Chlamydia trachomatis in subfertile women undergoing uterine instrumentation

The clinician's role

Susan Macmillan

1 Department of Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Foresterhill, Aberdeen, UK. E-mail: ogy167{at}abdn.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Screening
 Chlamydial antibodies
 Uterine instrumentation
 Prophylactic antibiotics
 Conclusions
 Acknowledgements
 References
 
Most women attending a fertility clinic will undergo uterine instrumentation either diagnostically and/or therapeutically. This places them at potential risk of chlamydial pelvic inflammatory disease. Clinicians remain unclear about the roles of screening, serology and prophylactic antibiotics. A review of the evidence suggests that women <25 years and those older with risk factors, men with risk factors and gamete donors should have their lower genital tract screened for Chlamydia trachomatis by a sensitive test. More information is required before screening men by age can be recommended. Serology in its present form cannot be advocated as a screening tool. Those women with a past history of chlamydial morbidity or a diagnosis of tubal pathology should, in addition to screening, be covered with prophylactic antibiotics when undergoing uterine instrumentation. The partner should be screened for sexually transmitted infections. Non-selective use of prophylactic antibiotics serves only to increase the problem of antibiotic resistance and maintain the bacterial load of chlamydia in the community.

Key words: Chlamydia trachomatis/prophylactic antibiotics/screening/subfertility/uterine instrumentation


    Introduction
 Top
 Abstract
 Introduction
 Screening
 Chlamydial antibodies
 Uterine instrumentation
 Prophylactic antibiotics
 Conclusions
 Acknowledgements
 References
 
Land et al. conclude that all subfertile women undergoing uterine instrumentation for fertility investigations should receive prophylactic antibiotics rather than screen and treat positive cases (Land et al., 2002Go). Their argument rests on the fact that in subfertile women, the prevalence of lower genital tract (LGT) infection by Chlamydia trachomatis(C. trachomatis) is low and that a significant proportion of subfertile women will have antibodies (Abs) to Chlamydiae, but that their absence does not exclude chlamydial infection.

The vast majority of subfertile women will have their cervical mucus breached either diagnostically (hysterosalpingogram/laparoscopy and dye hydrotubation) or therapeutically (intrauterine insemination/embryo transfer). Thus, the above question pertains to virtually all of a clinic's female population.

Regarding C. trachomatis infection in subfertile women, what are we, as clinicians, trying to achieve? Firstly, we want to prevent LGT infection spreading to the upper genital tract (UGT). This is achieved by secondary prevention, i.e. screening. Secondly, we wish to prevent further morbidity in those with established UGT colonization. This is tertiary prevention and where serology comes in. However, in the case of C. trachomatis infection tertiary prevention is less effective than secondary because substantial tubal damage will have occurred by the time a woman presents with an ectopic pregnancy (EP) or tubal factor infertility (TFI). Finally, the use of prophylactic antibiotics may supersede secondary prevention, though their role in tertiary prevention is uncertain.


    Screening
 Top
 Abstract
 Introduction
 Screening
 Chlamydial antibodies
 Uterine instrumentation
 Prophylactic antibiotics
 Conclusions
 Acknowledgements
 References
 
Acute C. trachomatis infection is a disease of the young. Age is an effective and simple characteristic for which to establish individual risk (Macmillan et al., 2000Go). Subfertile women tend to be older than women attending other healthcare settings. In our prevalence study, only 6% of subfertile women were <25 years. This compared with 68, 54, 34 and 25% in women attending family planning, induced abortion, miscarriage and antenatal clinics respectively (Macmillan et al., 2000Go). It is therefore not surprising that the prevalence of LGT chlamydial infection in the subfertile population is low. However, with increased media interest and the Royal College of Obstetricians and Gynaecologists (RCOG) guidelines (RCOG, 1998aGo) recommending referral at 18 months if `normal' and earlier if relevant risk factors are present, women in their 20s will continue to present for fertility investigation and treatment. Subfertile women <25 years, and probably <30 years (Macmillan et al., 2000Go), should receive the same opportunistic screening opportunities as the rest of the female population (Chief Medical Officer, 1998Go). Screening using nucleic acid amplification tests, for example, is highly sensitive and specific (Lee et al., 1995Go), and has the theoretical advantage of identifying positive women, testing for other sexually transmitted infections (STIs), checking treatment compliance and risk of reinfection, screening and treating the partner, tracing previous contacts and decreasing the bacterial load in the community.

