Overview

Infertility, which is defined as the inability to conceive after ≥12 months of regular unprotected sexual intercourse, is a common public health concern worldwide. Globally, 9% of reproductive-aged women, including nearly 1.5 million women in the United States, are infertile. The burden of infertility is inordinately higher among women in developing countries; in some regions of south and central Asia, sub-Saharan and northern Africa, the Middle East, and eastern Europe, infertility rates can reach up to 30% in reproductive-aged women. The inability to conceive not only creates a considerable cost burden for patients and the health care system but is also a major psychological stressor for millions of couples. In many areas of the world, especially in low- and middle-income countries where having biological children is highly valued and expected of couples, involuntary infertility can lead to stigmatization, economic deprivation, social isolation and loss of status, public shame and humiliation, and in some cases, violence. Female infertility may be attributed to a number of factors, typically divided into endocrine, vaginal, cervical, uterine, tubal, and pelvic-peritoneal factors, and although estimates vary, approximately 15-30% of cases still remain unexplained. Further insight into the causes of infertility is necessary to help alleviate this multifactorial burden on society.

Tubal factor infertility (TFI) ranks among the most common causes of infertility, accounting for 30% of female infertility in the United States, and is even more prevalent in certain communities. Paralleling the aforementioned global infertility disparity, TFI is disproportionately common in women in developing countries; for example, it has been shown to account for >85% of female infertility cases in regions of sub-Saharan Africa, compared to 33% of cases worldwide. Most cases of TFI are due to salpingitis, an inflammation of the epithelial surfaces of the fallopian tubes, and subsequent pelvic-peritoneal adhesions, both of which are most commonly caused by previous or persistent infections. Bacteria ascend along mucosal surfaces from the cervix to the endometrium and ultimately to the fallopian tubes. This causal pathway presents itself clinically as acute pelvic inflammatory disease (PID), which in turn is strongly associated with subsequent TFI. In fact, approximately 15% of women with PID develop TFI, and the number of episodes of PID a woman experiences is directly proportional to her risk of infertility. However, the majority of women with TFI do not have a history of clinically diagnosed acute PID, but rather develop asymptomatic or minimally symptomatic salpingitis as a result of upper genital tract infection. Examining the effect of those infections, particularly those that occur in the absence of clinically evident PID, is critical to understanding TFI.

Several sexually transmitted diseases (STDs), including Chlamydia trachomatis and Neisseria gonorrhoeae , have been widely studied to understand their role in salpingitis and infertility. Additionally, several other pathogens such as Mycoplasma genitalium , Trichomonas vaginalis , and other microorganisms within the vaginal microbiome, may also play roles in tubal damage and other potential causes of infertility. Still, data suggest that not all infections yield the same long-term sequelae. The roles of different STD pathogens, co-infections, and interactions with host characteristics, including their individual vaginal microbiome, may all affect a woman’s subsequent ability to conceive. While screening and treatment efforts for C trachomatis and N gonorrhoeae have been developed to reduce the incidence of PID and subsequent TFI, additional data are needed to determine the role of other potential pathogens and whether early detection can prevent tubal damage. In this article, we discuss the pathogens C trachomatis , N gonorrhoeae , Mycoplasma genitalium , T vaginalis , and other potential organisms that may affect female fertility, and we address the clinical importance of screening and preventing the spread of those infections.

Methodology

We conducted a comprehensive literature search to identify articles by using the electronic databases MEDLINE, Embase, Web of Science, and CINAHL, in addition to scrutinizing references of identified articles. Within each database, we combined the term “female infertility” with 4 different infection terms: “ Chlamydia trachomatis ,” “ Neisseria gonorrhoeae ,” “ Mycoplasma genitalium ,” and “ Trichomonas vaginalis .” Within the MEDLINE database, we refined the search by excluding the Medical Subject Headings unrelated to female infertility and at least 1 of the 4 organisms. Within the Embase search, we used Emtree to identify terms, and used both “female infertility” and “uterine tube occlusion” as focused search terms to combine with each infection. We filtered results to only include articles published in English between 1975 and April 2016. Additional relevant articles were identified from bibliographies and by the recommendation of medical experts. The inclusion of the articles used in the analysis was based on quality of the study and relevance to this review: studies were excluded if they were conducted with few participants, had no comparison group, or constituted case reports. Studies that did not report sufficient data to determine the association with female infertility or reproductive morbidities were excluded for lack of relevance to the topic of review.

