**12. Infertility: a major complication of** *C. trachomatis* **infection**

Potential factors affecting the association between chlamydia infection and infertility in women can be summarized in four categories; [1].


As stated in a review examining the sexually transmitted disease and infertility association, tubal factor infertility (TFI) is one of the most common causes of infertility. While it is responsible for up to 33% of female infertility cases worldwide, this rate is disproportionately high in developing countries. In sub-Saharan Africa, for example, it is more than 85%. The vast majority of TFI cases are caused by salpingitis and subsequent pelvic-peritoneal adhesions due to previous or persistent infections. Bacteria climb up the cervix along mucosal surfaces to reach the endometrium and eventually the fallopian tubes. This pathway manifests itself clinically as PID and it has a significant association with subsequent TFI. About 15% of women who have PID end up with TFI, and if the number of PID attacks increases, the likelihood of infertility also increases. However, most women with TFI do not have a clinically diagnosed PID history, but instead have minimally symptomatic or totally asymptomatic salpingitis as a result of an upper genital tract infection. Studying the effects of such infections, especially those without clinical PID, is necessary to explain TFI because of the mostly asymptomatic course of *C. trachomatis*. To date, evidence has shown that ascending *C. trachomatis* infection causes irreversible damage to the fallopian tubes, leading to obstructions and thus, infertility. Heat shock protein (HSP60) synthesized by *C. trachomatis* produces a proinflammatory immune response in the human fallopian tube epithelium, causing scarring and obstruction in the tube [104, 105].

In a series of sero-epidemiological studies examining antibodies to *C. trachomatis* and chlamydial hsp60 in laparoscopic or HSG-confirmed fallopian tube injury and ectopic pregnancies, previous *C. trachomatis* infection has been shown to significantly increase tubal infertility in women, regardless of whether it presents clinical symptoms or not. Patients with PID are also more likely to develop infertility later

in the presence of a history of *C. trachomatis* than those without a history of chlamydia [106, 107].

A cohort study, involving 1250 women with demonstrated tubal patency undergoing fertility treatment, examined *C. trachomatis* seropositivity using IgG1 and IgG3 antibody subtypes [108]. The presence of IgG3 from these two antibody subtypes was shown to be a strong indicator of both failure to conceive and ectopic pregnancy outcomes. This is because IgG3 is related to the inflammatory response in the early phase of the infection and its detection may indicate that either a recent or persistent infection has caused tube damage, although it has not yet caused tubal obstruction [108]. Another study of subfertile women without visible tubal pathology found 33% lower rates of spontaneous pregnancies in the presence of chlamydial antibodies [107, 108]. Coppus et al. suggest that this decline in pregnancy rates may not only be related to the known chronic inflammatory response but also to the fact that persistent CT infection impairs implantation and embryo development due to the autoimmune response to human heat shock proteins [108, 109]. Therefore, chlamydial antibody tests are likely to continue to be an important predictor both in the evaluation of tubal patency and in the evaluation of ectopic pregnancy, intrauterine insemination failure, and embryo and pregnancy loss independent of tubal damage.

In another systematic review investigating the effect of CT infection on female infertility, a positive correlation between infection and infertility was found in 76.47% of the included studies [110]. The study by Menon et al., which included 239 women, showed that up to half of the subfertile women may have CT infection as a concomitant factor [111]. den Heijer et al. also found that CT-positive women were 70% more likely to experience infertility [112]. Davies [113], Ramadhani [114], and Kayiira [115] also showed results that reinforce this relationship in different countries and populations, noting that routine chlamydia screening, along with interventions to prevent initial and recurrent infections, is extremely important to protect women's long-term reproductive health.

Considering PID, which causes significant adhesions and severe tubal damage, it is easy to conclude that these anatomical causes are detrimental to fertility. However, there are some cases where there is no apparent damage, suggesting that some molecular mechanisms are also involved. Since CT is an intracellular pathogen that disrupts endothelial and tubal muscle structure, it is highly likely to lead to impaired tubal motility and endothelial cilia function. This explains the changes observed in the form of constrictions in the intrauterine and tubal structure after the application of a saline solution to the female reproductive tract during the laparoscopy procedure. Even if CT remains in the female reproductive organs for a short time, it facilitates the settlement of other microorganisms in the area, leads to changes in the structure of the microbiota, and affects gametes and their conjunction by antigenic stimulation [116, 117]. These immunological changes also explain the state of mild endometriosis in women who have had a preliminary CT infection; once an immunological imbalance has occurred, lymphocyte activity becomes insufficient and, which leads to the retention of viable endometrial cells in the pelvic environment [118]. Thus, as well as the endometriosis, CT infection and the mechanical and biochemical damage it creates, induce a hostile environment for gametes in the female reproductive pathway. A significant point here to emphasize is that as age progresses, *C. trachomatis* is eliminated from the host and can no longer be detected by PCR. Therefore, a more accurate approach would be using long-standing IgG-specific antibodies to detect past infections that may be responsible for infertility [1].

*Chlamydia – Secret Enemy from Past to Present*