In addition to women <25 years of age, it has been recommended that women >25 years with risk factors should be screened (Chief Medical Officer, 1998Go). While it is assumed that a couple embarking on a pregnancy are monogamous, subfertility places great stress on relationships (Appleton, 1990Go; Tarlatzis et al., 1993Go). Up to 16% of the general population admit to concurrent partnerships (Johnson et al., 2001Go), with one Greek paper reporting higher levels of infidelity by infertile couples (Tarlatzis et al., 1993Go). This may or may not be generalized to infertile couples on the whole, as this area is under-researched. However, this sensitive issue could be addressed at the couple's first visit, by separate examination. Unit counsellors should encourage disclosure to clinical staff. Oocyte donors, regardless of age, should be screened routinely (Scottish Intercollegiate Guidelines Network, 2000Go).

The evidence to support screening men is less clear. Eggert-Kruse et al. found a prevalence of <1% testing 150 subfertile men (Eggert-Kruse et al., 1997Go). However, a recent large general population study found men and women to have a similar overall prevalence (Fenton et al., 2001Go). The highest age-specific prevalence for men was older at 25–35 years. Further research is required before a screening age limit can be recommended. This precludes sperm donors who should always be screened (Scottish Intercollegiate Guidelines Network, 2000Go).

So, if women <25 years, those older with risk factors [i. e. concurrent sexual partners, partners working in STI endemic regions, or those with a past history of STI, pelvic inflammatory disease (PID), EP or TFI], men with risk factors, and gamete donors should be screened, what about the rest of the clinic population?


    Chlamydial antibodies
 Top
 Abstract
 Introduction
 Screening
 Chlamydial antibodies
 Uterine instrumentation
 Prophylactic antibiotics
 Conclusions
 Acknowledgements
 References
 
A serological test with a high positive predictive value for C. trachomatis infection remains elusive (Ridgway and Taylor-Robinson, 1990). While the microimmunofluorescence (MIF) test is highly reliable for the detection of prior exposure to C. trachomatis, it is labour intensive and expensive, and therefore not suitable for use outside a research setting. The others detect Abs to all chlamydial species and are not specific for Abs to C. trachomatis. In one study of a genito-urinary medicine population (GUM) in the UK, Abs to C. pneumoniae and C. psittaci accounted for up to half of all chlamydia-specific IgG (Moss et al., 1993Go). As the majority of adults will have been exposed to C. pneumoniae, using non-MIF testing as a screen will result in women who test positive having normal pelvic organs and normal fertility (Eggert-Kruse et al., 1997Go; Johnson et al., 2000Go). In the study by Eggert-Kruse et al. while 33% of the study population was diagnosed with tubal pathology, only half of the population's serum was completely negative for C. trachomatis IgG Abs by ELISA (Eggert-Kruse et al., 1997Go). Furthermore, 50% of those with patent tubes were Ab-positive, and 30% of those with tubal pathology were Ab-negative. The researchers concluded that a highly specific test is required.

In our own unit, 219 consecutive women underwent medical history, transvaginal ultrasound, C. trachomatis Ab testing by ELISA, and laparoscopy and dye hydrotubation. The prevalence of tubal pathology was 31%. The sensitivity of positive C. trachomatis IgG Abs was 31% (95% confidence interval 21–43). Poorer than flipping a coin.

While the sensitivity and positive predictive value will increase by choosing higher cut-off titre levels, in their present form, non-MIF Ab tests are not sensitive enough to label positive women as `C. trachomatis exposed'. Furthermore, the action of then validating the Ab result by giving antibiotics cannot be justified. New recombinant protein ELISAs may overcome the problem, but the impact of antibiotics on Ab titre has still not been established.


    Uterine instrumentation
 Top
 Abstract
 Introduction
 Screening
 Chlamydial antibodies
 Uterine instrumentation
 Prophylactic antibiotics
 Conclusions
 Acknowledgements
 References
 
There is overwhelming evidence from induced abortion that women undergoing uterine instrumentation are at risk of PID (RCOG, 2000Go). The risk is quoted at 5–10%. In the case of subfertile women, the risk of post-diagnostic and therapeutic PID ranges from 0.3 to 4% (Bang, 1950Go; Marshak et al., 1950Go; Measday, 1960Go; Stumpf and March, 1980Go; Pittaway et al., 1983Go; Møller et al., 1984Go; Forsey et al., 1990Go; Bergh and Lunkvist, 1992Go; Jansen et al., 1997Go). However, many of these studies are >20 years old and more up-to-date figures using modern technology are required. There have been reports of transmission by artificial insemination (Nagel et al., 1986Go) and even cryopreserved embryo transfer (Friedler et al., 1996Go).