Methodology

We conducted a comprehensive literature search to identify articles by using the electronic databases MEDLINE, Embase, Web of Science, and CINAHL, in addition to scrutinizing references of identified articles. Within each database, we combined the term “female infertility” with 4 different infection terms: “ Chlamydia trachomatis ,” “ Neisseria gonorrhoeae ,” “ Mycoplasma genitalium ,” and “ Trichomonas vaginalis .” Within the MEDLINE database, we refined the search by excluding the Medical Subject Headings unrelated to female infertility and at least 1 of the 4 organisms. Within the Embase search, we used Emtree to identify terms, and used both “female infertility” and “uterine tube occlusion” as focused search terms to combine with each infection. We filtered results to only include articles published in English between 1975 and April 2016. Additional relevant articles were identified from bibliographies and by the recommendation of medical experts. The inclusion of the articles used in the analysis was based on quality of the study and relevance to this review: studies were excluded if they were conducted with few participants, had no comparison group, or constituted case reports. Studies that did not report sufficient data to determine the association with female infertility or reproductive morbidities were excluded for lack of relevance to the topic of review.

C trachomatis and N gonorrhoeae

C trachomatis and N gonorrhoeae have been extensively shown to be associated with infertility, particularly by causing tubal inflammation. In fact, early speculation regarding the effect of N gonorrhoeae on female fertility dates back to the 1870s, when the German-born gynecologist Emil Noeggerath published his revolutionary claims about gonorrhea as a clinical condition in his book Latent Gonorrhoea Especially with Regard to its Influence on Fertility in Women . Although he may have widely overestimated its repercussions (postulating that gonorrhea causes 90% of female infertility), his theories eventually sparked the initiation of further investigations. When the bacterium N gonorrhoeae was finally isolated, Noeggerath’s controversial claims regarding the persistence of this “venereal poison” in the reproductive organs and its pathologic consequences were reexamined. Studies conducted more than a century later have since demonstrated the impact of C trachomatis and N gonorrhoeae on subsequent infertility.

C trachomatis , the most common reportable disease in the United States, affects nearly 1.5 million people in the US annually. Unfortunately, however, because C trachomatis infections are asymptomatic in most women, infections are often unnoticed, untreated, and underreported. For almost 40 years, evidence has shown that untreated ascending C trachomatis infection can lead to irrevocable damage in the fallopian tubes including proximal and distal tubal occlusions leading to infertility. The increased amount of heat shock protein synthesized by C trachomatis induces a proinflammatory immune response in the human fallopian tube epithelia, resulting in scarring and tubal occlusion. A number of seroepidemiological studies have examined the prevalence of antibodies to C trachomatis and chlamydial heat shock protein in women with laparoscopically or hysterosalpingographically confirmed fallopian tube damage and ectopic pregnancies. The results of these studies indicate that history of C trachomatis infection is associated with a significantly increased risk of tubal infertility in women, regardless of the infection invoking clinical symptoms. Extensive research has also shown that C trachomatis infection can cause PID, which often precedes infertility. Today, C trachomatis accounts for approximately 50% of cases of acute PID in developed countries. Among PID patients, those with prior C trachomatis infection have been shown to be more likely to experience subsequent infertility than those without a history of C trachomatis infection.

While C trachomatis seropositivity has long been shown to influence fallopian tube patency, the use of a newer, more sensitive and specific anti-chlamydial assay by Geisler and coworkers has only recently been shown to hold promise as a measure of tubal function. In a cohort study of 1250 infertile women with documented tubal patency undergoing fertility treatment, C trachomatis seropositivity using the antibody subclasses IgG1 and IgG3 was tested. Results showed that of these 2 antibody subclasses tested, seropositivity to C trachomatis based on IgG3 detection was a strong predictor of both failure to conceive and ectopic pregnancy outcomes. Because IgG3 has been shown to be involved in early inflammatory response to infection, the detection of IgG3 in these women may reflect a recently cleared or persistent C trachomatis infection, contributing to fallopian tube damage while perhaps not yet leading to blockage of the fallopian tubes.

In another study of subfertile women with no visible tubal pathology, positive chlamydial antibody testing was associated with a 33% lower spontaneous pregnancy rate than those without chlamydial antibodies. Coppus and colleagues suggest that these low pregnancy rates may not only be caused by the known mechanism of chronic inflammatory response causing fallopian tube damage; persistent C trachomatis infections have also been shown to elicit an autoimmune response to human heat shock proteins, which may elevate the risk for impaired embryo development and implantation. Chlamydial antibody testing may therefore continue to become a valuable predictor of not only tubal patency, but also of ectopic pregnancy, intrauterine insemination failure, and embryo and pregnancy wastage, independent of tubal damage.

