Elucidating the link between Chlamydia trachomatis and ectopic pregnancy

Keywords::

• chlamydia screening
• Chlamydia trachomatis
• ectopic pregnancy
• Fallopian tube

Ectopic pregnancies (pregnancies implanted outside the uterus, most commonly in the Fallopian tube) have a major clinical and socioeconomic impact worldwide [1,2]. In a WHO analysis of maternal deaths, ectopic pregnancy was recorded as the cause in approximately 1% of deaths in pregnant women in developed countries and in approximately 5% of deaths in developing countries [3]. Ectopic pregnancies are also a considerable source of maternal morbidity, causing acute symptoms including pelvic pain and vaginal bleeding, and in the longer term, infertility [2]. Short- and long-term consequences of ectopic pregnancy on health-related quality of life and psychological issues, such as bereavement, are also likely to be significant, but have not been formally quantified. Chlamydia trachomatis infection is the risk factor most associated with ectopic pregnancy. However, there is a paucity of solid evidence to explain the underlying etiology of this link.

Chlamydia trachomatis screening

Annual health service costs in England due to C. trachomatis infection and its purported complications were estimated at approximately GB£100 million per annum in 2004 [4]. In the previous year, owing to concern regarding the public health impact of genital chlamydial infection, the National Chlamydia Screening Program (NCSP) was introduced in England, and in 2007/2008 the national rollout of the NCSP was completed. This offers screening to anyone under the age of 25 years who is sexually active [101]. The NCSP cost an estimated GB£42 million in 2008–2009 and over GB£150 million has been spent since its launch [102]. In Scotland no such program has been introduced. The Scottish Intercollegiate Guidelines Network (SIGN) state that “in the absence of a complication rate of 10% or more in women with untreated chlamydial infection, there is no evidence that a screening program is cost effective with regard to reducing morbidity” [103]. Furthermore, the National Institute for Health and Clinical Excellence (NICE) have recently recommended that C. trachomatis screening should not be offered to pregnant women, based on the evidence supporting the NICE Routine Antenatal Care Guideline (March 2008) [104].

Treatment of Chlamydia trachomatis infection

The standard antibiotic treatments for C. trachomatis infection are azithromycin (1 g stat) or doxycycline (100 mg twice daily for 1 week); however, C. trachomatis often goes unnoticed owing to lack of symptoms (as it is asymptomatic in over 70% of women), and because of this, many cases remain undiagnosed [103]. In addition, it takes an average of 3 years for untreated C. trachomatis infection to resolve spontaneously [5,6]. Although the prevalence and demographics of infection and the severity of disease associations suggest that a vaccine is desirable, no vaccine is currently available [7].

Genital Chlamydia trachomatis infection & adverse reproductive outcome

Difficulties in determining the effect of female genital chlamydial infection on pregnancy outcome stem from the design of the studies and the lack of a reliable method for not only measuring a history of pelvic infection, but also for confirming previous infection. Indeed, women often present years after the infective episode, by which time the majority of women will have resolved the infection [5,6]. Thus, microorganism-based measures of current infection fail to account for past exposure or the cumulative risk of infection over time. Much of the current assumptions on risk of ectopic pregnancy are based on retrospective case–control studies [8–15]. Many of these studies have been performed on populations where ectopic pregnancy was common (or rare), or use data that do not account for misdiagnoses, and thus there is considerable error in the estimates of risk ratios [11,16]. Both retrospective and prospective case–control studies of ectopic pregnancy are also prone to confounding variables that have not always been accounted for, such as the effect of other sexually transmitted infections (e.g., Neisseria gonorrhoea) and of smoking. Furthermore, in prospective studies, chlamydial infection can be reliably measured by nucleic acid amplification tests. However, in retrospective studies, a history of chlamydial infection is measured by the presence of a specific immune response (serum antibodies) using tests that have led to misclassification owing to a lack of sensitivity and specificity [17,18].

A scientific explanation for the link between Chlamydia trachomatis infection & ectopic pregnancy

Determining the exact mechanism by which C. trachomatis infection leads to ectopic pregnancy is difficult [19]. There are no suitable animal models of ectopic pregnancy (tubal implantation is rare in animals) and care needs to be taken when interpreting animal data for the pathogenesis of human chlamydial infections. Experimental infections are conducted using defined infectious doses under highly controlled conditions for relatively short periods in animals that have limited genetic variability and with different C. trachomatis immune-evasion strategies compared with humans [20–23]. Nevertheless, it is thought that lower genital tract chlamydial infection ascends to the upper reproductive tract resulting in salpingitis. The cellular paradigm of chlamydia pathogenesis [24,25] states that the host response to Chlamydiae is initiated and sustained by epithelial cells that are the primary targets of chlamydial infection. Infected host epithelial cells secrete chemokines and cytokines that induce and augment the cellular inflammatory response and these mediators induce direct damage to the tissues. At the time of reinfection, host cell release of chemokines leads to recruitment of chlamydia-specific immune cells that rapidly amplify the response [25]. The release of proteases, clotting factors and tissue growth factors from infected host cells and infiltrating inflammatory cells leads to tissue damage and eventual scarring [25], which predisposes to tubal implantation. Chlamydia heat shock protein-60 has been investigated as a potential antigen responsible for the induction of delayed-type hypersensitivity-induced disease [24,25] and it has been suggested that an antibody response to chlamydia heat shock protein-60 may have a role in the tubal inflammatory response [14,26]. In addition, a recent study from our group has also proposed that ligation of a tubal cell-surface recognition molecule (Toll-like receptor 2) and activation of the NF-κB cell-signaling pathway by C. trachomatis leads to increased tubal expression of a protein called PROKR2, thereby predisposing the tubal microenvironment to ectopic implantation [27].

Conclusion

It is apparent that there is an urgent need for well-designed case–control studies linking diagnostic observations with experimental data. We believe that this could be achieved using a recently developed highly sensitive and specific C. trachomatis antibody test to the C. trachomatis-specific Pgp3 protein [28,29] and laboratory-based studies to determine the underlying mechanism linking chlamydial infection to ectopic pregnancy in order to provide evidence for causality. This was highlighted in the recently published British Fertility Society Guidelines on the ‘Impact of C. trachomatis in the reproductive setting’ [30]. Quantifying population-attributable risk (the reduction in incidence that would be observed if the population were entirely unexposed, compared with its current [actual] exposure pattern) is fundamentally important because women diagnosed with apparently uncomplicated chlamydial infection need valid, evidence-based information on their subsequent risk of ectopic pregnancy. This information also significantly impacts on policy makers’ decisions regarding future investments and research into prophylactic and therapeutic vaccines against C. trachomatis.

Financial & competing interests disclosure

Andrew W Horne is supported by an MRC Clinician Scientist Fellowship. Gary Entrican is funded by the Scottish Government Rural and Environmental Research and Analysis Directorate (RERAD). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.