The risk of post-procedure PID is higher if tubal pathology is present (Pittaway et al., 1983Go; Forsey et al., 1990Go). The studies quoted by Land et al. reporting evidence of persistent C. trachomatis micro-organisms in the upper genital tract (Land et al., 2002Go) all took their specimens from macroscopically damaged tubes (Patton et al., 1994Go; Dieterle et al., 1998Go; Gérard et al., 1998Go). In addition to screening, it would therefore seem sensible to administer prophylactic antibiotics to those women with a past history of PID (Chief Medical Officer, 1998Go), EP (Coste et al., 1994Go) and known or diagnosed tubal pathology, regardless of evidence of LGT infection. The partner should also be screened for STIs. This is really tertiary prevention, aiming to prevent progression of mild disease in the UGT. Theoretically, this leaves surgery as a therapeutic option (RCOG, 1998bGo) and might improve live birth rates (Csemiczky et al., 1996Go). However, there is no conclusive evidence that antibiotic treatment leads to the re-establishment of adequate tubal function in chlamydial infected UGTs.


    Prophylactic antibiotics
 Top
 Abstract
 Introduction
 Screening
 Chlamydial antibodies
 Uterine instrumentation
 Prophylactic antibiotics
 Conclusions
 Acknowledgements
 References
 
Regarding the use of prophylactic antibiotics for all subfertile women undergoing uterine instrumentation, the issues to consider are those of partner notification, cost and antibiotic resistance. The concept is not a new one. Penney et al. concluded that it was more cost-effective than to screen and treat in an induced abortion population (Penney et al., 1998Go). However, their prophylaxis strategy failed to include complications of treatment and the screen and treat policy included bacterial vaginosis and gonorrhoea. Disappointingly, only 24% of the screened group attended GUM, negating the potential cost benefit of partner notification. Follow-up of induced abortion patients is fraught with difficulty. In contrast, subfertile couples are, for the most part, highly motivated and reasons for any non-attendance at GUM could be ascertained at their next review appointment.

Regarding cost, prescribing azithromycin [Phizer, UK National Health Service (NHS) cost £8.95] to all women undergoing diagnostic and therapeutic uterine instrumentation in our unit would cost ~£7000 per annum. This may seem small in the overall expense of assisted reproduction, but must be highlighted as moves are being made to make fertility services NHS funded and available to all. Furthermore, this figure would only cover one diagnostic or therapeutic episode per couple, as their infection status would be unknown.

Finally, the issue of antibiotic resistance has recently been highlighted (Huovinen and Cars, 1998Go; Wise et al., 2001) with national strategies in Europe and North America promoting judicious antibiotic use. Data suggest that up to 75% of antibiotic use is questionable (Wise et al., 2001). To prescribe prophylactic antibiotics when the overall prevalence of chlamydial infection in the LGT is low, post-procedure PID rates in cases of no relevant past history or actual tubal pathology are low, and with unproven benefit to the UGT, does not make for prudent prescribing.


    Conclusions
 Top
 Abstract
 Introduction
 Screening
 Chlamydial antibodies
 Uterine instrumentation
 Prophylactic antibiotics
 Conclusions
 Acknowledgements
 References
 
Both diagnostic and therapeutic uterine instrumentation places subfertile women at risk of chlamydial PID. Women <25 years, those older with risk factors (i.e. concurrent sexual partners, partners working in STI endemic regions, or those with a current or past history of STI, PID, EP or TFI), men with risk factors and gamete donors should have their LGT screened by a sensitive test. More information is required before screening men by age can be recommended.

More specific serology tests are eagerly awaited. In their present form they cannot be recommended as a screening tool.

Those women with a past history of chlamydial morbidity or a diagnosis of tubal pathology should, in addition to screening, be covered with prophylactic antibiotics when undergoing uterine instrumentation. The partner should be screened for STIs.

Units should audit the above recommendations using prevalence, PID and GUM attendance rates as outcome measures.

Non-selective use of prophylactic antibiotics serves to increase the problem of resistance and maintain the bacterial load of C. trachomatis in the community.


    Acknowledgements
 Top
 Abstract
 Introduction
 Screening
 Chlamydial antibodies
 Uterine instrumentation
 Prophylactic antibiotics
 Conclusions
 Acknowledgements
 References
 
I thank Professor Alan Templeton for his comments on the manuscript and Unit Manager Alison McTavish, Sister Sandra Cant and Sister Christina Morrison for providing data on patients from Aberdeen Fertility Centre. S.M. has received pELISA Ab tests (Medac, Germany) for use in research.


    References
 Top
 Abstract
 Introduction
 Screening
 Chlamydial antibodies
 Uterine instrumentation
 Prophylactic antibiotics
 Conclusions
 Acknowledgements
 References
 
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