Although less prevalent than C trachomatis in the United States, gonorrhea is still the second most common reportable disease in the United States. N gonorrhoeae infections are also often asymptomatic among women, but as Noeggerath suspected in the 1870s, the bacterium is capable of ascending to the upper genital tract and causing severe reproductive morbidities. In particular, N gonorrhoeae attacks the epithelial cells of the fallopian tube, both initially by attaching to the nonciliated mucosal cells and by sloughing off ciliated mucosal cells. The resulting damage hinders the fallopian tubes’ ability to transport the ovum for fertilization within the tubes and implantation in the uterus, thus ultimately elevating the risk of infertility and ectopic pregnancy.

Several seroepidemiological studies have demonstrated the pathogen’s effects on fallopian tube damage and subsequent infertility. Throughout those studies, women with laparoscopically and hysterosalpingographically confirmed TFI have consistently demonstrated a significantly higher prevalence of serologically confirmed N gonorrhoeae infection than women with normal fallopian tubes. Like chlamydial PID, gonococcal PID has been shown to be an important cause of fallopian tube damage, greatly increasing a woman’s risk of TFI. Between 10-19% of women with cervical N gonorrhoeae infections have clinical signs of acute PID and in regions of the United States that had high endemic rates of gonorrhea during the 1970s and 1980s, gonorrhea was found in >40-50% of patients with PID. In recent studies, the bacteria were identified in approximately 20% of women diagnosed with acute PID, suggesting that N gonorrhoeae is not as frequent a cause of acute PID as it was in the past. Still, the impact of both chlamydial and gonococcal infections on the fallopian tubes currently make these pathogens the most important known preventable causes of infertility, and improving screening programs for these prevalent and commonly asymptomatic pathogens may therefore make a critical impact in the prevention of tubal pathology and infertility.

Mycoplasma genitalium

While N gonorrhoeae and C trachomatis are known to be pathogens in salpingitis and tubal infertility, in many cases, neither organism is identified. Mycoplasma genitalium , a member of the Mollicutes class with the smallest known genome of any free-living organism, was discovered in 1981 when it was first isolated from men with nongonococcal urethritis. After the development of nucleic acid amplification assays in the early 1990s facilitating its detection, Mycoplasma genitalium has since been shown to be a common sexually transmitted organism. In 2007, the United States prevalence of Mycoplasma genitalium in young adults was 1%, placing it between the prevalences of N gonorrhoeae (0.4%) and C trachomatis (2.3%) infections, and it has been detected in 15-20% of high-risk, sexually active women in the United States.

Since its discovery, numerous studies demonstrate that Mycoplasma genitalium is strongly associated with male urethritis. In an analysis of 34 studies published from 1993 through 2011 studying men with nongonococcal urethritis, 13% of 7123 men tested positive for Mycoplasma genitalium , and several studies have demonstrated that Mycoplasma genitalium can cause persistent or recurrent urethritis. After the initial findings of Mycoplasma genitalium demonstrating its effects in males, investigators soon began to look at its effects on the female reproductive tract. While there are fewer studies in women, Mycoplasma genitalium has been investigated to evaluate its association with several morbidities in women, including cervicitis, urethritis, PID, ectopic pregnancy, and TFI.

Four serological studies have investigated the relationship between past Mycoplasma genitalium infection in women and tubal infertility. Two of those studies demonstrated a significant correlation between presence of antibodies against Mycoplasma genitalium and laparoscopically confirmed TFI, independent of C trachomatis seropositivity. According to Svenstrup and colleagues, among women with TFI, 23% had antibodies to C trachomatis and 17% to Mycoplasma genitalium ; whereas 15% and 4% of infertile women with normal fallopian tubes had antibodies to each, respectively. Although not quite as high as the prevalence of antibodies to C trachomatis , prior Mycoplasma genitalium infection is thought to be an independent risk factor for TFI. In a similar study by Clausen and colleagues, serological analyses of women with TFI reinforced the finding that Mycoplasma genitalium is independently associated with tubal inflammation leading to infertility. A more recent study by Idahl and colleagues examined the association between Mycoplasma genitalium antibodies and infertility in 239 women diagnosed with infertility of various causes, including laparoscopically and hysterosalpingographically confirmed TFI, compared to 244 fertile controls. The results indicate that Mycoplasma genitalium serum antibodies are more common among women with all causes of infertility (5.4%) than in fertile controls (1.6%). Among the infertile women in that sample diagnosed specifically with TFI, 9.1% were seropositive for Mycoplasma genitalium compared with 4.6% of the fertile controls, although the association between TFI and Mycoplasma genitalium was not statistically significant after adjusting for C trachomatis seropositivity.

