taken by the couple and their gynaecologist. It also depends on the type of treatment available ovulation induction, intrauterine insemination and donor insemination depend on normal fallopian tube function but in vitro fertilisation does 0 RCOG 000 BJOG 10,118

18 N.P. JOHNSON ET AL. not. Many couples feel that it is important to be fully investigated and for some a 90% reassurance that there is no tubal disease is insufficient. Some gynaecologists emphasise the importance of laparoscopy being performed by a surgeon experienced in laparoscopic adhesiolysis who could also take a decision concerning the suitability for tubal surgery. Laparoscopy remains the standard investigation for the diagnosis of pelvic pathology of relevance to infertility. Increasingly, with the advances made in the technology of assisted reproduction, there is a move away from a diagnostic workup towards a prognosisorientated approach to the investigation and treatment of infertility. With this philosophy the prognostic value of chlamydia antibody testing is doubtful5. Our study shows that routine testing for serum Chlamydia trachomatis antibodies cannot be used to avoid diagnostic laparoscopy in routine investigation of infertility. References 1 Punnonen R, Terho P, Nikkanen V, Meurman 0. Chlamydial serology in infertile women by immunofluorescence. Fertil Steril 199; : 656659. Dabekausen YA, Evers JL, Land JA, Stals FS. Chlamydia trachomatis antibody testing is more accurate than hysterosalpingography in predicting tubal factor infertility. Fertil Sterill99; 61: 83383. 3 Tanikawa M, Harada T, Katagiri C, Onohara Y, Yoshida S, Terakawa N. Chhydia trachomafis antibody titres by enzymelinked immunosorbent assay are useful in predicting seventy of adnexal adhesion. Hum Reprod 1996; 11: 181. Land JA, Even JL, Goossens VJ. How to use Chlamydia antibody testing in subfertility patients. Hum Reprod 1998; 13: 1091098. 5 Mol BWJ, Dijkman B, Wertheim P, Lijmer J, van der Veen F, Bossuyt PMM. The accuracy of serum chlamydial antibodies in the diagnosis of tubal pathology: a metaanalysis. Fertil Steril 199; 6: 10103. 6 Altman DG. In: Practical Statistics for Medical Research. London: Chapman and Hall, 1991: 10. Conway D, Glazener CM, Caul EO et al. Chlamydial serology in fertile and infertile women. Lancer 198; 830 191193. Accepted September 1999 0 RCOG 000 BJOG 10,118