Supporting evidence has shown an association between infection with Mycoplasma genitalium at the time of infertility evaluation and laparoscopically confirmed tubal infertility, rather than serologically investigating infection history. In a study comparing infertile and fertile women by polymerase chain reaction testing of cervical samples, Mycoplasma genitalium was detected more frequently in infertile women (19.6%) compared to fertile women (4.4%). However, in the study by Svenstrup and colleagues that examined the relationship between Mycoplasma genitalium seropositivity and TFI, none of the women had a cervical swab specimen indicating current Mycoplasma genitalium infection, and only 1 was positive for C trachomatis . There does not appear to be a role for screening for Mycoplasma genitalium infection at the time of infertility evaluation.

Several other studies, although not directly addressing fertility rates, have investigated the effects that Mycoplasma genitalium may have on tubal inflammation, damage, and occlusion. The mechanism by which Mycoplasma genitalium may cause the tubal scarring that leads to infertility has been studied through several in vitro models. McGowin and colleagues demonstrated that the organism can attach to reproductive tract epithelial cells and elicits cellular immune responses that result in inflammation. In another in vitro organ culture model, Mycoplasma genitalium adhered to human fallopian tube epithelium after experimental inoculation, causing swelling of the cilia and detachment of cilia from the epithelium. Svenstrup and colleagues also investigated whether mobile sperm could serve as a vector for transmitting Mycoplasma genitalium to the upper genital tract of women, demonstrating that the organism does adhere to human spermatozoa and could be transported by sperm to the uterus and fallopian tubes to colonize and destroy the ciliated epithelia.

When compared with the more severe damage that C trachomatis and N gonorrhoeae infection create in the fallopian tube, the damage caused by Mycoplasma genitalium tends to be moderate. However, when left untreated, damage may accumulate and yield serious long-term sequelae on fallopian tube function. Additionally, simultaneous infection with Mycoplasma genitalium and other sexually transmitted bacteria may cause even more severe tubal pathology. One study conducted in Saudi Arabia used polymerase chain reaction performed on tubal samples from women with ectopic pregnancy and compared them to samples from fertile women undergoing partial salpingectomy for sterilization or at the time of hysterectomy. They found a 6-fold higher rate of infection with C trachomatis and Mycoplasma genitalium in women with ectopic pregnancy compared to the controls. There was also a higher rate of other infections, including Ureaplasma urealyticum/U parvum , Gardnerella vaginalis , N gonorrhoeae , and T vaginalis , but these associations were not statistically significant. The investigators noted that co-infection with at least 2 organisms led to a 5-fold increase in the risk of ectopic pregnancy, providing further evidence that multiple infections lead to greater risk of tubal damage.

Animal studies have also been performed to investigate the potential role of Mycoplasma genitalium on tubal scarring and inflammation. Female grivet monkeys and marmosets inoculated with Mycoplasma genitalium developed severe endosalpingitis, along with luminal exudates and adhesions between mucosal folds in the fallopian tubes, similar to changes induced by chlamydial infection. Additionally, female Swiss Webster mice developed upper reproductive tract infection as early as 3 days after being inoculated with Mycoplasma genitalium , showing experimentally that Mycoplasma genitalium is capable not only of ascending through the upper genital tract, but persistently colonizing reproductive tract tissues that could lead to long-term tubal inflammation and occlusion.

Both serological and epidemiological studies have explored whether Mycoplasma genitalium is associated with clinical PID and salpingitis. In an analysis of 193 patients with clinically diagnosed PID and 246 healthy pregnant controls, 17% were Mycoplasma genitalium seropositive, although the association was not statistically significant after adjusting for age and presence of antibodies to C trachomatis . An older study by Møller and colleagues also showed an association; in a group of patients with acute PID without C trachomatis antibodies, almost 40% had a ≥4-fold change in the titre of Mycoplasma genitalium antibodies. Still, results are conflicting, as Lind and Kristensen assessed the significance of antibodies to Mycoplasma genitalium in patients with acute salpingitis and failed to confirm any association.

Recent studies have examined the relationship between current cervical or endometrial Mycoplasma genitalium infection and upper genital tract infection. In an analysis of 586 women who participated in the PID Evaluation and Clinical Health (PEACH) Study, a randomized multicenter clinical trial in the United States, 31% of women who tested positive for Mycoplasma genitalium in the endometrium reported recurrent PID, 42% had chronic pelvic pain, and 22% were infertile. However, a large prospective trial of 2378 young women in London failed to show an association between Mycoplasma genitalium and acute PID. Among women with Mycoplasma genitalium at baseline, 3.9% developed PID after 12 months compared with 1.7% of women without baseline infection; however, this difference was not statistically significant. Oakeshott and colleagues concluded that because the population attributable risk of PID due to Mycoplasma genitalium was only 4%, Mycoplasma genitalium infection is not an important risk factor for pelvic inflammation. This particular European population may not be generalizable to populations with higher prevalence rates of Mycoplasma genitalium infection, where, if confirmed, this 2-fold increased risk of PID due to Mycoplasma genitalium infection could constitute a major public health problem. Still, while evidence shows that Mycoplasma genitalium is often present in or associated with PID cases, more data are necessary to determine the role of this microorganism in the pathogenesis of PID and subsequent TFI.

Mycoplasma genitalium may not only affect tubal patency; several studies have investigated its effects on pregnancy outcomes such as ectopic pregnancy, recurrent pregnancy loss, and preterm birth. However, unlike for C trachomatis, there is limited evidence that the pathogen is associated with these adverse pregnancy outcomes. A serological case-control study by Jurstrand and coworkers showed no significant correlation between Mycoplasma genitalium antibodies and ectopic pregnancy. According to a recent meta-analysis, Mycoplasma genitalium infection has been shown to be significantly associated with increased risk of both spontaneous abortion and preterm birth in some studies, although evidence is inconsistent. While data are emerging on the impact of Mycoplasma genitalium on the reproductive health of women, further research is necessary to solidify any conclusions regarding Mycoplasma genitalium and adverse pregnancy outcomes.

T vaginalis

Like that of Mycoplasma genitalium, the role of T vaginalis infection in reproductive tract pathology has been understudied, but investigators have shown that it may be associated with female infertility. T vaginalis is the most common nonviral sexually transmitted pathogen in the United States. According to the World Health Organization, the protozoan T vaginalis accounts for more than half of all curable STDs worldwide. An estimated 7.4 million new infections occur annually in the United States and approximately 3.1% of reproductive-age women are infected. Given the high prevalence of T vaginalis in the population, any potential impact of the organism on the upper reproductive tract could constitute a serious public health concern.

Data associating T vaginalis with TFI and pelvic inflammation in the literature are relatively weak. Few retrospective studies have found that women with self-reported infertility were 2-3 times more likely to have a current T vaginalis infection, and women with a self-reported history of a T vaginalis infection have approximately a 2-fold risk of tubal infertility. Additionally, a trend exists between increasing number of episodes of T vaginalis infection and increasing risk of infertility. However, many of the epidemiologic studies analyzing the association between trichomoniasis and infertility failed to control for important confounding variables such as presence or history of other reproductive tract infections.

Upon investigation of endometrial inflammatory changes elicited by infections, immunohistochemical evidence shows that T vaginalis may contribute to upper genital tract inflammation. Pathologically, T vaginalis has been shown to be capable of ascending the upper genital tract and has been associated with up to 30% of acute salpingitis cases, although within the same study, trichomonads were not demonstrated in tubal cultures from cases of salpingitis. T vaginalis has been shown to be associated clinically with endometritis, salpingitis, and atypical PID, demonstrating that it may be an important pathogen in upper genital tract damage. Other potential mechanisms linking T vaginalis infection to infertility include disruption of sperm motility, phagocytosis of sperm, and transportation of other infectious agents to the upper genital tract by motile trichomonads, although these mechanisms do not directly affect the female reproductive tract.

Co-infection of T vaginalis and C trachomatis may increase the risk of upper genital tract infection more than the risk of C trachomatis infection alone, and women with both T vaginalis and HIV-1 have been shown to have a significantly higher risk of PID than women without T vaginalis . Because trichomonads are capable of phagocytizing bacteria, yeast, vaginal epithelial cells, mycoplasmas, and herpesviruses in vitro, investigators speculate that T vaginalis infection may be capable of spreading other pathogens throughout the upper genital tract, thereby indirectly eliciting tubal damage and infertility. Moreover, despite some of these weak associations, proposed mechanisms, and possible co-infection risks, there is currently no strong conclusive evidence regarding the causative effects of T vaginalis on PID or infertility.